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Kharazmi, M., Michaëlsson, K., Schilcher, J., Eriksson, N., Melhus, H., Wadelius, M. & Hallberg, P. (2019). A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture. Calcified Tissue International, 105(1), 51-67
Open this publication in new window or tab >>A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture
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2019 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Genome-wide association study, Atypical fractures, Bisphosphonate, Drug-related side effects and adverse reactions, Pharmacogenetics
National Category
Orthopaedics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-386428 (URN)10.1007/s00223-019-00546-9 (DOI)000469477400005 ()31006051 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440; 521-2014-337; 2015-035270Swedish Heart Lung FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceErik, Karin och Gösta Selanders FoundationÖstergötland County Council
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Karasik, D., Zillikens, M. C., Hsu, Y.-H., Aghdassi, A., Akesson, K., Amin, N., . . . Ohlsson, C. (2019). Disentangling the genetics of lean mass. American Journal of Clinical Nutrition, 109(2), 276-287
Open this publication in new window or tab >>Disentangling the genetics of lean mass
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2019 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 109, no 2, p. 276-287Article in journal (Refereed) Published
Abstract [en]

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Place, publisher, year, edition, pages
Oxford University Press, 2019
Keywords
body composition, skeletal muscle, body fat, meta-analysis of genome-wide association studies, metabolic profile
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-380499 (URN)10.1093/ajcn/nqy272 (DOI)000460615600007 ()30721968 (PubMedID)
Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2019-04-23Bibliographically approved
Larsson, S. C., Melhus, H. & Michaëlsson, K. (2018). Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study. Journal of Bone and Mineral Research, 33(5), 840-844
Open this publication in new window or tab >>Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study
2018 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 5, p. 840-844Article in journal (Refereed) Published
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.

Keywords
Bone Mineral Density, Mendelian Randomization, Osteoporosis, Single-Nucleotide Polymorphisms, Vitamin D
National Category
Orthopaedics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-344294 (URN)10.1002/jbmr.3389 (DOI)000432006800010 ()29338102 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-08-10Bibliographically approved
Kempen, T. & Melhus, H. (2018). Correspondence: A Trial of Blood-Pressure Reduction in Black Barbershops [Letter to the editor]. New England Journal of Medicine, 379(2), 199-199
Open this publication in new window or tab >>Correspondence: A Trial of Blood-Pressure Reduction in Black Barbershops
2018 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 2, p. 199-199Article in journal, Letter (Other academic) Published
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-365261 (URN)10.1056/NEJMc1806026 (DOI)000438249800020 ()29998726 (PubMedID)
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Michaëlsson, K., Wolk, A., Warensjö, E., Melhus, H. & Byberg, L. (2018). Intake of milk or fermented milk combined with fruit and vegetable consumption in relation to hip fracture rates: A cohort study of Swedish women.. Journal of Bone and Mineral Research, 33(3), 449-457
Open this publication in new window or tab >>Intake of milk or fermented milk combined with fruit and vegetable consumption in relation to hip fracture rates: A cohort study of Swedish women.
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2018 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 3, p. 449-457Article in journal (Refereed) Published
Abstract [en]

Milk products may differ in pro-oxidant properties and their effects on fracture risk could potentially be modified by the intake of foods with antioxidant activity. In the population-based Swedish Mammography Cohort study, we aimed to determine how milk and fermented milk combined with fruit and vegetable consumption are associated with hip fracture. Women born 1914-1948 (n=61 240) answered food frequency and lifestyle questionnaires in 1987-1990 and 38 071 women contributed with updated information in 1997. During a mean follow-up of 22 years, 5827 women had a hip fracture (ascertained via official register data). Compared with a low intake of milk (<1 glass/day) and a high intake of fruits and vegetables (≥5 servings/day), a high intake of milk (≥3 glasses/day) with a concomitant low intake of fruits and vegetables (<2 servings/day) resulted in a HR of 2.49 (95% CI, 2.03-3.05). This higher hip fracture rate among high consumers of milk was only modestly attenuated with a concomitant high consumption of fruit and vegetables (HR 2.14; 95% CI 1.69-2.71). The combination of fruits and vegetables with fermented milk (yogurt or soured milk) yielded a different pattern with lowest rates of hip fracture in high consumers: HR 0.81 (95% CI, 0.68-0.97) for ≥2 servings/day of fermented milk and ≥5 servings/day of fruits and vegetables compared with low consumption of both fruit and vegetables and fermented milk. We conclude that the amount and type of dairy products as well as fruit and vegetable intake are differentially associated with hip fracture rates in women.

Keywords
dairy, fruit, hip fracture, milk, vegetables
National Category
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-334436 (URN)10.1002/jbmr.3324 (DOI)000426731100011 ()29083056 (PubMedID)
Funder
Swedish Research Council, 2011-2427
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-08-24Bibliographically approved
Kaluza, J., Harris, H., Melhus, H., Michaëlsson, K. & Wolk, A. (2018). Questionnaire-Based Anti-Inflammatory Diet Index as a Predictor of Low-Grade Systemic Inflammation.. Antioxidants and Redox Signaling, 28(1), 78-84
Open this publication in new window or tab >>Questionnaire-Based Anti-Inflammatory Diet Index as a Predictor of Low-Grade Systemic Inflammation.
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2018 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 28, no 1, p. 78-84Article in journal (Refereed) Published
Abstract [en]

There is accumulating evidence that diet may be associated with markers of inflammation. We have evaluated if an empirically developed questionnaire-based Anti-Inflammatory Diet Index (AIDI) may predict low-grade systemic chronic inflammation in a Nordic population. The AIDI was developed using a 123-item food frequency questionnaire among 3503 women (56-74 years old) with high-sensitivity C-reactive protein (hsCRP) plasma concentration <20 mg/L. Using Spearman correlations, we identified 20 foods (AIDI-20) statistically significantly related to hsCRP. The median (range) of AIDI-20 was 8 (0-17) scores, and the median concentration of hsCRP in the lowest versus the highest quintile of AIDI-20 (≤6 vs. ≥11 scores) varied by 80% (1.8 vs. 1.0 mg/L, respectively). In a multivariable-adjusted linear regression model, women in the highest quintile of AIDI-20 compared with those in the lowest had a 26% (95% confidence interval [CI] 18-33%; p-trend <0.001) lower hsCRP concentration; each 1-score increment in the AIDI-20 was associated with a 0.06 (95% CI 0.04-0.08) mg/L lower hsCRP. The observed association between the AIDI-20 and hsCRP was robust by all hsCRP levels and in subgroups defined by inflammatory-related factors. Our results lead to the hypothesis that the empirically developed questionnaire-based dietary anti-inflammatory index may predict low-grade systemic inflammation. Antioxid. Redox Signal. 28, 78-84.

Keywords
C-reactive protein, anti-inflammatory index, diet, food, inflammation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-337200 (URN)10.1089/ars.2017.7330 (DOI)000415967200006 ()28877589 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2015-00778Swedish Research Council, 2015-05997Swedish Research Council Formas, FR 2016/0004
Available from: 2017-12-21 Created: 2017-12-21 Last updated: 2018-01-17Bibliographically approved
Michaëlsson, K., Melhus, H. & Larsson, S. C. (2018). Serum 25-Hydroxyvitamin D Concentrations and Major Depression: A Mendelian Randomization Study. Nutrients, 10(12), Article ID 1987.
Open this publication in new window or tab >>Serum 25-Hydroxyvitamin D Concentrations and Major Depression: A Mendelian Randomization Study
2018 (English)In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 10, no 12, article id 1987Article in journal (Refereed) Published
Abstract [en]

Whether vitamin D insufficiency is a contributing cause of depression remains unclear. We assessed whether serum 25-hydroxyvitamin D (S-25OHD) concentrations, the clinical marker of vitamin D status, were associated with major depression using Mendelian randomization. We used summary statistics data for six single-nucleotide polymorphisms significantly associated with S-25OHD concentrations in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) consortium and the corresponding data for major depression (n = 59,851 cases and 113,154 controls) from the Psychiatric Genomics Consortium. Genetically predicted S-25OHD concentrations were not associated with major depression. The odds ratio per genetically predicted one standard deviation decrease in S-25OHD concentrations was 1.02 (95% confidence interval 0.97-1.08; p = 0.44). The results of this study indicate that genetically lowered S-25OHD concentrations are not associated with increased risk of developing major depression.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
depression, Mendelian randomization, single nucleotide polymorphisms, vitamin D
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-375576 (URN)10.3390/nu10121987 (DOI)000455073200168 ()30558284 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically approved
Lind, T., Lind, P. M., Hu, L. & Melhus, H. (2018). Studies of indirect and direct effects of hypervitaminosis A on rat bone by comparing free access to food and pair-feeding.. Upsala Journal of Medical Sciences, 123(2), 82-85
Open this publication in new window or tab >>Studies of indirect and direct effects of hypervitaminosis A on rat bone by comparing free access to food and pair-feeding.
2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 2, p. 82-85Article in journal (Refereed) Published
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.

Keywords
Bone, bone turnover serum biomarkers, pQCT, pair-fed, rat, vitamin A
National Category
Nutrition and Dietetics General Practice
Identifiers
urn:nbn:se:uu:diva-351381 (URN)10.1080/03009734.2018.1448020 (DOI)000438159000002 ()29697007 (PubMedID)
Available from: 2018-05-24 Created: 2018-05-24 Last updated: 2018-09-14Bibliographically approved
Mitchell, A., Fall, T., Melhus, H., Wolk, A., Michaëlsson, K. & Byberg, L. (2018). Type 2 Diabetes in Relation to Hip Bone Density, Area, and Bone Turnover in Swedish Men and Women: A Cross-Sectional Study. Calcified Tissue International, 103(5), 501-511
Open this publication in new window or tab >>Type 2 Diabetes in Relation to Hip Bone Density, Area, and Bone Turnover in Swedish Men and Women: A Cross-Sectional Study
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2018 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 103, no 5, p. 501-511Article in journal (Refereed) Published
Abstract [en]

Men and women with type 2 diabetes mellitus (T2DM) have higher risk of hip fracture, but the mechanisms are not fully understood. We aimed to investigate how T2DM, glucose, and insulin were associated with femoral bone mineral density (BMD), bone mineral area (BMA), and bone turnover markers. We used two cross-sectional cohorts: the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 452, mean age 82 years) and the Swedish Mammography Cohort Clinical (SMCC, n = 4713, mean age 68 years). We identified men and women with normal fasting glucose (NFG), impaired fasting plasma glucose (IFG), and T2DM. BMD and BMA at the total hip and femoral shaft were measured using dual energy X-ray absorptiometry (DXA). Bone turnover markers; CrossLaps and osteocalcin were measured in women. Linear regression models were applied. Men and women showed a progressively higher BMD following the clinical cutoffs of fasting glucose from NFG to IFG to T2DM. In contrast, there was a progressively lower BMA. Men and women with T2DM, compared to those with NFG, had lower BMA at the total hip (- 1.7%; 95% CI - 3.2, - 0.2 and - 1.0%; 95% CI - 1.6, - 0.4) and the femoral shaft (- 2.0%; 95% CI - 3.5, - 0.4 and - 0.6%; 95% CI - 1.2, - 0.01), respectively. T2DM was associated with lower concentrations of CrossLaps (- 8.1%; 95% CI - 12.7, - 3.6) and osteocalcin (- 15.2%; 95% CI - 19.0, - 11.2). These cross-sectional results indicate that those with T2DM have smaller bone area and lower bone turnover, which could increase the risk of hip fracture.

Keywords
Bone mineral area, Bone turnover markers, Glucose, Insulin, Type 2 diabetes mellitus
National Category
Public Health, Global Health, Social Medicine and Epidemiology Orthopaedics
Identifiers
urn:nbn:se:uu:diva-366085 (URN)10.1007/s00223-018-0446-9 (DOI)000447965400005 ()29946974 (PubMedID)
Available from: 2018-11-16 Created: 2018-11-16 Last updated: 2019-01-08Bibliographically approved
Lind, T., Öhman, C., Calounova, G., Rasmusson, A., Andersson, G., Pejler, G. & Melhus, H. (2017). Excessive dietary intake of vitamin A reduces skull bone thickness in mice. PLoS ONE, 12(4), Article ID e0176217.
Open this publication in new window or tab >>Excessive dietary intake of vitamin A reduces skull bone thickness in mice
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0176217Article in journal (Refereed) Published
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.

National Category
Clinical Medicine Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-322801 (URN)10.1371/journal.pone.0176217 (DOI)000399875900119 ()28426756 (PubMedID)
Available from: 2017-09-12 Created: 2017-09-12 Last updated: 2017-11-29Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-6857-5973

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