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  • 1.
    Andersson, Kristofer
    et al.
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Huddinge, Sweden..
    Dahllöf, Goran
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Huddinge, Sweden.;Ctr Pediat Oral Hlth Res, Stockholm, Sweden..
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Grigelioniene, Giedre
    Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Åström, Eva
    Karolinska Inst, Dept Woman & Child Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Pediat Neurol & Musculoskeletal Disorders & Home, Stockholm, Sweden..
    Malmgren, Barbro
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Huddinge, Sweden..
    Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta - A retrospective cohort study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176466Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes (COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p. Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p. Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.

  • 2.
    Björk, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Mellström, Dan
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.
    Karlsson, Magnus
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped Surg, Malmo, Sweden.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Haplotypes in the CYP2R1 gene are associated with levels of 25(OH)D and bone mineral density, but not with other markers of bone metabolism (MrOS Sweden)2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209268Article in journal (Refereed)
    Abstract [en]

    Objective: Polymorphisms in the CYP2R1 gene encoding Vitamin D 25-hydroxylase have been reported to correlate with circulating levels of 25-OH vitamin D3 (25(OH)D). It is unknown whether these variations also affect overall bone metabolism. In order to elucidate the overall associations of polymorphisms in the CYP2R1, we studied haplotype tagging single nucleotide polymorphisms (SNPs) in the gene and serum levels of 25(OH)D, calcium, phosphate, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23), as well as bone mineral density (BMD).

    Methods: Baseline data on serum parameters and BMD from MrOS Sweden, a prospective population-based cohort study of elderly men (mean age 75 years, range 69-81), were analyzed. Genotyping was performed for eight SNPs covering the CYP2R1 gene in 2868 men with available samples of DNA. Subjects were followed up concerning incidence of fracture during five years.

    Results: There was a significant genetic association with circulating levels of 25(OH)D (4.6-18.5% difference in mean values between SNP alleles), but there were no correlations with levels of calcium, phosphate, PTH or FGF23 for any genetic variant. No differences were found in fracture incidence between the variants. There was an inverse relationship between lower BMD and concomitant higher 25(OH)D for three of the haplotypes (p < 0.005).

    Conclusions: Common variants in the CYP2R1 gene encoding Vitamin D 25-hydroxylase correlate with levels of circulating 25(OH)D but do not otherwise associate with measures of calcium and phosphate homeostasis. Presence of the specific haplotypes may be an indicator of risk for low 25(OH)D levels, and may in addition be correlated to bone mineral density.

  • 3.
    Björk, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ribom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Scragg, R.
    Univ Auckland, Sch Populat Hlth, Sect Epidemiol & Biostat, Auckland, New Zealand.
    Mellstrom, D.
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin, Geriatr Med,Nutr, Gothenburg, Sweden.
    Grundberg, E.
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
    Ohlsson, C.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.
    Karlsson, M.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped Surg, Malmo, Sweden.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men: Data from MrOS Sweden2019In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 187, p. 160-165Article in journal (Refereed)
    Abstract [en]

    The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.

  • 4.
    Brändström, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gerdhem, P.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Obrant, K. J.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkesson, K.
    Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women2004In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 74, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50-0.64, C1217T P = 0.51-1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61-0.66, C1217T P = 0.14-0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.

  • 5.
    Brändström, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nyström, F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öhman, K. P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Malmqvist, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients: The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA)2004In: Blood Pressure, ISSN 0803-7051, E-ISSN 1651-1999, Vol. 13, no 3, p. 152-157Article in journal (Refereed)
    Abstract [en]

    Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n=24) showed a significantly increased IMT compared to those with the TC (n=52, p=0.007) and TT (n=24, p=0.009) genotype, in the hypertensive group only (mean +/- SD for TT=0.88 +/- 0.21 mm, TC=0.90 +/- 0.16 mm, CC=1.05 +/- 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.

  • 6.
    Brändström, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 293, no 1, p. 13-17Article in journal (Refereed)
    Abstract [en]

    Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and has previously been shown to regulate bone mass by inhibiting osteoclast differentiation and activation. Recent evidence indicates that OPG also plays a role in the vascular system, since ablation of the OPG gene in mice results in calcification of the aorta and renal arteries, and association has been found between serum levels of OPG and cardiovascular mortality. This study presents a novel single nucleotide polymorphism, a T/C transition located 129 bp upstream the TATA-box of the human OPG gene, detected by sequence analysis. The OPG genotype was determined by restriction fragment length polymorphism in a cohort consisting of 59 healthy subjects. The intima-media thickness (IMT) in the common carotid artery and maximal post-ischemic forearm blood flow (FBF) were investigated. Subjects with the CC genotype showed a significantly increased IMT (p<0.05) and a concommitantly reduced maximal FBF (p<0.01) as compared to those with the T allele. Thus, our results show that the polymorphism in the promoter region of OPG is associated with both vascular morphology and function in apparently healthy subjects.

  • 7.
    Bäckström, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Taipalensuu, Jan
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Svensson, Ann-Cathrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genetic variation in the ATP-binding cassette transporter gene ABCG2(BCRP) in a Swedish population2003In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 18, no 5, p. 359-364Article in journal (Refereed)
    Abstract [en]

    The ATP-binding cassette transporter ABCG2 (also named breast cancer resistance protein, BCRP) functions as a drug efflux transporter and is expressed at high levels in the human small intestine. The aim of this study was to screen the human ABCG2 gene for genetic variation. The regions of the gene most likely to affect function, namely the coding parts, exon/intron boundaries, 5' untranslated region and 3' untranslated region and the proposed promoter region, were included in the screening. DNA was obtained from 60 Swedish individuals. The screening was performed using a polymerase chain reaction-denaturing high-performance liquid chromatography approach followed by sequence analysis. Eight sites of genetic variation were identified. The sequence variations considered to be most likely to affect transcription level or transport function were a CTCA deletion in the 5' flanking region, a single nucleotide polymorphism (SNP) in a 5' flanking CpG island, two non-synonymous SNPs, changing valine at amino acid position 12 to methionine and glutamine at position 141 to lysine, respectively. Genotyping of these sequence variations revealed linkage between the CTCA deletion and the SNP changing glutamine 141 for lysine. This information forms the basis for future association studies to investigate the genetic basis of differences of drug disposition due to sequence variation in the ABCG2 gene.

  • 8. Carling, T
    et al.
    Kindmark, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Hellman, P
    Holmberg, L
    Akerström, G
    Rastad, J
    Vitamin D receptor alleles b, a, and T: risk factors for sporadic primary hyperparathyroidism (HPT) but not HPT of uremia or MEN 1.1997In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 231, no 2, p. 329-32Article in journal (Other scientific)
  • 9.
    Clewemar, Pantelis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Hailer, Nils P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hailer, Yasmin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Klar, Joakim
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Stattin, Eva-Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Expanding the phenotypic spectrum of osteogenesis imperfecta type V including heterotopic ossification of muscle origins and attachments2019In: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, Vol. 7, no 7, article id e00723Article in journal (Refereed)
    Abstract [en]

    Background

    Osteogenesis imperfecta (OI) is a clinical and genetic heterogeneous group of connective tissue disorders, characterized by bone fragility and a propensity to fracture.

    Methods

    In this report we describe the clinical phenotype of two patients, a 28‐year‐old woman and her mother (54 years old), both with a history of short stature and multiple fractures.

    Results

    Exome sequencing revealed the recurring IFITM5:c.‐14 C>T variant causing OI type V. Both patients had several fractures during childhood. CT‐scan and scintigraphy showed ossification of the origin and attachment of muscles and hypertrophic callus formation.

    Conclusion

    Ossification of the origin and attachment of muscles seems to be part of the phenotype in patients with OI type V.

  • 10.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jacobson, Annica
    Rorsman, Fredrik
    Artursson, Per
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Anders
    Differential expression of ABC transporters in colonic and rectal mucosa during active and inactive phases of ulcerative colitisManuscript (Other academic)
  • 11.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1)2007In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 13, no 3, p. 291-297Article in journal (Refereed)
    Abstract [en]

    Background: Efflux transport proteins are important components of the intestinal barrier against bacterial toxins, carcinogens, and drugs. This investigation was conducted to determine the expression of Breast Cancer Resistance Protein (BCRP/ABCG2), P-glycoprotein (Pgp/MDR1/ABCB1), and Multidrug Resistance Protein 2 (MRP2/ABCC2) in the gut mucosa of patients with ulcerative colitis (UC). Methods: Patients were thoroughly diagnosed according to well-established clinical, endoscopic, and histologic criteria to be included in the group of patients with active UC (n = 16) or UC in remission (n = 17). Colonic and rectal mucosa from patients with UC were compared with tissues from control subjects (n = 15). The mRNA expression (TaqMan) of the efflux transporters and the proinflammatory cytokines interleukin (IL)-1β and IL-6 was determined. Western blot was used in the analysis of protein expression and the tissue localization of BCRP was determined with confocal microscopy. Results: BCRP and Pgp expression was strongly reduced in individuals with active inflammation compared with controls and was negatively correlated with the levels of IL-6 mRNA. The BCRP staining of colonic epithelium seen in healthy mucosa was diminished in inflamed tissues, with concurrent disruption of epithelial F-actin structure. Conclusions: Two of the efflux transporters of importance for the barrier function of the gut mucosa, Pgp and BCRP, are expressed at strongly reduced levels during active inflammation in patients with UC. Investigations are warranted to determine whether the low levels of efflux transporters during active UC contribute to altered transport and tissue exposure of carcinogens, bacterial toxins, and drugs.

  • 12.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lazorova, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gråsjö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional levels of drug transporters along the human intestinal tract: Co-expression of ABC and SLC transporters and comparison with Caco-2 cells2006In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 29, no 3-4, p. 269-277Article in journal (Refereed)
    Abstract [en]

    A vast number of drugs are subjected to active or facilitated transport and multiple transport mechanism may contribute to the net flux during drug absorption. The main objective of this study was to quantify the regional mRNA expression and determine the co-expression of drug transporters from the ABC (Pgp, BCRP, MRP2, MRP3) and SLC (PEPT1, MCT1, OATPB, OCTN2, OCT1) families along the human intestine (duodenum, jejunum, ileum, and colon). A second objective was to compare the transporter expression between the different intestinal regions and Caco-2 cells. Eight out of nine of the investigated transporters exhibited significant regional differences in expression. OATPB was the only transporter that did not show a region-dependency in the expression along the human intestinal canal. The expression of Pgp, BCRP, OCTN2 and MCT1 differed along the small intestine, but the expression differences were greater than five-fold only for Pgp. The rank order of transcript prevalence was identical in the ileum and the jejunum. Between the ileum and colon, seven transcripts were differentially expressed, and MCT1, OCTN2 and MRP3 were expressed at higher levels in the colon than in the small intestine. The expression of transporters in Caco-2 was closest to the expression pattern in the small intestine, although the expression of OATPB, BCRP and MRP2 differed more than five-fold between the Caco-2 cells and ileum. In conclusion, this study provides quantitative data on the expression of transporters from the ABC and SLC families along the human intestine, which can be useful in the interpretation of clinical studies where more than one intestinal transporter contribute to the net transport and in the computer modelling of drug absorption.

  • 13.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lazorova, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gråsjö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    mRNA expression of drug-transporting proteins along the human intestine and comparison with expression in Caco-2 cells2012Article in journal (Refereed)
  • 14. Felsenberg, Dieter
    et al.
    Beller, Gisela
    Fiore, Carmelo
    Lyritis, George
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Boerst, Hendrikje
    Bock, Oliver
    Hartard, Manfred
    Runge, Martin
    Brandi, Maria Luisa
    Sergi, Giuseppe
    Bergström, Ingrid
    Beneficial effects of strontium ranelate compared to alendronate on bone mass and strength parameters at the tibia in postmenopausal osteoporotic women: A 2-year study2012In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 23, no S2, p. S113-S114Article in journal (Other academic)
  • 15. Figtree, G. A.
    et al.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grundberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Speller, B.
    Robinson, B.G.
    Channon, K.M.
    Watkins, H.
    Novel estrogen receptor alpha promoter polymorphism increases ventricular hypertrophic response to hypertension2007In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 103, no 2, p. 110-118Article in journal (Refereed)
    Abstract [en]

    Given the strong genetic contribution to blood pressure and left ventricular hypertrophy (LVH), and the influence of estrogen on these parameters, we hypothesized that polymorphisms in the estrogen receptor alpha (ERα) promoter may influence LVH. Three novel polymorphisms were identified upstream of the ERα alternatively spliced exon 1E, within sequence which demonstrated significant promoter activity in vitro. Demonstration of ERα E isoform expression in human ventricle by RT-PCR supported a possible functional role for the 1E novel polymorphisms in estrogen signaling in the heart. Indeed, G > A (-721 E) was significantly associated with LVH after controlling for systolic blood pressure and sex in a healthy population (n = 74), contributing to 23% of interventricular septum (IVS) width variance (p < 0.001) and 9.4% of left ventricular mass index (LVMI) variance (p = 0.035). In a separate hypertensive cohort, male carriers of the A allele (n = 8) had a 17% increase in IVS (95% CI: 6-28%) and a 19% increase in LVMI (3-34%) compared to GG homozygotes (n = 84). We conclude that a novel polymorphism in the promoter of a cardiac mRNA splice isoform of ERα is associated with LVH.

  • 16. Gerdhem, P.
    et al.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Obrant, K.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkesson, K.
    Association of the collagen type 1 (COL1A 1) Sp1 binding site polymorphism to femoral neck bone mineral density and wrist fracture in 1044 elderly Swedish women2004In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 74, no 3, p. 264-269Article in journal (Refereed)
    Abstract [en]

    Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis and related fragility fractures. A polymorphism of the binding site for the transcription factor Sp1 of the collagen I alpha 1 gene (COLIA1) has shown an association to bone mass and fracture, but the findings have not been consistent, which may be related to population differences. The Sp1 polymorphism was determined in 1044 women, all 75 years old, participating in the population-based Osteoporosis Prospective Risk Assessment study in Malmö (OPRA). Bone mineral density, heel ultrasound and all previous fractures were registered. BMD was 2.7% lower in the femoral neck in women carrying at least one copy of the "s" allele ( P = 0.027). There was no difference in bone mass at any other site, weight, BMI or age at menopause. Women with a prevalent wrist fracture (n = 181) had an increased presence of the "s" allele. The odds ratio for prevalent wrist fracture was 2.73 (95% CI 1.1-6.8) for the ss homozygotes and 1.4 (95% CI 1.0-2.0) for the Ss heterozygotes when compared with the SS homozygotes. In conclusion, in this large and homogeneous cohort of 75-year-old Swedish women, there was an association among the Sp1 COLIA1 polymorphism, bone mass, and fracture. The presence of at least one copy of the "s" allele was associated with lower femoral neck BMD and previous wrist fracture and in addition, it was related to an increased risk for wrist fracture.

  • 17.
    Grundberg, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carling, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Brändström, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Huang, S
    Ribom, E. L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ljunggren, O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Kindmark, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A deletion polymorphism in the RIZ gene, a female sex steroid hormone receptor coactivator, exhibits decreased response to estrogen in vitro and associates with low bone mineral density in young Swedish women2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 12, p. 6173-6178Article in journal (Refereed)
    Abstract [en]

    Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture, and the trait is under genetic control by a large number of genes. It is recognized that estrogen plays an important role in the maintenance of bone mass by binding to estrogen receptor a (ERa). RIZ1 has previously been shown to be a specific ERa coactivator and strongly enhances its function both in vivo and in vitro. We performed in vitro studies comparing the abilities of RIZ1 P704 polymorphic variants (homozygous presence, P704+; absence, P704-; heterozygosity P704+/- of a proline at position 704) to coactivate the ERa and also examined the polymorphism associated to BMD of 343 Swedish women, aged 20-39 yr. The expression vector containing P704- RIZ1 showed an impaired response in coactivating ERa in a ligand- and dose-dependent manner compared with P704+ RIZ (P < 0.0001). The genotype frequencies were 19% (P704+), 32% (P704-), and 49% (P704+/-) and were in Hardy-Weinberg equilibrium. BMD at the heel was higher in the P704+ genotype group than in the P704+/- group (P = 0.02), which was evident also after corrections for fat and lean mass (P = 0.03). We conclude that RIZ1 may be a new candidate gene for involvement in the variation seen in BMD.

  • 18.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lam, Kevin C. L.
    Gurd, Scott
    Ge, Bing
    Harmsen, Eef
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells2008In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 33, no 3, p. 301-11Article in journal (Refereed)
    Abstract [en]

    Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.

  • 19.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ribom, Eva L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women2004In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 150, no 3, p. 323-328Article in journal (Refereed)
    Abstract [en]

    Objective: Bone mineral density (BMD) is under strong genetic control and a number of candidategenes have been associated with BMD. Both muscle strength and body weight are considered to beimportant predictors of BMD but far less is known about the genes affecting muscle strength andfat mass. The purpose of this study was to investigate the poly adenosine (A) repeat and the BsmISNP in the vitamin D receptor (VDR) in relation to muscle strength and body composition in healthywomen.

    Design: A population-based study of 175 healthy women aged 20–39 years was used.

    Methods: The polymorphic regions in the VDR gene (the poly A repeat and the BsmI SNP) were amplifiedby PCR. Body mass measurements (fat mass, lean mass, body weight and body mass index) andmuscle strength (quadriceps, hamstring and grip strength) were evaluated.

    Results: Individuals with shorter poly A repeat, ss and/or absence of the linked BsmI restriction site(BB) have higher hamstring strength (ss vs LL, P ¼ 0.02), body weight (ss vs LL, P ¼ 0.049) andfat mass (ss vs LL, P ¼ 0.04) compared with women with a longer poly A repeat (LL) and/or thepresence of the linked BsmI restriction site (bb).

    Conclusions: Genetic variation in the VDR is correlated with muscle strength, fat mass and bodyweight in premenopausal women. Further functional studies on the poly A microsatellite areneeded to elucidate whether this is the functionally relevant locus or if the polymorphism is in linkagedisequilibrium with a functional variant in a closely situated gene further downstream of the VDR30UTR.

  • 20.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kwan, Tony
    Ge, Bing
    Lam, Kevin C.
    Koka, Vonda
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Dias, Joana
    Verlaan, Dominique J.
    Ouimet, Manon
    Sinnett, Daniel
    Rivadeneira, Fernando
    Estrada, Karol
    Hofman, Albert
    van Meurs, Joyce M.
    Uitterlinden, André
    Beaulieu, Patrick
    Graziani, Alexandru
    Harmsen, Eef
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ohlsson, Claes
    Mellström, Dan
    Karlsson, Magnus K.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Population genomics in a disease targeted primary cell model2009In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, no 11, p. 1942-1952Article in journal (Refereed)
    Abstract [en]

    The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < approximately 10(-3)) were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 x 10(-10) - 7 x 10(-16)) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P(combined) = 5.6 x 10(-5)). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r(2) = 0.5, P = 2.6 x 10(-15)). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

  • 21.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lau, Edith M. C.
    Pastinen, Tomi
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mellström, Dan
    Orwoll, Eric
    Redlund-Johnell, Inga
    Holmberg, Anna
    Gurd, Scott
    Leung, Ping Chung
    Kwok, Timothy
    Ohlsson, Claes
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vitamin D receptor 3' haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: the MrOS Study in Sweden and Hong Kong2007In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 22, no 6, p. 832-840Article in journal (Refereed)
    Abstract [en]

    The VDR is a prime candidate gene for osteoporosis. Here, we studied three common VDR haplotypes in relation to bone phenotypes in 5014 participants of the global MrOS Study. We also studied the relative expression of the haplotypes in human bone cells. One haplotype was associated with increased fracture risk and differently expressed in primary human bone cells. Introduction: Vitamin D plays an essential role in skeletal metabolism by binding to its nuclear steroid receptor, the vitamin D receptor (VDR). The heritability of BMD is well established, and the VDR gene is considered a prime candidate suggested to partially account for genetically controlled BMD variance in the population. Materials and Methods: Here, we reconstructed common haplotypes in the VDR 3′ untranslated region (UTR) and studied the association to BMD and risk of vertebral fractures in elderly men from Sweden (n = 3014) and Hong Kong (n = 2000), all participants of the global MrOS Study. To assess any functional implications of the VDR polymorphisms, we studied allele-specific expressions of the different VDR 3′ UTR haplotypes in the normal chromosomal context of 70 unrelated human trabecular bone samples. This was performed by quantitative genotyping of coding polymorphisms in RNA samples and in corresponding DNA samples isolated from the bone samples. Results: Three major haplotypes were reconstructed and in agreement with the previously well-defined baT, BAt, and bAT haplotypes, herein denoted Hap1, Hap2, and Hap3. The Hap1 haplotype was independently associated with increased risk of vertebral fractures in Swedish men (OR, 1.655; 95% CI, 1.146-2.391; p < 0.01) and with lower lumbar spine BMD in elderly men from Sweden (p < 0.01) and Hong Kong (p < 0.05). The VDR gene was also shown to exhibit a 3′ UTR haplotype dependent allelic imbalance, indicating that the VDR Hap1 allele was overexpressed in human trabecular bone samples. Conclusions: The results indicate that the relatively overexpressed VDR Hap1 haplotype could be considered a risk allele for osteoporosis regardless of ethnicity.

  • 22.
    Grundberg, Elin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Ribom, Eva L
    Department of Surgical Sciences.
    Brändström, Helena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Osten
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Department of Surgical Sciences.
    Kindmark, Andreas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    A TA-repeat polymorphism in the gene for the estrogen receptor alpha does not correlate with muscle strength or body composition in young adult Swedish women.2005In: Maturitas, ISSN 0378-5122, Vol. 50, no 3, p. 153-60Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: There are conflicting data in the literature whether estrogens affect muscle strength. Prospective studies with hormone replacement therapy have not been able to convincingly demonstrate a muscular effect and the putative role of estrogen in the development of lean body mass is not established. Both lean mass and fat mass are known to be under strong genetic control and therefore we have investigated the relation between a TA-repeat in the gene for the estrogen receptor alpha (ERalpha) and muscle strength and body composition. METHODS: 175 healthy Swedish women, aged 20-39 were randomly selected from the population registry and included in the study. Body mass measurements (lean mass, fat mass, body weight and BMI) and muscle strength (quadriceps, hamstring and grip strength) were evaluated. The TA-repeat in the ERalpha gene was amplified by polymerase chain reaction. RESULTS: Alleles with a TA-repeat length of 16 repeats or shorter were denoted short (e), and repeat length of 17 repeats or longer were denoted long (E). Women homozygous for the short and long genotype were denoted ee (31%) and EE (21%), respectively, while heterozygous individuals were denoted Ee (48%). The frequencies were in Hardy-Weinberg equilibrium. No associations were found between ERalpha genotypes and muscle strength or body composition. CONCLUSION: The TA-repeat in the human ERalpha gene does not correlate with muscle strength or body mass measurements, indicating that body composition is not as sensitive to genetic variation in this receptor as other target organs for estrogen.

  • 23.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkesson, Kristina
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gerdhem, Paul
    Holmberg, Anna
    Mellström, Dan
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Orwoll, Eric
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ohlsson, Claes
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The impact of estradiol on bone mineral density is modulated by the specific estrogen receptor-alpha cofactor retinoblastoma-interacting zinc finger protein-1 insertion/deletion polymorphism2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 6, p. 2300-2306Article in journal (Refereed)
    Abstract [en]

    Context: Estrogens regulate bone mass by binding to the estrogen receptor (ER)-α as well as ER-β. The specific ERα cofactor retinoblastoma-interacting zinc finger protein (RIZ)-1 enhances ERα function in the presence of estrogen. Objective: The objective of the study was to determine whether a RIZ P704 insertion (+)/deletion (-) (indel) polymorphism modulates the impact of estradiol on bone mineral density (BMD) and study the association between the polymorphism and BMD in elderly subjects. Design: This was a population-based, prospective, and crosssectional study, the Swedish MrOS Study, and the Malmö OPRA Study, respectively. Setting: The study was conducted at three academic medical centers: Sahlgrenska Academy in Gothenburg, Malmö University Hospital, and Uppsala University Hospital. Participants: In total, 4058 men and women, aged 69-81 yr, were randomly selected from population registries. Main Outcome Measures: BMD(grams per square centimeter) was measured at femoral neck, trochanter, lumbar spine, and total body. Results: The RIZ P704+/+ genotype was associated with low BMD in both women (femoral neck, P < 0.001; trochanter, P < 0.01; lumbar spine, P < 0.05; total body, P < 0.01) and men (lumbar spine, P < 0.05). However, the association between the polymorphism and BMD was dependent on estradiol status. The positive correlation between serum estradiol and BMD was significantly modulated by the genotype with a stronger correlation in the P704+/+ group than the P704-/- group (r = 0.19 vs. r = 0.08, P < 0.05). Conclusions: These large-scale studies of elderly men and women indicate that the ERα cofactor RIZ gene has a prominent effect on BMD, and the P704 genotype modulates the impact of estradiol on BMD. Further studies are required to determine whether this polymorphism modulates the estrogenic response to estradiol treatment.

  • 24.
    Hughes, Derralynn
    et al.
    Royal Free London NHS Fdn Trust, London, England;UCL, London, England.
    Mikosch, Peter
    Landesklinikum Mistelbach, Dept Internal Med 2, Mistelbach, Austria;Med Univ Vienna, Externe Lehre, Vienna, Austria.
    Belmatoug, Nadia
    Univ Hosp Paris Nord Val de Seine, Assistance Publ Hop Paris, Dept Internal Med, Referral Ctr Lysosomal Dis, Clichy, France.
    Carubbi, Francesca
    Univ Modena & Reggio Emilia, NOCSAE Hosp, AOU Modena, Dept Biomed Metab & Neural Sci, Modena, Italy.
    Cox, Timothy M.
    Univ Cambridge, Dept Med, Cambridge, England.
    Goker-Alpan, Ozlem
    Lysosomal Disorders Res & Treatment Unit, Fairfax, VA USA.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Mistry, PramodK
    Yale Univ, Sch Med, Dept Internal Med Digest Dis, New Haven, CT USA.
    Poll, Ludger
    Heinrich Heine Univ Dusseldorf, Practice Radiol & Nucl Med Duisburg Moers, Duisburg, Germany.
    Weinreb, Neal
    Univ Miami, Miller Sch Med, Dept Human Genet, Coral Gables, FL 33124 USA;Univ Miami, Miller Sch Med, Dept Med Hematol, Coral Gables, FL 33124 USA.
    Deegan, Patrick
    Addenbrookes Hosp, Lysosomal Disorders Unit, Box 135,Hills Rd, Cambridge CB2 0QQ, England.
    Gaucher Disease in Bone: From Pathophysiology To Practice2019In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 34, no 6, p. 996-1013Article, review/survey (Refereed)
    Abstract [en]

    Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years' of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X-ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow-up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need.

  • 25. Jensen, Per
    et al.
    Keeling, L.
    Schutz, K.
    Andersson, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mormede, P.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Forkman, B.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ohlsson, C.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Feather pecking in chickens is genetically related to behavioural and developmental traits2005In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 86, no 1-2, p. 52-60Article in journal (Refereed)
    Abstract [en]

    Feather pecking (FP) is a detrimental behaviour in chickens, which is performed by only some individuals in a flock. FP was studied in 54 red junglefowl (ancestor of domestic chickens), 36 White Leghorn laying hens, and 762 birds from an F(2)-intercross between these two lines. From all F(2)-birds, growth and feed consumption were measured. Age at sexual maturity and egg production in females, and corticosterone levels in males were also measured. From 333 F(2)-birds of both sexes, and 20 parental birds, body composition with respect to bone mineral content, muscle and fat was obtained by post-mortem examinations using Dual X-Ray Absorptiometry (DXA). In femurs of the same birds, the bone density and structure were analysed using DXA and Peripheral Quantitative Computerized Tomography (pQCT), and a biomechanical analysis of bone strength was performed. Furthermore, plumage condition was determined in all birds as a measure of being exposed to feather pecking. Using 105 DNA-markers in all F(2)-birds, a genome-wide scan for Quantitative Trait Loci (QTL), associated with the behaviour in the F(2)-generation was performed. FP was at least as frequent in the red junglefowl as in the White Leghorn strain studied here, and significantly more common among females both in the parental strains and in the F(2)-generation. In the F(2)-birds, FP was phenotypically linked to early sexual maturation, fast growth, weak bones, and, in males, also high fat accumulation, indicating that feather peckers have a different resource allocation pattern. Behaviourally, F(2) feather peckers were more active in an open field test, in a novel food/novel object test, and in a restraint test, indicating that feather pecking might be genetically linked to a proactive coping strategy. Only one suggestive QTL with a low explanatory value was found on chromosome 3, showing that many genes, each with a small effect, are probably involved in the causation of feather pecking. There were significant effects of sire and dam on the risk of being a victim of feather pecking, and victims grew faster pre- and post-hatching, had lower corticosterone levels and were less active in a restraint test. Hence, a wide array of behavioural and developmental traits were genetically linked to FP.

  • 26.
    Johansson, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vitaminer är inte alltid nyttigt!2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, no 11, p. 1252-5Article in journal (Other academic)
  • 27.
    Kindmark, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jawaid, A
    Harbron, C G
    Barratt, B J
    Bengtsson, O F
    Andersson, T B
    Carlsson, S
    Cederbrant, K E
    Gibson, N J
    Armstrong, M
    Lagerström-Fermér, M E
    Dellsén, A
    Brown, E M
    Thornton, M
    Dukes, C
    Jenkins, S C
    Firth, M A
    Harrod, G O
    Pinel, T H
    Billing-Clason, S M E
    Cardon, L R
    March, R E
    Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis2008In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 8, no 3, p. 186-195Article in journal (Refereed)
    Abstract [en]

    One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case–control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1*07 and DQA1*02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.

  • 28.
    Kindmark, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Effects of retinoids on bone metabolism and calcium homeostasis2002In: Modern trends in skin pharmacology, Athens: Parissianos Medical Publications , 2002Chapter in book (Other (popular science, discussion, etc.))
  • 29.
    Kindmark, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Petrén-Mallmin, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oral Isotretinoin Therapy in Severe Acne Induces Transient Suppression of Biochemical Markers of Bone Turnover and Calcium Homeostasis1998In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 78, no 4, p. 266-269Article in journal (Refereed)
    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.

  • 30. Kwan, Tony
    et al.
    Grundberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Koka, Vonda
    Ge, Bing
    Lam, Kevin C. L.
    Dias, Christel
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rivadeneira, Fernando
    Estrada, Karol
    van Meurs, Joyce B.
    Uitterlinden, Andre
    Karlsson, Magnus
    Ohlsson, Claes
    Mellström, Dan
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Majewski, Jacek
    Tissue effect on genetic control of transcript isoform variation2009In: PLoS genetics, ISSN 1553-7390, Vol. 5, no 8, p. e1000608-Article in journal (Refereed)
    Abstract [en]

    Current genome-wide association studies (GWAS) are moving towards the use of large cohorts of primary cell lines to study a disease of interest and to assign biological relevance to the genetic signals identified. Here, we use a panel of human osteoblasts (HObs) to carry out a transcriptomic survey, similar to recent studies in lymphoblastoid cell lines (LCLs). The distinct nature of HObs and LCLs is reflected by the preferential grouping of cell type-specific genes within biologically and functionally relevant pathways unique to each tissue type. We performed cis-association analysis with SNP genotypes to identify genetic variations of transcript isoforms, and our analysis indicates that differential expression of transcript isoforms in HObs is also partly controlled by cis-regulatory genetic variants. These isoforms are regulated by genetic variants in both a tissue-specific and tissue-independent fashion, and these associations have been confirmed by RT-PCR validation. Our study suggests that multiple transcript isoforms are often present in both tissues and that genetic control may affect the relative expression of one isoform to another, rather than having an all-or-none effect. Examination of the top SNPs from a GWAS of bone mineral density show overlap with probeset associations observed in this study. The top hit corresponding to the FAM118A gene was tested for association studies in two additional clinical studies, revealing a novel transcript isoform variant. Our approach to examining transcriptome variation in multiple tissue types is useful for detecting the proportion of genetic variation common to different cell types and for the identification of cell-specific isoform variants that may be functionally relevant, an important follow-up step for GWAS.

  • 31.
    Laxman, Navya
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    miR-203 and miR-320 regulate Bone Morphogenetic Protein-2-induced osteoblast differentiation by targeting Distal-less Homeobox 5 (Dlx5)2017In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, no 1, article id E4Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17–24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism.

  • 32.
    Laxman, Navya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Grundberg, Elin
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Global miRNA expression and correlation with mRNA levels in primary human bone cells2015In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 21, no 8, p. 1433-1443Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, alpha 1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

  • 33.
    Laxman, Navya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 84, p. 181-188Article in journal (Refereed)
    Abstract [en]

    We investigated the impact of treatment with parathyroid hormone (PTH) and dexamethasone (DEX) for 2 and 24 h by RNA sequencing of miRNAs in primary human bone (HOB) cells. A total of 207 million reads were obtained, and normalized absolute expression retrieved for 373 most abundant miRNAs. In naive control cells, 7 miRNAs were differentially expressed (FDR < 0.05) between the two time points. Ten miRNAs exhibited differential expression (FDR < 0.05) across two time points and treatments after adjusting for expression in controls and were selected for downstream analyses. Results show significant effects on miRNA expression when comparing PTH with DEX at 2 h with even more pronounced effects at 24 h. Interestingly, several miRNAs exhibiting differences in expression are predicted to target genes involved in bone metabolism e.g. miR-30c2, miR-203 and miR-205 targeting RUNX2, and miR-320 targeting beta-catenin (CTNNB1) mRNA expression. CTNNB1 and RUNX2 levels were decreased after DEX treatment and increased after PTH treatment. Our analysis also identified 2 putative novel miRNAs in PTH and DEX treated cells at 24 h. RNA sequencing showed that PTH and DEX treatment affect miRNA expression in HOB cells and that regulated miRNAs in turn are correlated with expression levels of key genes involved in bone metabolism.

  • 34.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Astrom, Eva
    Karolinska Univ Hosp, Pediat Neurol, Astrid Lindgren Childrens Hosp, Stockholm, Sweden;Karolinska Inst, Dept Woman & Child Hlth, Stockholm, Sweden.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Symoens, Sofie
    Univ Hosp Ghent, Dept Med Genet, Ghent, Belgium.
    Coucke, Paul
    Univ Hosp Ghent, Dept Med Genet, Ghent, Belgium.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Paschalis, Eleftherios
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Roschger, Paul
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Gamsjaeger, Sonja
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Klaushofer, Klaus
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Fratzl-Zelman, Nadja
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy2018In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 114, p. 268-277Article in journal (Refereed)
    Abstract [en]

    Background: Mutations of the endoplasmic reticulum (ER) stress transducer OASIS (encoded by CREB3L1), cause severe recessive osteogenesis imperfecta (OI) not compatible with surviving the neonatal period, as has been shown in two unrelated families through a whole gene deletion vs. a qualitative alteration of OASIS Heterozygous carriers in the described families have exhibited a mild phenotype. OASIS is a transcription factor highly expressed in osteoblasts, and OASIS(-/-) mice exhibit severe osteopenia and spontaneous fractures. Here, we expand the clinical spectrum by a detailed phenotypic characterization of the first case of OASIS-associated OI surviving the neonatal period, with heterozygous family members being unaffected.

    Methods: All OI-associated genes were sequenced. Primary human osteoblast-like cell (hOB) and fibroblast (FB) cultures were obtained for qPCR, and steady-state collagen biochemistry. FB, hOB and skin biopsies were ultrastructurally analyzed. Bone was analyzed by |mu CT, histomorphometry, quantitative backscattered electron imaging (qBEI), and Raman microspectroscopy.

    Results: The proband, a boy with severe OI, had blue sclera and tooth agenesis A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%), however, collagen I levels were only reduced in hOBs (5-10%) Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to lifelong bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures.

    Conclusions: Deficiency of OASIS can cause severe OI compatible with surviving the neonatal period A marked decrease of collagen type I transcription was noted in bone tissue, but not in skin, and ultrastructure of hOBs was pathological. Results also suggested OASIS involvement in glycosaminoglycan secretion in bone.

  • 35.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Astrom, Eva
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grigelioniene, Giedre
    Malmgren, Barbro
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 8, p. 1042-1050Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on 4100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the alpha 1-and alpha 2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the alpha 1-chain were associated with blue sclera (P = 0.0110). Comparing glycine with serine substitutions, alpha 1-alterations were associated with more severe phenotype (P = 0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P < 0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in > 95% of an entire OI population.

  • 36.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Laxman, Navya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Åström, Eva
    Karolinska Institutet.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels: a Novel Therapeutic Approach in Osteogenesis Imperfecta2013In: International Journal of Medical Sciences, ISSN 1449-1907, E-ISSN 1449-1907, Vol. 10, no 10, p. 1333-1343Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta, also known as "brittle bone disease", is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis imperfecta.

  • 37.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Malmgren, B.
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Stockholm, Sweden..
    Grigelioniene, G.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp Stockholm, Dept Clin Genet, Stockholm, Sweden..
    Soderhall, S.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Åstrom, E.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 87, p. 11-18Article in journal (Refereed)
    Abstract [en]

    Background: Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe 01; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated.

    Materials and methods: COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n = 33, type III n = 25 and type IV n = 21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non vertebral and vertebral fractures were collected prior to, and at several time points during treatment.

    Results: An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to A LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p < 0.0003, < 0.0001 and 0.0003 for all 01 types 1, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4 yrs Pamidronate. Twice as many boys as girls with 01 type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p = 0.0236). Greater Delta LS BMD, but smaller Delta fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11 years of age at treatment initiation. (p < 0.0001).

    Conclusion: Pamidronate treatment in children with all types of 01 increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type.

  • 38.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Langdahl, Bente
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapy of Endocrine Disease: Treatment of osteogenesis imperfecta in adults2014In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 171, no 2, p. R79-R90Article, review/survey (Refereed)
    Abstract [en]

    Background: Osteogenesis imperfecta (OI) is a heterogeneous rare connective tissue disorder commonly caused by mutations in the collagen type I genes. Pharmacological treatment has been most extensively studied in children, and there are only few studies comprising adult OI patients. Objectives: i) To review the literature on the current medical management of OI in children and adults, and thereby identify unmet medical needs and ii) to present an overview of possible future treatment options. Results: Individualization and optimization of OI treatment in adults remain a challenge, because available treatments do not target the underlying collagen defect, and available literature gives weak support for treatment decisions for adult patients. Conclusions: Bisphosphonates are still the most widely used pharmacological treatment for adult OI, but the current evidence supporting this is sparse and investigations on indications for choice and duration of treatment are needed.

  • 39.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Astrom, E.
    Malmgren, B.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Genotype-phenotype correlations and pharmacogenetic studies in 140 Swedish families with osteogenesis imperfecta2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, p. S109-S109Article in journal (Other academic)
    Abstract [en]

    Objective: Osteogenesis imperfecta (OI) is a rare heterogeneous disease of connective tissue leading to varying degrees of bone fragility. The worst form (type II) is peri-natally lethal whereas the mildest form (type I) is compatible with a normal life span. Over 1000 mutations causing OI have been described in the genes encoding collagen type I. As COL1A1 and COL1A2 are large genes, there are still many codon positions where no mutations have been reported and only a fraction of theoretically possible glycine substitutions have been described. In this study the spectrum of mutations causing OI in Sweden will be investigated and genotype–phenotype correlations as well as pharmacogenetics will be studied.

    Method: All patients with OI cared for at the Uppsala Osteoporosis Unit (Uppsala University Hospital) or Astrid Lindgren's Paediatric Hospital (Karolinska Institutet, Stockholm) were offered to enter the study. Patients from 140 unrelated families with OI accepted participation; 77 type I, 34 type IV, 20 type III, 5 without previous diagnosis and 4 with unclear OI type. Extensive clinical data is currently being collected on enrolled patients. Exons and flanking intron sequences of COL1A1 and COL1A2 are being sequenced in these families.

    Results: So far 133/140 families have been completely analyzed and in 27 no mutation was found. A total of 120 mutations have been detected, of which 104 are of a typical OI-type. In COL1A1 73 mutations were found and in COL1A2 31 mutations were noted. In 7 families 2 mutations were present, but only one of these was a typical OI-causing mutation. To date 16 amino acid changing mutations that were not of a typical OI-causing type have been noted and the majority of these have an unclear significance. Calculations of delta BMD Z-score response to bisphosphonate treatment did not show a difference in treatment response between groups with different types of OI or between patients with OI type I due to a qualitative vs. a quantitative collagen type I defect.

    Conclusion: The spectrum of mutations causing OI described in this Swedish cohort is of the expected type, with the exception of the amino acid changing mutations. It is notable that in seven families two separate mutations were identified. Calculations do not support a mutation dependent response to bisphosphonate treatment.

  • 40.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Magnus K.
    Holmberg, Anna
    Ohlsson, Claes
    Mellström, Dan
    Orwoll, Eric
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk2009In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 384, no 4, p. 501-505Article in journal (Refereed)
    Abstract [en]

    Genetic variation plays an important role in osteoporosis and a prime candidate gene is Collagen alpha2(I) (COL1A2). A coding polymorphism (rs42524) in COL1A2 has previously been associated with intracranial aneurysms. Here the effects of this polymorphism have been studied in relation to bone mineral density (BMD) and prevalences of stroke and myocardial infarction (MI). rs42524 was genotyped in elderly men (n = 2004) from the Swedish MrOS cohort. Genotypes were analysed for association to BMD and certain health parameters. Significant associations (overall P < 0.05), were observed between rs42524 genotype and BMD at several skeletal sites. Surprisingly, the heterozygote genotype class exhibited lower BMD than either homozygote group. When subjects were classified as heterozygotes or homozygotes, the heterozygous genotype was found to confer a lower BMD at total hip, femoral neck and trochanter Furthermore, the heterozygote genotype had an increased risk of stroke and MI, with population Attributable Risks being 0.12 and 0.08, respectively.

  • 41.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Allele dependent silencing of COL1A2 using small interfering RNAs2008In: International journal of medical sciences, ISSN 1449-1907, Vol. 5, no 6, p. 361-365Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is generally caused by a dominant mutation in Collagen I, encoded by the genes COL1A1 and COL1A2. To date there is no satisfactory therapy for OI, but inactivation of the mutant allele through small interfering RNAs (siRNA) is a promising approach, as siRNAs targeting each allele of a polymorphism could be used for allele-specific silencing irrespective of the location of the actual mutations. In this study we examined the allele dependent effects of several tiled siRNAs targeting a region surrounding an exonic COL1A2 T/C polymorphism (rs1800222) in heterozygous primary human bone cells. Relative abundances of COL1A2 alleles were determined by cDNA sequencing and overall COL1A2 abundance was analyzed by quantitative PCR. One of the siRNAs decreased overall COL1A2 abundance by 71% of which 75% was due to silencing of the targeted T-allele. In conclusion, allele-preferential silencing of Collagen type I genes may be a future therapeutic approach for OI.

  • 42.
    Ljunggren, Östen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Allele-Specific Gene Silencing in Osteogenesis Imperfecta2011In: Cartilage and Bone Development and Its Disorders / [ed] C. Camacho-Hübner, O. Nilsson, L. Sävendahl, 2011, p. 85-90Conference paper (Refereed)
    Abstract [en]

    OI is caused by mutations in the genes encoding for collagen type I COL1A1 and COL1A2, respectively. The patients suffer from bone fragility, and the severity can range from mild, with fractures in the youth, to lethal forms. Today, there is no effective treatment for the disorder. OI is caused by dominant negative mutations. A tempting approach to treat the disease would be to silence the allele carrying the mutation. This could in theory be done with siRNAs. Today, more than 800 various mutations are reported, and to create siRNA against a specific mutation is difficult. Instead, by developing siRNA against common polymorphic variations, it would be possible to silence the mutation by a standardized method regardless where the mutation is located on the allele. If the concept of allele-specific gene silencing by inhibitory RNA directed towards dominant negative mutations could be proven, this might be a novel approach to gene therapy in OI.

  • 43.
    Ljunggren, Östen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Allele-specific gene silencing in osteogenesis imperfecta2011In: Endocrine Development, ISSN 1421-7082, E-ISSN 1662-2979, Vol. 21, p. 85-90Article in journal (Refereed)
    Abstract [en]

    OI is caused by mutations in the genes encoding for collagen type I COL1A1 and COL1A2, respectively. The patients suffer from bone fragility, and the severity can range from mild, with fractures in the youth, to lethal forms. Today, there is no effective treatment for the disorder. OI is caused by dominant negative mutations. A tempting approach to treat the disease would be to silence the allele carrying the mutation. This could in theory be done with siRNAs. Today, more than 800 various mutations are reported, and to create siRNA against a specific mutation is difficult. Instead, by developing siRNA against common polymorphic variations, it would be possible to silence the mutation by a standardized method regardless where the mutation is located on the allele. If the concept of allele-specific gene silencing by inhibitory RNA directed towards dominant negative mutations could be proven, this might be a novel approach to gene therapy in OI.

  • 44.
    Malmgren, B.
    et al.
    Karolinska Inst, Div Pediat Dent, Dept Dent Med, Stockholm, Sweden..
    Andersson, K.
    Karolinska Inst, Div Pediat Dent, Dept Dent Med, Stockholm, Sweden..
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Grigelioniene, G.
    Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Zachariadis, V.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Dahllof, G.
    Karolinska Inst, Div Pediat Dent, Dept Dent Med, Stockholm, Sweden..
    Astrom, E.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Tooth agenesis in osteogenesis imperfecta related to mutations in the collagen type I genes2017In: Oral Diseases, ISSN 1354-523X, E-ISSN 1601-0825, Vol. 23, no 1, p. 42-49Article in journal (Refereed)
    Abstract [en]

    BackgroundOsteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, mainly caused by mutations in the collagen type I genes (COL1A1 and COL1A2). Tooth agenesis is a common feature of OI. We investigated the association between tooth agenesis and collagen type I mutations in individuals with OI. Subjects and methodsIn this cohort study, 128 unrelated individuals with OI were included. Panoramic radiographs were analyzed regarding dentinogenesis imperfecta (DGI) and congenitally missing teeth. The collagen I genes were sequenced in all individuals, and in 25, multiplex ligation-dependent probe amplification was performed. ResultsMutations in the COL1A1 and COL1A2 genes were found in 104 of 128 individuals. Tooth agenesis was diagnosed in 17% (hypodontia 11%, oligodontia 6%) and was more frequent in those with DGI (P=0.016), and in those with OI type III, 47%, compared to those with OI types I, 12% (P=0.003), and IV, 13% (P=0.017). Seventy-five percent of the individuals with oligodontia (6 missing teeth) had qualitative mutations, but there was no association with OI type, gender, or presence of DGI. ConclusionThe prevalence of tooth agenesis is high (17%) in individuals with OI, and OI caused by a qualitative collagen I mutation is associated with oligodontia.

  • 45. McCloskey, Eugene V
    et al.
    Odén, Anders
    Harvey, Nicholas C
    Leslie, William D
    Hans, Didier
    Johansson, Helena
    Barkmann, Reinhard
    Boutroy, Stephanie
    Brown, Jacques
    Chapurlat, Roland
    Elders, Petra Jm
    Fujita, Yuki
    Glüer, Claus-C
    Goltzman, David
    Iki, Masayuki
    Karlsson, Magnus
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kotowicz, Mark
    Kurumatani, Norio
    Kwok, Timothy
    Lamy, Oliver
    Leung, Jason
    Lippuner, Kurt
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lorentzon, Mattias
    Mellström, Dan
    Merlijn, Thomas
    Oei, Ling
    Ohlsson, Claes
    Pasco, Julie A.
    Rivadeneira, Fernando
    Rosengren, Björn
    Sornay-Rendu, Elisabeth
    Szulc, Pawel
    Tamaki, Junko
    Kanis, John A
    A meta-analysis of trabecular bone score in fracture risk prediction and its relationship to FRAX2016In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 31, no 5, p. 940-948Article in journal (Refereed)
    Abstract [en]

    Trabecular bone score (TBS) is a grey-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a BMD-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables and outcomes during follow up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% CI: 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR 1.32, 95%CI: 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95%CI: 1.65, 1.87 vs. 1.70, 95%CI: 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines.

  • 46.
    Mehta, Atul
    et al.
    UCL, Royal Free London NHS Fdn Trust, London, England..
    Panahloo, Zoya
    Shire, Zug, Switzerland..
    Di Rocco, Maja
    Giannina Gaslini Inst, Dept Pediat, Unit Rare Dis, Genoa, Italy..
    Goker-Alpand, Ozlem
    O&O Alpan LLC, Lysosomal Disorders Unit, Fairfax, VA USA.;O&O Alpan LLC, Ctr Clin Trials, Fairfax, VA USA..
    Hughes, Derralynn
    UCL, Royal Free London NHS Fdn Trust, London, England..
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala Univ Hosp, Uppsala, Sweden..
    Kuter, David
    Harvard Med Sch, Massachusetts Gen Hosp, Ctr Hematol, Boston, MA USA..
    Lukina, Elena
    Natl Res Ctr Hematol, Moscow, Russia..
    Nakamura, Kimitoshi
    Kumamoto Univ Hosp, Kumamoto, Japan..
    Oliveri, Beatriz
    UBA, CONICET, INIGEMUBACONICET, Lab Osteoporosis & Enfermedades Metabol Oseas, Buenos Aires, DF, Argentina..
    Perez-Lopez, Jordi
    Hosp Valle De Hebron, Unit Rare Dis, Barcelona, Spain..
    Schwartzk, Ida V. D.
    Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil.;Univ Fed Rio Grande do Sul, Dept Genet, Porto Alegre, RS, Brazil..
    Serratrice, Christine
    Geneva Univ Hosp, Thonex, Switzerland..
    Szer, Jeff
    Royal Melbourne Hosp, Parkville, Vic, Australia..
    Zimran, Ari
    Hebrew Univ Jerusalem, Gaucher Clin, Shaare Zedek Med Ctr, Hadassah Med Sch, Jerusalem, Israel..
    Pastores, Gregory
    Univ Coll Dublin, Dublin, Ireland.;Mater Misericordiae Univ Hosp, Dublin, Ireland..
    Management goals and normalization concept for type 1 Gaucher disease: Results from a survey of expert physicians2018In: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 123, no 2, p. S94-S94Article in journal (Other academic)
  • 47.
    Melhus, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Amér, Stefan
    Wilén, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindh, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vitamin D receptor genotypes in osteoporosis1994In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 344, no 8927, p. 949-950Article in journal (Refereed)
  • 48.
    Melhus, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Wilén, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Cloning of a novel retinoic acid-inducible mRNA from human osteoblast-like cells1997In: Biochemistry and Molecular Biology International, ISSN 1039-9712, Vol. 43, no 5, p. 1145-1150Article in journal (Refereed)
    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.

  • 49.
    Michaëlsson, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Jacobsson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grundberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The positive effect of dietary vitamin D intake on bone mineral density in men is modulated by the polyadenosine repeat polymorphism of the vitamin D receptor2006In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 39, no 6, p. 1343-1351Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Few studies have considered the dietary influence of vitamin D intake on bone mineral density (BMD). Numerous studies have examined the association between VDR polymorphism and BMD, but no previous study has examined the joint influence of dietary vitamin D intake and VDR polymorphism on BMD. METHODS: We therefore conducted a study in 230 men aged 41-76 years of age. BMD was measured with DXA. A second bone scan was performed on average 2.7 years after the first investigation. Dietary habits were assessed by 14 dietary 24-h recall interviews. The polyadenosine (A) VDR genotypes were determined. RESULTS: Dietary vitamin D intake was associated with BMD at all sites, also after multivariate adjustment. Those in the highest quintile of intake had 9% higher femoral neck BMD (p = 0.004), 6% higher BMD at the lumbar spine (p = 0.06) and 5% higher total body BMD (p = 0.003) compared to men in the lowest quintile of dietary vitamin D intake. However, the positive association between vitamin D intake and BMD was especially apparent among those with the L/L polyadenosine (A) VDR genotype explaining between 10 and 15% of the variability in BMD depending on site (p < 0.004). There was furthermore a trend, in the lumbar spine, of less reduction in BMD with increasing vitamin D intake (p = 0.07) but not at the other sites. Calcium intake conferred no association with BMD. CONCLUSIONS: Our results indicate that the extent of positive association between dietary vitamin D intake and BMD in men is dependent on VDR polymorphism, a novel conceivable important gene-environmental interaction.

  • 50.
    Ohlsson, Claes
    et al.
    Univ Gothenburg, Ctr Bone & Arthrit Res, Sahlgrenska Acad, Dept Internal Med & Clin Nutr,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden.
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, Gothenburg, Sweden.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lorentzon, Mattias
    Univ Gothenburg, Ctr Bone & Arthrit Res, Sahlgrenska Acad, Dept Internal Med & Clin Nutr,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, Gothenburg, Sweden.
    Rosengren, Bjorn E.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Lund, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Karlsson, Magnus K.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Lund, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Mellstrom, Dan
    Univ Gothenburg, Ctr Bone & Arthrit Res, Sahlgrenska Acad, Dept Internal Med & Clin Nutr,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, Gothenburg, Sweden.
    Vandenput, Liesbeth
    Univ Gothenburg, Ctr Bone & Arthrit Res, Sahlgrenska Acad, Dept Internal Med & Clin Nutr,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden.
    Low Serum DHEAS Predicts Increased Fracture Risk in Older Men: The MrOS Sweden Study2017In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 32, no 8, p. 1607-1614Article in journal (Refereed)
    Abstract [en]

    The adrenal-derived hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the most abundant circulating hormones and their levels decline substantially with age. DHEAS is considered an inactive precursor, which is converted into androgens and estrogens via local metabolism in peripheral target tissues. The predictive value of serum DHEAS for fracture risk is unknown. The aim of this study was, therefore, to assess the associations between baseline DHEAS levels and incident fractures in a large cohort of older men. Serum DHEAS levels were analyzed with mass spectrometry in the population-based Osteoporotic Fractures in Men study in Sweden (n = 2568, aged 69 to 81 years). Incident X-ray validated fractures (all, n = 594; non-vertebral major osteoporotic, n = 255; hip, n = 175; clinical vertebral, n = 206) were ascertained during a median follow-up of 10.6 years. DHEAS levels were inversely associated with the risk of any fracture (hazard ratio [HR] per SD decrease = 1.14, 95% confidence interval [CI] 1.05-1.24), non-vertebral major osteoporotic fractures (HR = 1.31, 95% CI 1.16-1.48), and hip fractures (HR = 1.18, 95% CI 1.02-1.37) but not clinical vertebral fractures (HR = 1.09, 95% CI 0.95-1.26) in Cox regression models adjusted for age, body mass index (BMI) and prevalent fractures. Further adjustment for traditional risk factors for fracture, bone mineral density (BMD), and/or physical performance variables as well as serum sex steroid levels only slightly attenuated the associations between serum DHEAS and fracture risk. Similarly, the point estimates were only marginally reduced after adjustment for FRAX estimates with BMD. The inverse association between serum DHEAS and all fractures or major osteoporotic fractures was nonlinear, with a substantial increase in fracture risk (all fractures 22%, major osteoporotic fractures 33%) for those participants with serum DHEAS levels below the median (0.60 mg/mL). In conclusion, low serum DHEAS levels are a risk marker of mainly non-vertebral fractures in older men, of whom those with DHEAS levels below 0.60 mg/mL are at highest risk.

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