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  • 51.
    Kempen, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Correspondence: A Trial of Blood-Pressure Reduction in Black Barbershops2018Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, nr 2, s. 199-199Artikel i tidskrift (Övrigt vetenskapligt)
  • 52.
    Kharazmi, Mohammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Schilcher, Jorg
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala Univ, Dept Med Sci, Uppsala, Sweden.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Hallberg, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture2019Ingår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, nr 1, s. 51-67Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n=51) with population-based controls (n=4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n=324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p<5x10(-8) was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p<5.7x10(-6)). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

  • 53.
    Khezri, Banafsheh Seyyed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Cederblad, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Helmersson-Karlqvist, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Karlsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Seasonal variability of NT-proBNP in Swedish primary care patients2017Ingår i: Chronobiology International, ISSN 0742-0528, E-ISSN 1525-6073, Vol. 34, nr 10, s. 1473-1477Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to determine if there is a seasonal variation in the widely used heart failure marker NT-proBNP. The study included all primary care requests for NT-proBNP in the county of Uppsala, Sweden, between January 2007 and December 2015. For seasonal variation, the NT-proBNP results for individual months were compared. The NT-proBNP values were highest in July to September, but there was also a minor peak in December-January. In conclusion, a seasonal periodicity for NT-proBNP was demonstrated in primary care patients. The data could be useful for practitioners for evaluation of NT-proBNP results and monitoring of patients with heart failure.

  • 54.
    Khoschnau, Shwan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Jacobson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rahme, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Bengtsson, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ribom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Grundberg, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Mallmin, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Type I collagen alpha1 Sp1 polymorphism and the risk of cruciate ligament ruptures or shoulder dislocations2008Ingår i: American Journal of Sports Medicine, ISSN 0363-5465, E-ISSN 1552-3365, Vol. 36, nr 12, s. 2432-2436Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Cruciate ligament ruptures and shoulder dislocations are often caused by trauma, but predisposing intrinsic factors might also influence the risk. These injuries are more common in those with a previously injured sibling, an observation that might indicate a genetic predisposition. It is well known that polymorphisms in the collagen I gene are associated not only with osteoporosis and osteoporotic fracture risk, but also with osteoarthritis.

    HYPOTHESIS: Because collagen I is abundant in ligaments and tendons, the authors hypothesized that collagen I alpha1 Sp1 polymorphism also was related to the occurrence of cruciate ligament ruptures and shoulder dislocations.

    STUDY DESIGN: Case-control study; Level of evidence, 3.

    METHODS: A total of 358 patients and 325 randomly selected population-based female controls were included in the study. Of the cases, 233 had a cruciate ligament rupture and 126 had had a shoulder dislocation. Age-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) estimated by unconditional logistic regression were used as measures of association.

    RESULTS: Compared with the homozygous SS category, the heterozygous participants displayed a similar risk (OR, 1.06; 95% CI, 0.76-1.49), whereas the ss genotype was underrepresented in the injured population compared with the controls (OR, 0.15; 95% CI, 0.03-0.68). This latter estimate was similar for both cruciate ligament ruptures and shoulder dislocations, and was furthermore not modified by general joint laxity.

    CONCLUSION: The authors found a substantially decreased risk of these injuries associated with collagen type I alpha1 Sp1 polymorphism. The study might encourage other investigators to consider further research in the area of genes and soft tissue injuries.

  • 55.
    Kindmark, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Johansson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Effects of retinoids on bone metabolism and calcium homeostasis2002Ingår i: Modern trends in skin pharmacology, Athens: Parissianos Medical Publications , 2002Kapitel i bok, del av antologi (Övrig (populärvetenskap, debatt, mm))
  • 56.
    Kindmark, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rollman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Mallmin, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Petrén-Mallmin, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Ljunghall, Sverker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Oral Isotretinoin Therapy in Severe Acne Induces Transient Suppression of Biochemical Markers of Bone Turnover and Calcium Homeostasis1998Ingår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 78, nr 4, s. 266-269Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although dietary vitamin A is required for normal growth and development, long-term or high-dose administration of vitamin A derivatives (retinoids) may produce a variety of skeletal side-effects in man. In this study we investigated the early effects of oral isotretinoin therapy on bone turnover and calcium homeostasis in eleven consecutive patients with nodulocystic acne. The effects on bone metabolism were correlated to radiological and bone mineral density measurements following drug therapy for six months. Markers of bone turnover, i.e. serum osteocalcin, the carboxyterminal propeptide of type I collagen, bone specific alkaline phosphatase, the carboxyterminal telopeptide of type I collagen, and urine levels of calcium and hydroxyproline decreased significantly within five days of treatment (p < 0.05). There was also a statistically significant decrease in serum calcium, with a minimum on day five, and a marked increase in serum parathyroid hormone (p < 0.05). With continued treatment, however, the abnormal levels of these markers returned to baseline values within 14 days. No significant roentgenological changes or effects on bone mineral density were found in response to the drug. The observed inhibitory effects of isotretinoin on bone turnover, despite elevated parathyroid hormone levels, indicates that the drug exerts a direct effect on bone tissue.

  • 57.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, Julia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kahan, Thomas
    Malmqvist, Karin
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial2004Ingår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 17, nr 1, s. 8-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment. METHODS: Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta(1)-adrenergic receptor blocker atenolol (n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment. RESULTS: The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment (P =.001 when -6 AA+AG was compared with GG and P =.008 for presence of the 235T variant compared with 235 MM). CONCLUSIONS: We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

  • 58.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lithell, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Farmakogenetik: genvägen till skräddarsydd antihypertensiv terapi2003Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 100, nr 8, s. 600-603Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The variations in response to pharmacotherapy can in part be explained by genetic factors. Pharmacogenetics, a term coined in the 1950's, describes these relationships. Great technological advances in molecular biology and computational sciences, crowned by the sequencing of the human genome, have brought forth the current interest in pharmacogenetics. Continued technological developments may lead to the understanding of the molecular mechanisms behind complex diseases like cardiovascular disease, and holds the promise of individualized pharmacotherapy. The article gives a background to the field, with emphasis on antihypertensive therapy, and prospects for the future.

  • 59.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Using genotyping to predict responses to anti-hypertensive treatment2005Ingår i: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 26, nr 9, s. 443-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypertension is prevalent and affects approximately 1 in every 4 adults in the Western world. Although many drugs are effective in treating hypertension, an individual's response to treatment is unpredictable. Pharmacogenetics holds the promise of becoming a tool to predict this response but obstacles and shortcomings need to be overcome. Significant developments in molecular biology, including the sequencing of the genome, the cataloguing of genetic variation and the development of microarray techniques, enable analysis of many genotypes simultaneously. However, despite these technical advances there are, as yet, no clinical applications of pharmacogenetics in anti-hypertensive treatment. It is therefore necessary to design prospective pharmacogenetic studies that aim to identify a genetic profile that will predict the response to anti-hypertensive treatment.

  • 60.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, Julia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, K. Peter
    Nyström, Fredrik
    Hägg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients2001Ingår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 19, nr 10, s. 1783-1787Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.

  • 61.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, Julia
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, Peter
    Nyström, Fredrik
    Hägg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial2002Ingår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 15, nr 5, s. 389-93Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. METHODS: Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. RESULTS: After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 +/- 19 SD mm Hg, n = 17) than both the TC (-14 +/- 18 mm Hg, n= 18) and CC (0 +/- 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. CONCLUSIONS: The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan.

  • 62.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, Julia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, Peter
    Nyström, Fredrik
    Hägg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial2002Ingår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 20, nr 4, s. 657-663Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Our aim was to determine if gene polymorphisms in the renin-angiotensin-aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment. METHODS AND RESULTS: Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (-23 +/- 31SD g/m2 for TM and +0.5 +/- 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (-0.1 +/- 19 g/m2 for AA and -18 +/- 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol. DISCUSSION: The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.

  • 63.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sarabi, Mahziar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Millgård, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ljunghall, Sverker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects2001Ingår i: Clinical Physiology, ISSN 0144-5979, E-ISSN 1365-2281, Vol. 21, nr 3, s. 343-349Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Our aim was to test the hypothesis that genes encoding components in the renin-angiotensin system influence endothelial vasodilatory function.

    METHODS: In 59 apparently healthy, normotensive individuals, endothelium-dependent vasodilation (EDV) and endothelial-independent vasodilation (EIDV) was evaluated by infusing metacholine and sodium nitroprusside into the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography. The ACE insertion (I)/deletion (D) polymorphism, the T174M and M235T angiotensinogen restriction fragments length polymorphisms, the angiotensin II receptor type 1 (AT1R) A1166C, and the aldosterone synthase gene (CYP11B2) C-344T polymorphisms were analysed.

    RESULTS: When analysing the ACE, the two angiotensinogen and the aldosterone synthase CYP11B2 genotypes independently, no significant association with endothelial vasodilatory function was found. However, a significant reduction in endothelium-dependent vasodilation was observed in the subjects (n=9) with the ACE D allele and the angiotensinogen T174M genotype (P<0.05). Subjects with the AT1R genotype AC showed a reduction in both EDV (P=0.05) and EIDV (P=0.04) when compared with those with the AA genotype.

    CONCLUSIONS: The subjects with the ACE D allele in combination with the angiotensinogen T174M genotype are associated with a reduced EDV. This together with the observation that the AC AT1R genotype is associated with a reduction in both EDV and EIDV, supports the hypothesis that endothelial vasodilatory function is influenced by genes in the renin-angiotensinogen system.

  • 64.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Reference intervals for parathyroid hormone for 70-year-old males and females: exclusion of individuals from the reference interval based on sex, calcium, diabetes, cardiovascular diseases or reduced kidney function has limited effects on the interval2015Ingår i: Annals of Clinical Biochemistry, ISSN 0004-5632, E-ISSN 1758-1001, Vol. 52, nr 1, s. 39-43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: A problem when producing reference intervals for elderly individuals is that they often suffer from a number of diseases and they are most often on medication. If all such persons are excluded, there is a risk that the residual subgroup may not be representative of the population, we therefore wanted to compare the effects different exclusion criteria has on the reference intervals.

    METHODS: We measured parathyroid hormone (PTH), calcium, albumin and cystatin C in a cohort of 70-year-old males and females (n = 1003). Reference intervals for PTH for males and females were calculated for the entire population and after exclusion of persons with calcium >2.60 mmol/L, calcium >2.51 mmol/L, diabetes, reduced glomerular filtration rate (GFR), and cardiovascular diseases.

    RESULTS: The calculated PTH reference interval 16 (CI 14-17) to 94 (CI 87-101) ng/L. Exclusion of study subjects resulted in smaller reference sample groups, but the reference limits remained within the 90% confidence intervals of the original reference limits. The selections thus had a very limited effect on the calculated reference interval for PTH.

    CONCLUSIONS: Exclusion of elderly individuals with high calcium concentrations, diabetes, reduced GFR or cardiovascular disease has little effect on the reference interval for PTH. It is better not to exclude these individuals, as it will provide a broader base for the reference interval.

  • 65.
    Larsson, Susanna C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, Stockholm, Sweden.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study2018Ingår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, nr 5, s. 840-844Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is considerable discussion of the importance for increased serum 25‐hydroxyvitamin D (S‐25OHD) concentration associated with adequacy for bone health. Accordingly, whether long‐term high S‐25OHD concentration in general positively affects bone mineral density (BMD) is uncertain. We used a Mendelian randomization design to determine the association between genetically increased S‐25OHD concentrations and BMD. Five single‐nucleotide polymorphisms (SNPs) in or near genes encoding enzymes and carrier proteins involved in vitamin D synthesis or metabolism were used as instrumental variables to genetically predict 1 standard deviation increase in S‐25OHD concentration. Summary statistics data for the associations of the S‐25OHD‐associated SNPs with dual‐energy X‐ray absorptiometry (DXA)‐derived femoral neck and lumbar spine BMD were obtained from the Genetic Factors for Osteoporosis (GEFOS) Consortium (32,965 individuals) and ultrasound‐derived heel estimated BMD from the UK Biobank (142,487 individuals). None of the SNPs were associated with BMD at Bonferroni‐corrected significance level, but there was a suggestive association between rs6013897 near CYP24A1 and femoral neck BMD (p = 0.01). In Mendelian randomization analysis, genetically predicted 1 standard deviation increment of S‐25OHD was not associated with higher femoral neck BMD (SD change in BMD 0.02; 95% confidence interval [CI] –0.03 to 0.07; p = 0.37), lumbar spine BMD (SD change in BMD 0.02; 95% CI –0.04 to 0.08; p = 0.49), or estimated BMD (g/cm2 change in BMD –0.03; 95% CI –0.05 to –0.01; p = 0.02). This study does not support a causal association between long‐term elevated S‐25OHD concentrations and higher BMD in generally healthy populations. These results suggest that more emphasis should be placed on the development of evidence‐based cut‐off points for vitamin D inadequacy rather than a general recommendation to increase S‐25OHD.

  • 66.
    Leavy, Breiffni
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Åberg, Anna Cristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. School of Education, Health and Society, Dalarna University.
    The fall descriptions and health characteristics of older adults with hip fracture: a mixed methods study2015Ingår i: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 15, nr 1, artikel-id 40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    In light of the multifactorial etiology of fall-related hip fracture, knowledge of fall circumstances may be especially valuable when placed in the context of the health of the person who falls. We aimed to investigate the circumstances surrounding fall-related hip fractures and to describe fall circumstances in relation to participants' health and functional characteristics.

    METHODS:

    The fall circumstances of 125 individuals (age ≥ 50 years) with hip fracture were investigated using semi-structured interviews. Data concerning participants' health (comorbidities and medications) and function (self-reported performance of mobility, balance, personal activities of daily living and physical activity, previous falls and hand grip strength) were collected via medical records, questionnaires and dynamometry. Using a mixed methods design, both data sets were analysed separately and then merged in order to provide a comprehensive description of fall events and identify eventual patterns in the data.

    RESULTS:

    Fall circumstances were described as i) Activity at the time of the fall: Positional change (n = 24, 19%); Standing (n = 16, 13%); Walking (n = 71, 57%); Balance challenging (n = 14, 11%) and ii) Nature of the fall: Environmental (n = 32, 26%); Physiological (n = 35, 28%); Activity-related indoor (n = 8, 6%) and outdoor (n = 8, 6%); Trips and slips on snow (n = 20, 16%) and in snow-free conditions (n = 12, 10%) and Unknown (n = 10, 8%). We observed the following patterns regarding fall circumstances and participants' health: those who fell i) during positional change had the poorest functional status; ii) due to environmental reasons (indoors) had moderate physical function, but high levels of comorbidity and fall risk increasing medications; iii) in snow-free environments (outdoors) appeared to have a poorer health and functional status than other outdoor groups.

    CONCLUSIONS:

    Our findings indicate that patterns exist in relation to the falls circumstances and health characteristics of people with hip fracture which build upon that previously reported. These patterns, when verified, can provide useful information as to the ways in which fall prevention strategies can be tailored to individuals of varying levels of health and function who are at risk for falls and hip fracture.

  • 67.
    Leavy, Breiffni
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Physiotherapy, Huddinge, Sweden; Stockholms Sjukhem Fdn, Stockholm, Sweden.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Åberg, Anna Cristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    The Impact of Disease and Drugs on Hip Fracture Risk2017Ingår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 00, nr 1, s. 1-12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report the risks of a comprehensive range of disease and drug categories on hip fracture occurrence using a strict population-based cohort design. Participants included the source population of a Swedish county, aged ≥50 years (n = 117,494) including all incident hip fractures during 1 year (n = 477). The outcome was hospitalization for hip fracture (ICD-10 codes S72.0-S72.2) during 1 year (2009-2010). Exposures included: prevalence of (1) inpatient diseases [International Classification of Diseases (ICD) codes A00-T98 in the National Patient Register 1987-2010] and (2) prescribed drugs dispensed in 2010 or the year prior to fracture. We present age- and sex-standardized risk ratios (RRs), risk differences (RDs) and population attributable risks (PARs) of disease and drug categories in relation to hip fracture risk. All disease categories were associated with increased risk of hip fracture. Largest risk ratios and differences were for mental and behavioral disorders, diseases of the blood and previous fracture (RRs between 2.44 and 3.00; RDs (per 1000 person-years) between 5.0 and 6.9). For specific drugs, strongest associations were seen for antiparkinson (RR 2.32 [95 % CI 1.48-1.65]; RD 5.2 [1.1-9.4]) and antidepressive drugs (RR 1.90 [1.55-2.32]; RD 3.1 [2.0-4.3]). Being prescribed ≥10 drugs during 1 year incurred an increased risk of hip fracture, whereas prescription of cardiovascular drugs or ≤5 drugs did not appear to increase risk. Diseases inferring the greatest PARs included: cardiovascular diseases PAR 22 % (95 % CI 14-29) and previous injuries (PAR 21 % [95 % CI 16-25]; for specific drugs, antidepressants posed the greatest risk (PAR 16 % [95 % CI 12.0-19.3]).

  • 68.
    Leavy, Breiffni
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Åberg, Anna Cristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Mallmin, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    When and where do hip fractures occur?: A population-based study2013Ingår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 24, nr 9, s. 2387-2396Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    SUMMARY

    We investigated the effects of socio-demographic and health factors on timing and location of hip fracture among 484 subjects. Time of fracture varied between community dwellers and residential care facility dwellers, and in relation to subjects' psychotropic drug status. Indoor hip fracture incidence increased on snow-covered days.

    INTRODUCTION

    This paper aims to describe the timing and whereabouts of hip fracture cases in a population-based setting and to relate these factors with residential and health status, seasonal variation, and snow-covered ground.

    METHODS

    We consecutively included 484 incident hip fracture events (age ≥50 years) admitted to a Swedish orthopedic department during a 1-year period. Data concerning socio-demographic details, fall location, time of fracture, comorbidity, and medications were collected from in-patient medical records and through patient or caregiver interviews.

    RESULTS

    The expected peak in fracture occurrence during daytime was observed among community dwellers but not among subjects living in residential care. Hip fracture was twice as likely to occur during nighttime hours among psychotropic drug users (adjusted odds ratio (Adj. OR), 2.20; 95 % confidence interval (CI), 1.12-4.30) compared to those not receiving these medications. Subjects without dementia, taking psychotropic drugs, were also more likely to fracture during nighttime hours (Adj. OR, 2.91; 95 % CI, 1.40-6.0). We observed an increase in indoor hip fracture incidence on snow-covered days among community dwellers (incidence rate ratio, 1.34; 95 % CI, 1.02-1.74). We observed only a weak seasonal trend in hip fracture incidence, based on month, among community dwellers who fractured indoors.

    CONCLUSIONS

    Special attention and possibly fall-preventive efforts should be directed not only toward those living in residential care facilities but also toward community-dwelling subjects taking psychotropic drugs since these groups have a higher incidence of nighttime hip fracture. Further research aiming to explain the seasonal variation of indoor fracture incidence among community dwellers is warranted.

  • 69.
    Lejonklou, Margareta Halin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Karimullina, Elina
    Larsson, Sune
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Lind, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Jacobson Rasmusson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Rönn, Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Blumberg, Bruce
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Does developmental exposure to bisphenol A induce bone and adipose tissue disturbances?2014Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, s. S243-S243Artikel i tidskrift (Övrigt vetenskapligt)
  • 70.
    Lejonklou, Margareta Halin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Lind, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Rasmusson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Larsson, Sune
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lind, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Developmental low-dose exposure to bisphenol A results in gender-specific and non-monotonic effects on Fischer F344 rat bone2015Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, nr 2, s. S255-S255Artikel i tidskrift (Övrigt vetenskapligt)
  • 71. Levin, G. P.
    et al.
    Robinson-Cohen, C.
    De Boer, I. H.
    Houston, D. K.
    Lohman, K.
    Liu, Y.
    Kritchevsky, S. B.
    Cauley, J. A.
    Tanaka, T.
    Ferrucci, L.
    Bandinelli, S.
    Patel, K. V.
    Hagström, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Wang, T.
    Wolf, M.
    Psaty, B. M.
    Siscovick, D.
    Kestenbaum, B.
    Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes2012Ingår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 308, nr 18, s. 1898-1905Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.

    Objective To investigate whether common variation within genes encoding the vitamin D–binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.

    Design, Setting, and Participants Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

    Main Outcome Measure Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.

    Results Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.

    Conclusion Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

  • 72.
    Lidén, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wilén, B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ljunghall, Sverker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Polymorphism at the Sp 1 binding site in the collagen type I alpha 1 gene does not predict bone mineral density in postmenopausal women in sweden1998Ingår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 63, nr 4, s. 293-295Artikel i tidskrift (Refereegranskat)
    Abstract [en]

     Polymorphisms at the binding site of the Sp 1 transcription factor of the collagen type I alpha1 gene have recently been suggested to be an important marker for low bone mineral density (BMD) and vertebral fracture in a population of predominantly postmenopausal British women. We examined whether the unfavorable "s" allele was associated with low BMD in 64 patients with primary osteoporosis and in 72 healthy controls. We found no statistically significant differences between COLIA1 genotypes with regard to BMD at the spine and femoral neck. In 36 patients with severe osteoporosis with vertebral fracture the genotype frequencies were similar to that observed in 67 age-matched controls. These data indicate that the Sp 1 polymorphisms in the COLIA1 gene are unlikely to be of clinical value in identifying Swedish subjects who are at risk of postmenopausal osteoporosis.

  • 73.
    Liljedahl, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kahan, Thomas
    Malmqvist, Karin
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kurland, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Single nucleotide polymorphisms predict the change in left ventricular mass in response to antihypertensive treatment2004Ingår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 22, nr 12, s. 2321-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control. METHODS: Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis. RESULTS: The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corresponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor alpha2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction. CONCLUSION: SNPs in the angiotensinogen, apolipoprotein B, and the alpha2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.

  • 74.
    Liljedahl, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, Julia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kurland, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lindersson, Marie
    Kahan, Thomas
    Nyström, Fredrik
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response2003Ingår i: Pharmacogenetics, ISSN 0960-314X, E-ISSN 1473-561X, Vol. 13, nr 1, s. 7-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aimed to develop a microarray genotyping system for multiplex analysis of a panel of single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in blood pressure regulation, and to apply this system in a pilot study demonstrating its feasibility in the pharmacogenetics of hypertension. A panel of 74 SNPs in 25 genes involved in blood pressure regulation was selected from the SNP databases, and genotyped in DNA samples of 97 hypertensive patients. The patients had been randomized to double-blind treatment with either the angiotensin II type 1 receptor blocker irbesartan or the beta 1-adrenergic receptor blocker atenolol. Genotyping was performed using a microarray based DNA polymerase assisted 'minisequencing' single nucleotide primer extension assay with fluorescence detection. The observed genotypes were related to the blood pressure reduction using stepwise multiple regression analysis. The allele frequencies of the selected SNPs were determined in the Swedish population. The established microarray-based genotyping system was validated and allowed unequivocal multiplex genotyping of the panel of 74 SNPs in every patient. Almost 7200 SNP genotypes were generated in the study. Profiles of four or five SNP-genotypes that may be useful as predictors of blood pressure reduction after antihypertensive treatment were identified. Our results highlight the potential of microarray-based technology for SNP genotyping in pharmacogenetics.

  • 75.
    Lind, Monica
    et al.
    Institute of Environmental Medicine, Karolinska Institutet.
    Johansson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönn, Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Subclinical Hypervitaminosis A in Rat: Measurements of bone mineral density (BMD) do not reveal adverse skeletal changes2006Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 159, nr 1, s. 73-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

  • 76. Lind, P. M.
    et al.
    Johansson, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönn, M.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Subclinical hypervitaminosis A in rat: measurements of bone mineral density (BMD) do not reveal adverse skeletal changes2006Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 159, nr 1, s. 73-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

  • 77.
    Lind, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hu, Lijuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Sugars, Rachael
    Andersson, Göran
    Jacobson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Microarray Profiling of Diaphyseal Bone of Rats Suffering from Hypervitaminosis A2012Ingår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 90, nr 3, s. 219-229Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vitamin A is the only known compound that produces spontaneous fractures in rats. In an effort to resolve the molecular mechanism behind this effect, we fed young male rats high doses of vitamin A and performed microarray analysis of diaphyseal bone with and without marrow after 1 week, i.e., just before the first fractures appeared. Of the differentially expressed genes in cortical bone, including marrow, 98% were upregulated. In contrast, hypervitaminotic cortical bone without marrow showed reduced expression of 37% of differentially expressed genes. Gene ontology (GO) analysis revealed that only samples containing bone marrow were associated with a GO term, which principally represented extracellular matrix. This is consistent with the histological findings of increased endosteal/marrow osteoblast number. Fourteen genes, including Cyp26b1, which is known to be upregulated by vitamin A, were selected and verified by real-time PCR. In addition, immunohistochemical staining of bone sections confirmed that the bone-specific molecule osteoadherin was upregulated. Further analysis of the major gene-expression changes revealed apparent augmented Wnt signaling in the sample containing bone marrow but reduced Wnt signaling in cortical bone. Moreover, induced expression of hypoxia-associated genes was found only in samples containing bone marrow. Together, these results highlight the importance of compartment-specific analysis of bone and corroborate previous observations of compartment-specific effects of vitamin A, with reduced activity in cortical bone but increased activity in the endosteal/marrow compartment. We specifically identify potential key osteoblast-, Wnt signaling-, and hypoxia-associated genes in the processes leading to spontaneous fractures.

  • 78.
    Lind, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lejonklou, Margareta Halin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Dunder, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Kushnir, Mark M.
    ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA;Univ Utah, Dept Pathol, Salt Lake City, UT USA.
    Öhman-Mägi, Caroline
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Larsson, Sune
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only2019Ingår i: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 177, artikel-id 108584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Developmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size.

    Objective: To analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development.

    Methods: As in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 mu g/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 mu g/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination.

    Results: Compared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone man ow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timpl (in BPA50) were increased exclusively in female offspring.

    Conclusions: Developmental BPA exposure at an environmentally relevant concentration resulted in female specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 mu g/kg BW/day, appeared to induce bone stiffness reduction, bone man ow fibrosis and chronic inflammation in female rat offspring later in life.

  • 79.
    Lind, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lejonklou, Margareta Halin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Dunder, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Rasmusson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Larsson, Sune
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Low-dose developmental exposure to bisphenol A induces sex-specific effects in bone of Fischer 344 rat offspring2017Ingår i: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 159, s. 61-68, artikel-id S0013-9351(17)30727-2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Bisphenol A (BPA) is a component of polycarbonate plastics to which humans are regularly exposed at low levels, and an endocrine disruptor with effects on several hormonal systems. Bone is a sensitive hormone target tissue, and we have recently shown that in utero and lactational exposure to 25µg BPA/kg BW/day alters femoral geometry in rat offspring.

    OBJECTIVE: To investigate bone effects in rat offspring after developmental exposure to a BPA dose in the range of human daily exposure (0.1-1.5µg/kg BW/day) as well as a dose to corroborate previous findings.

    METHODS: Pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5µg/kg BW/day: [0.5], (n=21) or 50µg/kg BW/day: [50], (n = 16) from gestational day 3.5 until postnatal day 22, while controls were given only vehicle (n = 25). The offspring was sacrificed at 5 weeks of age. Bone effects were analyzed using peripheral quantitative computed tomography (pQCT), the 3-point bending test, plasma markers of bone turnover, and gene expression in cortical bone and bone marrow.

    RESULTS: Compared to controls, male offspring developmentally exposed to BPA had shorter femurs. pQCT analysis revealed effects in the [0.5] group, but not in the [50] group; BPA reduced both trabecular area (-3.9%, p < 0.01) and total cross sectional area (-4.1%, p < 0.01) of femurs in the [0.5] group, whereas no effects were seen on bone density. Conversely, bone length and size were not affected in female offspring. However, the procollagen type I N-terminal propeptide (P1NP), a peptide formed during type 1 collagen synthesis, was increased in plasma (42%: p < 0.01) in female offspring exposed to [0.5] of BPA, although collagen gene expression was not increased in bone. The biomechanical properties of the bones were not altered in either sex. Bone marrow mRNA expression was only affected in male offspring.

    CONCLUSIONS: Developmental low-dose exposure to BPA resulted in sex-specific bone effects in rat offspring. A dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4µg/kg BW/day, reduced bone length and size in male rat offspring. Long-term studies are needed to clarify whether the increased plasma levels of P1NP in female offspring reflect development of fibrosis.

  • 80.
    Lind, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Lind, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Jacobson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Hu, Lijuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Sundqvist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Risteli, Juha
    Yebra-Rodriguez, Africa
    Larsson, Sune
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Rodriguez-Navarro, Alejandro
    Andersson, Göran
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats2011Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 48, nr 3, s. 496-506Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vitamin A (retinol) is the only molecule known to induce spontaneous fractures in laboratory animals and we have identified retinol as a risk factor for fracture in humans. Since subsequent observational studies in humans and old animal data both show that high retinol intake appears to only have small effects on bone mineral density (BMD) we undertook a mechanistic study of how excess retinol reduces bone diameter while leaving BMD essentially unaffected. We fed growing rats high doses of retinol for only 1week. Bone analysis involved antibody-based methods, histology, pQCT, biomechanics and bone compartment-specific PCR together with Fourier Transform Infrared Spectroscopy of bone mineral. Excess dietary retinol induced weakening of bones with little apparent effect on BMD. Periosteal osteoclasts increased but unexpectedly endosteal osteoclasts disappeared and there was a reduction of osteoclastic serum markers. There was also a lack of capillary erythrocytes, endothelial cells and serum retinol transport protein in the endosteal/marrow compartment. A further indication of reduced endosteal/marrow blood flow was the increased expression of hypoxia-associated genes. Also, in contrast to the inhibitory effects in vitro, the marrow of retinol-treated rats showed increased expression of osteogenic genes. Finally, we show that hypervitaminotic bones have a higher degree of mineralization, which is in line with biomechanical data of preserved stiffness in spite of thinner bones. Together these novel findings suggest that a rapid primary effect of excess retinol on bone tissue is the impairment of endosteal/marrow blood flow leading to hypoxia and pathological endosteal mineralization.

  • 81.
    Lind, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Hu, Lijuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Studies of indirect and direct effects of hypervitaminosis A on rat bone by comparing free access to food and pair-feeding.2018Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, nr 2, s. 82-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The most prominent features of hypervitaminosis A in rats are spontaneous fractures and anorexia. Since caloric restriction induces alterations in bone, some effects could be secondary to loss of appetite. To clarify the mechanisms behind vitamin A-induced bone fragility it is necessary to distinguish between direct and indirect effects.

    MATERIALS AND METHODS: In this study we compared rats fed high doses of vitamin A both with pair-fed controls, which were fed the same amount of chow as that consumed by the vitamin A group to keep food intake the same, and to controls with free access to food.

    RESULTS: In contrast to the pair-fed animals, rats in the free access group fed high doses of vitamin A for 7 days had 13% lower food intake, 15% lower body weight, and 2.7% shorter femurs compared with controls. In addition, serum biomarkers of bone turnover were reduced. Peripheral quantitative computed tomography of the femurs showed that the bone mineral content, cross sectional area, and periosteal circumference were similarly reduced in the pair-fed and free access groups. However, bone mineral density (BMD) and cortical parameters were only significantly decreased in the free access group.

    CONCLUSIONS: Our data indicate that the major direct short-term effect of high doses of vitamin A on rat bone is a reduced bone diameter, whereas the effects on bone length, serum biomarkers of bone turnover, BMD, and bone cortex appear to be mainly indirect, caused by a systemic toxicity with loss of appetite, reduced food intake, and general effects on growth.

  • 82.
    Lind, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Sundqvist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Hu, Lijuan
    Pejler, Gunnar
    Andersson, Goran
    Jacobson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Vitamin A Is a Negative Regulator of Osteoblast Mineralization2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e82388-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An excessive intake of vitamin A has been associated with an increased risk of fractures in humans. In animals, a high vitamin A intake leads to a reduction of long bone diameter and spontaneous fractures. Studies in rodents indicate that the bone thinning is due to increased periosteal bone resorption and reduced radial growth. Whether the latter is a consequence of direct effects on bone or indirect effects on appetite and general growth is unknown. In this study we therefore used pair-feeding and dynamic histomorphometry to investigate the direct effect of a high intake of vitamin A on bone formation in rats. Although there were no differences in body weight or femur length compared to controls, there was an approximately halved bone formation and mineral apposition rate at the femur diaphysis of rats fed vitamin A. To try to clarify the mechanism(s) behind this reduction, we treated primary human osteoblasts and a murine preosteoblastic cell line (MC3T3-E1) with the active metabolite of vitamin A; retinoic acid (RA), a retinoic acid receptor (RAR) antagonist (AGN194310), and a Cyp26 inhibitor (R115866) which blocks endogenous RA catabolism. We found that RA, via RARs, suppressed in vitro mineralization. This was independent of a negative effect on osteoblast proliferation. Alkaline phosphatase and bone gamma carboxyglutamate protein (Bglap, Osteocalcin) were drastically reduced in RA treated cells and RA also reduced the protein levels of Runx2 and Osterix, key transcription factors for progression to a mature osteoblast. Normal osteoblast differentiation involved up regulation of Cyp26b1, the major enzyme responsible for RA degradation, suggesting that a drop in RA signaling is required for osteogenesis analogous to what has been found for chondrogenesis. In addition, RA decreased Phex, an osteoblast/osteocyte protein necessary for mineralization. Taken together, our data indicate that vitamin A is a negative regulator of osteoblast mineralization.

  • 83.
    Lind, Thomas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Öhman, Caroline
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Calounova, Gabriela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rasmusson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Andersson, Goran
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Div Pathol, Dept Lab Med, Stockholm, Sweden..
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Excessive dietary intake of vitamin A reduces skull bone thickness in mice2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 4, artikel-id e0176217Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Calvarial thinning and skull bone defects have been reported in infants with hypervitaminosis A. These findings have also been described in humans, mice and zebrafish with loss-of-function mutations in the enzyme CYP26B1 that degrades retinoic acid (RA), the active metabolite of vitamin A, indicating that these effects are indeed caused by too high levels of vitamin A and that evolutionary conserved mechanisms are involved. To explore these mechanisms, we have fed young mice excessive doses of vitamin A for one week and then analyzed the skull bones using micro computed tomography, histomorphometry, histology and immunohistochemistry. In addition, we have examined the effect of RA on gene expression in osteoblasts in vitro. Compared to a standard diet, a high dietary intake of vitamin A resulted in a rapid and significant reduction in calvarial bone density and suture diastasis. The bone formation rate was almost halved. There was also increased staining of tartrate resistant acid phosphatase in osteocytes and an increased perilacunar matrix area, indicating osteocytic osteolysis. Consistent with this, RA induced genes associated with bone degradation in osteoblasts in vitro. Moreover, and in contrast to other known bone resorption stimulators, vitamin A induced osteoclastic bone resorption on the endocranial surfaces.

  • 84.
    Liu, Wei
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Li, Qing
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Yu, Wen-Ru
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Juhlin, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Nordlinder, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rollman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Törmä, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Biosynthesis and function of all-trans- and 9-cis retinoic acid in parathyroid cells1996Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 229, nr 3, s. 922-929Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We demonstrate that cultured human and bovine parathyroid cells incubated with all-trans-[11,12-3H]-retinol convert this tracer into all-trans- and 9-cis-retinoic acid. By using RT-PCR, cellular retinol-binding protein type I (CRBP I), cellular retinoic acid binding protein I and II (CRABP I and II), retinoic acid receptors (RARs) alpha, beta and gamma, and 9-cis-retinoic acid receptor (RXR) alpha transcripts were detected in human parathyroid cDNA. CRBP I and CRABP I expression was confirmed by immunohistochemistry. Both 9-cis- and all-trans-RA were found to suppress parathyroid hormone (PTH) secretion from dispersed human adenomatous parathyroid cells, which was augmented by combined treatment with 1mM RA and 100 nM 1,25 (OH)2D3. The present data establish parathyroid gland as a target for retinoids and as a site of synthesis of the hormonal forms of vitamin A (retinol), all-trans- and 9-cis-retinoic acid.

  • 85. Lund, Lars H.
    et al.
    Svennblad, Bodil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Hallberg, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Dahlstrom, Ulf
    Edner, Magnus
    Association of Spironolactone Use With All-Cause Mortality in Heart Failure A Propensity Scored Cohort Study2013Ingår i: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 6, nr 2, s. 174-183Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background-In 3 randomized controlled trials in heart failure (HF), mineralocorticoid receptor antagonists reduced mortality. The net benefit from randomized controlled trials may not be generalizable, and eplerenone was, but spironolactone was not, studied in mild HF. We tested the hypothesis that spironolactone is associated with reduced mortality also in a broad unselected contemporary population with HF and reduced ejection fraction, in particular New York Heart Association (NYHA) I-II. Methods and Results-We prospectively studied 18 852 patients (age 71+/-12 years; 28% women) with NYHA I-IV and ejection fraction <40% who were registered in the Swedish Heart Failure Registry between 2000 and 2012 and who were (n=6551) or were not (n=12 301) treated with spironolactone. We derived propensity scores for spironolactone treatment based on 41 covariates. We assessed survival by Cox regression with adjustment for propensity scores and with matching based on propensity score. We performed sensitivity and residual confounding analyses and analyzed the NYHA I-II and III-IV subgroups separately. One-year survival was 83% versus 84% in treated versus untreated patients (log rank P<0.001). After adjustment for propensity scores, the hazard ratio for spironolactone was 1.05 (95% confidence interval, 1.00-1.11; P=0.054). Spironolactone interacted with NYHA (P<0.001). In the NYHA I-II subgroup, after adjustment for propensity scores, the hazard ratio for spironolactone was 1.11 (95% confidence interval, 1.02-1.21; P=0.019). Conclusions-In an unselected contemporary population of HF with reduced ejection fraction, spironolactone was not associated with reduced mortality. The net benefits of spironolactone may be lower outside the clinical trial setting and in milder HF.

  • 86. Maggio, Marcello
    et al.
    De Vita, Francesca
    Lauretani, Fulvio
    Ceda, Gian Paolo
    Volpi, Elena
    Giallauria, Francesco
    De Cicco, Giuseppe
    Cattabiani, Chiara
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Cederholm, Tommy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Vitamin D and Endothelial Vasodilation in Older Individuals: Data From the PIVUS Study2014Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, nr 9, s. 3382-3389Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CONTEXT:

    Vitamin D plays a role in a wide range of extraskeletal processes, including vascular function. Endothelial dysfunction is a predictor of cardiovascular disease, especially in older subjects. However, the relationship between vitamin D levels and indexes of endothelial vasodilation has never been fully addressed in older individuals.

    OBJECTIVE:

    The objective of this study was to examine the association between vitamin D and endothelial function in a large community-based sample of older subjects.

    METHODS:

    This cross-sectional study involved 852 community-dwelling men and women aged 70 years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), with complete data on vascular function and 25-hydroxyvitamin D. We evaluated endothelium-dependent vasodilation by an invasive forearm technique with acetylcholine, endothelium-independent vasodilation by sodium nitroprussiate, flow-mediated vasodilation, and the pulse wave analysis (reflectance index). Vitamin D levels were measured by chemiluminescence. We used multivariate regression models adjusted for body mass index (model 1) and for multiple confounders (high-sensitivity C-reactive protein, insulin, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, smoking, sex hormones, season of blood collection, hypertension, diabetes, cardiovascular medications and diseases, statin usage, plasma calcium and calcium intake, PTH, physical exercise, liver and kidney function tests, albumin; model 2).

    RESULTS:

    In women, but not in men, vitamin D levels were positively associated with endothelium-independent vasodilation in both model 1 (β ± SE = 1.41 ± 0.54; P = .001), and model 2 (β ± SE = 2.01 ± 0.68; P = .003).We found no significant relationship between vitamin D levels and endothelium-dependent vasodilation, flow-mediated vasodilation, and reflectance index in both sexes.

    CONCLUSIONS:

    In older women, but not in men, vitamin D is positively and independently associated with EIDV.

  • 87.
    Manousaki, Despoina
    et al.
    McGill Univ, Dept Human Genet, Montreal.
    Dudding, Tom
    Univ Bristol, IEU, MRC, Bristol, Avon.
    Haworth, Simon
    Univ Bristol, IEU, MRC, Bristol, Avon.
    Hsu, Yi-Hsiang
    Hebrew SeniorLife, Inst Aging Res, Boston.
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston.
    Medina-Gomez, Carolina
    Erasmus MC, Dept Internal Med, Rotterdam.
    Voortman, Trudy
    Erasmus MC, Dept Epidemiol, Rotterdam.
    van der Velde, Nathalie
    Erasmus MC, Dept Internal Med, Rotterdam.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Robinson-Cohen, Cassiane
    Univ Washington, Div Nephrol, Kidney Res Inst, Seattle.
    Cousminer, Diana
    Childrens Hosp Philadelphia, Div Human Genet, Philadelphia.
    Nethander, Maria
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, Gothenburg.
    Vanderput, Liesbeth
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, Gothenburg.
    Noordam, Raymond
    Leiden Univ, Sect Gerontol & Geriatr, Dept Internal Med, Med Ctr, Leiden.
    Forgetta, Vincenzo
    McGill Univ, Dept Human Genet, Montreal, PQ.
    Greenwood, Celia
    McGill Univ, Dept Human Genet, Montreal, PQ.
    Biggs, Mary Lou
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle.
    Psaty, Bruce
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle.
    Rotter, Jerome
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance.
    Zemel, Babette
    Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia.
    Mitchell, Jonathan
    Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia.
    Taylor, Bruce
    Univ Tasmania, Menzies Res Inst Tasmania, Hobart.
    Lorentzon, Matthias
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med, Sahlgrenska Acad, Gothenburg.
    Karlsson, Magnus
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Lund, Sweden.;Skane Univ Hosp, Dept Orthopaed, Malmö.
    Jaddoe, Vincent
    Erasmus MC, Generat Study Grp R, Rotterdam.
    Tiemeier, Henning
    Erasmus MC, Generat Study Grp R, Rotterdam.
    Campos-Obando, Natalia
    Erasmus MC, Dept Internal Med, Rotterdam.
    Franco, Oscar
    Erasmus MC, Dept Epidemiol, Rotterdam.
    Uitterlinden, Andre
    Erasmus MC, Dept Internal Med, Rotterdam.
    Broer, Linda
    Erasmus MC, Dept Internal Med, Rotterdam.
    van Schoor, Natasja
    Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam.
    Ham, Annelies
    Erasmus MC, Dept Internal Med, Rotterdam.
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, Rotterdam.
    Karasik, David
    Hebrew SeniorLife, Inst Aging Res, Boston.
    de Mutsert, Renee
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden.
    Rosendaal, Fritz
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden.
    den Heijer, Martin
    Vrije Univ Amsterdam, Dept Endocrinol, Med Ctr, Amsterdam.
    Wang, Thomas
    Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Orwoll, Eric
    Oregon Hlth & Sci Univ, Bone & Mineral Unit, Portland.
    Mook-Kanamori, Dennis O.
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Kestenbaum, Bryan
    Univ Washington, Div Nephrol, Kidney Res Inst, Seattle.
    Ohlsson, Claes
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, Gothenburg.
    Mellstrom, Dan
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, Gothenburg.
    de Groot, Lisette
    Wageningen Univ, Dept Human Nutr, Wageningen.
    Grant, Struan
    Childrens Hosp Philadelphia, Div Human Genet, Philadelphia.
    Kiel, Douglas
    Hebrew SeniorLife, Inst Aging Res, Boston.
    Zillikens, Carola
    Erasmus MC, Dept Internal Med, Rotterdam.
    Rivadeneira, Fernando
    Erasmus MC, Dept Internal Med, Rotterdam.
    Sawcer, Stephen
    Univ Cambridge, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge.
    Timpson, Nicholas
    Univ Bristol, IEU, MRC, Bristol, Avon.
    Richards, Brent
    McGill Univ, Dept Human Genet, Montreal.
    Low Frequency Coding Variation in CYP2R1 has Large Effects on Vitamin D Level and Risk of Multiple Sclerosis2017Ingår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 32, nr S1, s. S319-S320, artikel-id Meeting Abstract: MO0459Artikel i tidskrift (Övrigt vetenskapligt)
  • 88.
    Manousaki, Despoina
    et al.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada..
    Dudding, Tom
    Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Haworth, Simon
    Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Hsu, Yi-Hsiang
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02142 USA..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Medina-Gomez, Carolina
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Voortman, Trudy
    Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    van der Velde, Nathalie
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Acad Med Ctr, Dept Internal Med, Sect Geriatr, NL-1105 AZ Amsterdam, Netherlands..
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Robinson-Cohen, Cassianne
    Univ Washington, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA..
    Cousminer, Diana L.
    Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA..
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, S-41390 Gothenburg, Sweden..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden..
    Noordam, Raymond
    Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, NL-2333 ZA Leiden, Netherlands..
    Forgetta, Vincenzo
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada..
    Greenwood, Celia M. T.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada.;McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Oncol, Montreal, PQ H4A 3T2, Canada..
    Biggs, Mary L.
    Univ Washington, Dept Med & Biostat, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Kaiser Permanente Washington Hlth Res Unit, Seattle, WA 98101 USA..
    Rotter, Jerome I.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Zemel, Babette S.
    Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA..
    Mitchell, Jonathan A.
    Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA..
    Taylor, Bruce
    Univ Tasmania, Menzies Inst Med Res, Locked Bag 23, Hobart, Tas 7000, Australia..
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, S-43180 Molndal, Sweden.;Sahlgrens Univ Hosp, Geriatr Med, S-43180 Molndal, Sweden..
    Karlsson, Magnus
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, S-22241 Malmo, Sweden.;Skane Univ Hosp, Dept Orthopaed, S-22241 Malmo, Sweden..
    Jaddoe, Vincent V. W.
    Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Tiemeier, Henning
    Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Child & Adolescent Psychiat Psychol, NL-3015 GE Rotterdam, Netherlands..
    Campos-Obando, Natalia
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Utterlinden, Andre G.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Broer, Linda
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    van Schoor, Natasja M.
    Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands..
    Ham, Annelies C.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, NL-3015 GE Rotterdam, Netherlands..
    Karasik, David
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA..
    de Mutsert, Renee
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 ZA Leiden, Netherlands..
    Rosendaal, Frits R.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 ZA Leiden, Netherlands..
    den Heijer, Martin
    Vrije Univ Amsterdam, Med Ctr, Dept Endocrinol, NL-1081 HV Amsterdam, Netherlands..
    Wang, Thomas J.
    Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Orwoll, Eric S.
    Oregon Hlth & Sci Univ, Bone & Mineral Unit, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 ZA Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2333 ZA Leiden, Netherlands..
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Kestenbaum, Bryan
    Univ Washington, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden..
    Mellström, Dan K
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, S-43180 Molndal, Sweden..
    de Groot, Lisette C. P. G. M.
    Wageningen Univ, Div Human Nutr, NL-6708 WE Wageningen, Netherlands..
    Grant, Struan F. A.
    Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Endocrinol, Philadelphia, PA 19104 USA..
    Kiel, Douglas P.
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02142 USA.;Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA..
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Rivadeneira, Fernando
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Sawcer, Stephen
    Univ Cambridge, Dept Clin Neurosci, Box 165,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0QQ, England..
    Timpson, Nicholas J.
    Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Richards, J. Brent
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England.;McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada..
    Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis2017Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 101, nr 2, s. 227-238Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 x 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 3 10 x(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 3 10 x(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

  • 89.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Intag av höga doser E-vitamin ger svårare luftvägsinfektioner hos äldre2002Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 99, nr 47, s. 4749-Artikel, recension (Övrig (populärvetenskap, debatt, mm))
  • 90.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Soluble RANKL and risk of nontraumatic fracture2004Ingår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 291, nr 22, s. 2703-4Artikel i tidskrift (Refereegranskat)
  • 91.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vilka vitaminer bör jag ta, doktorn?2002Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 99, nr 13, s. 1466-Artikel, recension (Övrig (populärvetenskap, debatt, mm))
  • 92.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vitamin A and fracture risk2003Ingår i: Nutritional aspects of bone health / [ed] Susan A. New & Jean-Philippe Bonjour, Cambridge: Royal Society of Chemistry , 2003Kapitel i bok, del av antologi (Övrig (populärvetenskap, debatt, mm))
  • 93.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Amér, Stefan
    Wilén, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lindh, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ljunghall, Sverker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vitamin D receptor genotypes in osteoporosis1994Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 344, nr 8927, s. 949-950Artikel i tidskrift (Refereegranskat)
  • 94.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Serum retinol levels and fracture risk: Authors reply2003Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, nr 19, s. 1928-Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm))
  • 95.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Vitamin D och hälsa: Evidensbristen är det stora problemet2012Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, nr 12, s. 604-605Artikel i tidskrift (Refereegranskat)
  • 96.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Dietary vitamin A intake and risk for hip fracture: Response1999Ingår i: Annals of Internal Medicine, ISSN 0003-4819, E-ISSN 1539-3704, Vol. 131, nr 5, s. 392-392Artikel i tidskrift (Refereegranskat)
  • 97.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Larsson, Susanna C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, SE-17177 Stockholm, Sweden.
    Serum Parathyroid Hormone and Risk of Coronary Artery Disease: Exploring Causality Using Mendelian Randomization2019Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, nr 11, s. 5595-5600Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Elevated circulating parathyroid hormone concentrations have been associated with increased risk of cardiovascular disease in observational studies, but whether the association is causal is unknown.

    Objective: We used the Mendelian randomization design to test whether genetically increased serum parathyroid hormone (S-PTH) concentrations are associated with coronary artery disease (CAD).

    Design, Setting, and Participants: Five single-nucleotide polymorphisms robustly associated with S-PTH concentrations were used as instrumental variables to estimate the association of genetically higher S-PTH concentrations with CAD. Summary statistics data for CAD were obtained from a genetic consortium with data from 184,305 individuals (60,801 CAD cases and 123,504 noncases).

    Main Outcome Measure: OR of CAD per genetically predicted one SD increase of S-PTH concentrations.

    Results: Genetically higher S-PTH concentration was not associated with CAD as a whole or myocardial infarction specifically (similar to 70% of total cases). The ORs per genetically predicted one SD increase in S-PTH concentration were 1.01 (95% CI: 0.93 to 1.09; P = 0.88) for CAD and 1.02 (95% CI: 0.94 to 1.10; P = 0.64) for myocardial infarction. The lack of association remained in various sensitivity analyses.

    Conclusion: Genetic predisposition to higher S-PTH concentrations does not appear to be an independent risk factor for CAD.

  • 98.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Warensjö, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Wernroth, Mona-Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Jensevik, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Berglund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Vessby, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    A high activity index of stearoyl-CoA desaturase is associated with increased risk of fracture in men2008Ingår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 19, nr 7, s. 929-934Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The activity index of stearoyl-CoA desaturase (SCD), a key enzyme in lipogenesis, was associated with increased risk of fracture in a longitudinal population-based cohort of men. This indicates that elevated levels of endogenous lipogenesis increase the risk of fracture and suggest a role for saturated fat in the pathogenesis of osteoporosis. INTRODUCTION: Osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, and experimental studies have indicated that increased adipogenesis can occur at the expense of osteoblasts, leading to bone loss. Stearoyl-CoA desaturase (SCD) converts saturated to monounsaturated fatty acids and is a key enzyme in lipogenesis. METHODS: Analysis was performed in a population-based, longitudinal cohort study of men (n = 2009). A product-to-precursor index (palmitoleic acid/palmitic acid) was used to estimate SCD activity in fasting serum analyzed in samples obtained at enrollment at age 50 years. Fractures were documented in 422 men during 35 years of follow-up. Cox regression analysis was used to determine the risk of fracture according to SCD activity index. RESULTS: The risk of fracture was highest among men with the highest levels of SCD activity index. Multivariable analysis of the risk of fracture in the highest quintile as compared to the lowest one showed that the rate ratio was 1.71 (95% CI 1.26-2.33) for any fracture, with an estimated population attributable risk of 15%. The risk was further increased within the highest quintile. CONCLUSIONS: Our results indicate that elevated levels of endogenous lipogenesis increase the risk of fracture and suggest a role for saturated fat in the pathogenesis of osteoporosis.

  • 99.
    Melhus, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Wilén, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Ljunghall, Sverker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Cloning of a novel retinoic acid-inducible mRNA from human osteoblast-like cells1997Ingår i: Biochemistry and Molecular Biology International, ISSN 1039-9712, Vol. 43, nr 5, s. 1145-1150Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Retinoids have long been known to influence skeletal development and bone remodeling. Cells of the osteoblastic lineage play a key role in these processes. In this study we have used the differential display PCR technique to identify retinoic acid (RA)-induced mRNAs in human osteoblast-like cells. We report the cloning and sequencing of one such mRNA, AT-RA 6, which was specifically induced by all-trans RA both in normal human osteoblast-like cells and in MG-63 osteosarcoma cells. Maximal expression was found after 60 min, suggesting that this may be an early response gene. Expression was found in all tissues examined. No homology to known mRNA sequences was detected.

  • 100.
    Michaëlsson, Karl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Baron, John A
    Snellman, Greta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Gedeborg, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Berglund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Blomhoff, Rune
    Wolk, Alicja
    Garmo, Hans
    Regional Oncologic Center, Uppsala University, Uppsala.
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Plasma vitamin D and mortality in older men: a community-based prospective cohort study2010Ingår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 92, nr 4, s. 841-848Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Vitamin D status is known to be important for bone health but may also affect the development of several chronic diseases, including cancer and cardiovascular diseases, which are 2 major causes of death. Objective: We aimed to examine how vitamin D status relates to overall and cause-specific mortality. Design: The Uppsala Longitudinal Study of Adult Men, a community-based cohort of elderly men (mean age at baseline: 71 y; n = 1194), was used to investigate the association between plasma 25-hydroxyvitamin D [25(OH)D] and mortality. Total plasma 25(OH)D was determined with HPLC atmospheric pressure chemical ionization mass spectrometry. Proportional hazards regression was used to compute hazard ratios (HRs). Results: During follow-up (median: 12.7 y), 584 (49%) participants died. There was a U-shaped association between vitamin D concentrations and total mortality. An approximately 50% higher total mortality rate was observed among men in the lowest 10% (<46 nmol/L) and the highest 5% (>98 nmol/L) of plasma 25(OH)D concentrations compared with intermediate concentrations. Cancer mortality was also higher at low plasma concentrations (multivariable-adjusted HR: 2.20; 95% CI: 1.44, 3.38) and at high concentrations (HR: 2.64; 95% CI: 1.46, 4.78). For cardiovascular death, only low (HR: 1.89; 95% CI: 1.21, 2.96) but not high (HR: 1.33; 95% CI: 0.69, 2.54) concentrations indicated higher risk. Conclusions: Both high and low concentrations of plasma 25(OH)D are associated with elevated risks of overall and cancer mortality. Low concentrations are associated with cardiovascular mortality.

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