1.
Jutberger, Hans, et al.
(författare)
Smoking Predicts Incident Fractures in Elderly Men : Mr OS Sweden
2010
Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 25:5, s. 1010-1016
Tidskriftsartikel (refereegranskat) abstract
The aim of the present study was to investigate the association between smoking and BMD, radiographically verified prevalent vertebral fractures and incident fractures in elderly men. At baseline 3003 men, aged 69 - 80 years old from the Swedish Mr Os study, completed a standard questionnaire concerning smoking habits and had BMD of the hip and spine measured using DXA; 1412 men had an X-ray of the thoracic-/lumbar spine. Radiological registers were used to confirm reported new fractures after the baseline visit. At baseline 8.4 % were current smokers. Current smokers had 6.2 % lower BMD at the total hip and 5.4 % at the lumbar spine (p<0.001). Current smoking remained independently, inversely associated with BMD at the hip and lumbar spine after adjusting for age, height, weight, calcium intake, physical activity and centres as co-variates. Prevalent vertebral fractures among current smokers were increased in unadjusted analyses (OR 1.90; 95% CI: 1.26-2.87) and after adjustment for lumbar BMD (OR 1.67; 1.09-2.55). Smokers had a high risk for two or more prevalent vertebral fractures (OR 3.18; 1.88-5.36). During the average follow-up of 3.3 years, 209 men sustained an X-ray verified fracture. Incident fracture risk among smokers was calculated with Cox proportional hazard models. Current smokers had increased risk of all new fractures (HR 1.76; 1.19-2.61), non-vertebral osteoporotic fractures defined as humerus, radius, pelvis and hip fractures (HR 2.14; 1.18-3.88), clinical and X-ray verified vertebral fractures (HR 2.53; 1.37-4.65) as well as of hip fracture (HR 3.16; 1.44-6.95). After adjustment for BMD, including other co-variates, no significant association between smoking and incident fractures was found. Current tobacco smoking in elderly men is associated with low BMD, prevalent vertebral fractures and incident fractures, especially vertebral and hip fractures.
2.
Estrada, Karol, et al.
(författare)
Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
2012
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
Tidskriftsartikel (refereegranskat) abstract
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
3.
Atroshi, Isam, et al.
(författare)
Low calcaneal bone mineral density and the risk of distal forearm fracture in women and men: a population-based case-control study.
2009
Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 45:4, s. 789-93
Tidskriftsartikel (refereegranskat) abstract
OBJECTIVE: We used dual X-ray absorptiometry (DXA) to measure calcaneal bone mineral density (BMD) and estimate the prevalence of osteoporosis in a population with distal forearm fracture and a normative cohort. METHODS: Patients 20 to 80 years of age with distal forearm fracture treated at one emergency hospital during two consecutive years were invited to calcaneal BMD measurement; 270 women (81%) and 64 men (73%) participated. A DXA heel scanner estimated BMD (g/cm(2)) and T-scores. Osteoporosis was defined as T-score< or =-2.5 SD. Of the fracture cohort, 254 women aged 40-80 years and 27 men aged 60-80 years were compared with population-based control cohorts comprising 171 women in the age groups 50, 60, 70 and 80 years and 75 men in the age groups 60, 70, and 80 years. RESULTS: In the fracture population no woman below 40 years or man below 60 years of age had osteoporosis. In women aged 40-80 years the prevalence of osteoporosis in the distal forearm fracture cohort was 34% and in the population-based controls was 25%; the age-adjusted prevalence ratio (PR) was 1.32 (95% CI 1.00-1.76). In the subgroup of women aged 60-80 years the age-adjusted prevalence ratio of osteoporosis was 1.28 (95% CI 0.95-1.71). In men aged 60-80 years the prevalence of osteoporosis in the fracture cohort was 44% and in the population-based controls was 8% (PR 6.31, 95% CI 2.78-14.4). The age-adjusted odds ratio for fracture associated with a 1-SD reduction in calcaneal BMD was in women aged 40-80 years 1.4 (95% CI 1.1-1.8), in the subgroup of women aged 60-80 years 1.2 (95% CI 0.95-1.6), and in men aged 60-80 years 2.6 (95% CI 1.7-4.1). Among those aged 60-80 years the area under the ROC curve was in women 0.56 (95% CI 0.49-0.63) and in men 0.80 (95% CI 0.70-0.80). CONCLUSIONS: The age-adjusted prevalence of osteoporosis based on calcaneal BMD is higher in individuals with distal forearm fracture than in population-based controls. BMD impairment is associated with increased odds ratio for forearm fracture in both women and men but the differences between cases and controls are more pronounced in men than in women, which may have implications in fracture prevention.
4.
Kwan, Tony, et al.
(författare)
Tissue effect on genetic control of transcript isoform variation.
2009
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 5:8
Tidskriftsartikel (refereegranskat) abstract
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.
5.
Lindahl, Katarina, et al.
(författare)
Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk.
2009
Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 384:4, s. 501-5
Tidskriftsartikel (refereegranskat) abstract
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.
6.
Vandenput, Liesbeth, 1974, et al.
(författare)
Androgens and Glucuronidated Androgen Metabolites are Associated with Metabolic Risk Factors in Men.
2007
Ingår i: Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:11, s. 4130-7
Tidskriftsartikel (refereegranskat) abstract
Context: Androgens are associated with metabolic risk factors in men. However, the independent impact of androgens and androgen metabolites on metabolic risk factors in men is unclear. Objective: Our objective was to determine the predictive value of serum levels of androgens and glucuronidated androgen metabolites for metabolic risk factors. Design and Study Subjects: We conducted a population-based study of two Swedish cohorts (1068 young adult and 1001 elderly men). Main Outcome Measures: We measured correlation of serum dihydrotestosterone (DHT), testosterone (T) and glucuronidated androgen metabolites with fat mass, fat distribution, serum lipids and insulin resistance. Results: Both DHT and T were negatively associated with different measures of fat mass in both cohorts (P<0.001). Further statistical analysis indicated that DHT, but not T, was independently negatively associated with different measures of fat mass and insulin resistance (P<0.001). The glucuronidated androgen metabolite androstane-3alpha,17beta-diol-17glucuronide (17G) was independently positively associated with fat mass (P<0.001). Most importantly, the 17G/DHT ratio was strongly correlated, not only with fat mass, but also with central fat distribution, intra-hepatic fat, disturbed lipid profile, insulin resistance and diabetes, explaining a substantial part of the total variance in total body fat (12% in young adult men, 15% in elderly men), the HOMA index (10%) and HDL cholesterol (7%). Conclusion: Our findings demonstrate that 17-glucuronidation of the DHT metabolite androstane-3alpha,17beta-diol is strongly associated with several metabolic risk factors in men. Future longitudinal studies are required to determine the possible impact of the 17G/DHT ratio as a metabolic risk factor in men.
7.
Björk, Anne, et al.
(författare)
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 Sweden
2019
Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 187, s. 160-165
Tidskriftsartikel (refereegranskat) abstract
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.
8.
Björk, Anne, et al.
(författare)
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)
2018
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
Tidskriftsartikel (refereegranskat) abstract
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.
9.
Paternoster, Lavinia, et al.
(författare)
Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
2013
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 9:2
Tidskriftsartikel (refereegranskat) abstract
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10⁻¹⁴; LOC285735, rs271170, p = 2.7×10⁻¹²; OPG, rs7839059, p = 1.2×10⁻¹⁰; and ESR1/C6orf97, rs6909279, p = 1.1×10⁻⁹). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10⁻⁹). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
10.
Movérare-Skrtic, Sofia, et al.
(författare)
Serum insulin-like growth factor-I concentration is associated with leukocyte telomere length in a population-based cohort of elderly men.
2009
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:12, s. 5078-84
Tidskriftsartikel (refereegranskat) abstract
CONTEXT: Both leukocyte telomere length and IGF-I are associated with the aging process. A previous in vitro study suggested that IGF-I may modulate telomerase activity in white blood cells, but little is known whether these two systems interact in vivo. PATIENTS AND METHODS: Leukocyte telomere length was determined using a quantitative PCR assay in 2744 elderly men (mean age 75.5 yr, range 69-81 yr) included in the population-based Osteoporotic Fractures in Men-Sweden study. Serum IGF-I concentration was measured using RIA. RESULTS: Subjects with a leukocyte telomere length in the lowest tertile group had lower serum IGF-I concentration than subjects in the two tertile groups with longer telomere lengths (P = 0.005). Logistic regression analyses showed that a higher serum IGF-I concentration was associated with a significantly reduced risk of having a leukocyte telomere length in the lowest tertile group and also after adjustment for multiple covariates (P < 0.01). Multivariate linear regression analyses demonstrated that tertile of leukocyte telomere length was positively, whereas age was negatively, associated with serum IGF-I concentration in elderly men. CONCLUSIONS: In this large population-based, cross-sectional study, leukocyte telomere length was positively associated with serum IGF-I concentration in elderly men. The mechanisms underlying the association between serum IGF-I concentration and leukocyte telomere length remain to be determined.
