| 1. |
- Karasik, D., et al.
(författare)
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Disentangling the genetics of lean mass
- 2019
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 109:2, s. 276-287
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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| 2. |
- Zillikens, M. C., et al.
(författare)
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Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
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| 3. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 4. |
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| 5. |
- Jiang, X., et al.
(författare)
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Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7x10(-9) at rs8018720 in SEC23A, and P = 1.9x10(-14) at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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| 6. |
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| 7. |
- Holvik, K, et al.
(författare)
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Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture : A NOREPOS study
- 2014
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 25:11, s. 2545-2554
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the risk of hip fracture according to circulating alpha-tocopherol, a plant-derived substance with antioxidant properties, in community-dwelling older Norwegians. We found a linear increasing risk of hip fracture with lower serum alpha-tocopherol concentrations, with a 51 % higher risk in the lowest compared to the highest quartile.INTRODUCTION:Oxidative stress is a suggested contributing cause of osteoporosis and fractures. Vitamin E (α-tocopherol) has potent antioxidant properties in humans. The relationship between circulating α-tocopherol and fracture risk is not established. The aim of this study was to investigate the association between serum α-tocopherol concentrations and risk of hip fracture during up to 11 years of follow-up.METHODS:We performed a case-cohort analysis among 21,774 men and women aged 65-79 years who participated in four community-based health studies in Norway 1994-2001. Serum α-tocopherol concentrations at baseline were determined in 1,168 men and women who subsequently suffered hip fractures (median follow-up 8.2 years) and in a random sample (n = 1,434) from the same cohort. Cox proportional hazard regression adapted for gender-stratified case-cohort data was performed.RESULTS:Median (25, 75 percentile) serum α-tocopherol was 30.0 (22.6, 38.3) μmol/L, and it showed a linear inverse association with hip fracture: hazard ratio (HR) 1.11 (95 % confidence interval (CI) 1.04-1.20) per 10-μmol/L decrease in serum α-tocopherol, adjusted for gender and study center. The lowest compared to the highest quartile conferred an HR of 1.51 (95 % CI 1.17-1.95), adjusted for gender and study center. Adjustment for smoking, month of blood sample, BMI, education, physical inactivity, self-rated health, and serum 25-hydroxyvitamin D (25(OH)D) yielded similar results. Taking serum total cholesterol concentration into account attenuated the association somewhat: HR of hip fracture was 1.37 (95 % CI 1.05-1.77) in first versus fourth quartile of serum α-tocopherol/total cholesterol ratio.CONCLUSIONS:Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegians.
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| 8. |
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| 9. |
- Vimaleswaran, Karani S, et al.
(författare)
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Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
- 2014
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Ingår i: The lancet. Diabetes & endocrinology. - 2213-8595 .- 2213-8587. ; 2:9, s. 719-29
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Tidskriftsartikel (refereegranskat)abstract
- Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97–0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96–0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
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| 11. |
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| 12. |
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| 13. |
- Benetou, V., et al.
(författare)
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Mediterranean diet and hip fracture incidence among older adults : the CHANCES project
- 2018
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Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 29:7, s. 1591-1599
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Tidskriftsartikel (refereegranskat)abstract
- The association between adherence to Mediterranean diet (MD) and hip fracture incidence is not yet established. In a diverse population of elderly, increased adherence to MD was associated with lower hip fracture incidence. Except preventing major chronic diseases, adhering to MD might have additional benefits in lowering hip fracture risk.INTRODUCTION: Hip fractures constitute a major public health problem among older adults. Latest evidence links adherence to Mediterranean diet (MD) with reduced hip fracture risk, but still more research is needed to elucidate this relationship. The potential association of adherence to MD with hip fracture incidence was explored among older adults.METHODS: A total of 140,775 adults (116,176 women, 24,599 men) 60 years and older, from five cohorts from Europe and the USA, were followed-up for 1,896,219 person-years experiencing 5454 hip fractures. Diet was assessed at baseline by validated, cohort-specific, food-frequency questionnaires, and hip fractures were ascertained through patient registers or telephone interviews/questionnaires. Adherence to MD was evaluated by a scoring system on a 10-point scale modified to be applied also to non-Mediterranean populations. In order to evaluate the association between MD and hip fracture incidence, cohort-specific hazard ratios (HR), adjusted for potential confounders, were estimated using Cox proportional-hazards regression and pooled estimates were subsequently derived implementing random-effects meta-analysis.RESULTS: A two-point increase in the score was associated with a significant 4% decrease in hip fracture risk (pooled adjusted HR 0.96; 95% confidence interval (95% CI) 0.92-0.99, pheterogeneity = 0.446). In categorical analyses, hip fracture risk was lower among men and women with moderate (HR 0.93; 95% CI 0.87-0.99) and high (HR 0.94; 95% CI 0.87-1.01) adherence to the score compared with those with low adherence.CONCLUSIONS: In this large sample of older adults from Europe and the USA, increased adherence to MD was associated with lower hip fracture incidence.
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| 14. |
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| 15. |
- Byberg, Liisa, et al.
(författare)
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Total mortality after changes in leisure time physical activity in 50 year old men : 35 year follow-up of population based cohort
- 2009
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Ingår i: The BMJ. - : BMJ. - 1756-1833 .- 0959-8138 .- 1468-5833. ; 43:7, s. 482-
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine how change in level of physical activity after middle age influences mortality and to compare it with the effect of smoking cessation. DESIGN: Population based cohort study with follow-up over 35 years. SETTING: Municipality of Uppsala, Sweden. PARTICIPANTS: 2205 men aged 50 in 1970-3 who were re-examined at ages 60, 70, 77, and 82 years. MAIN OUTCOME MEASURE: Total (all cause) mortality. RESULTS: The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking). CONCLUSIONS: Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation.
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| 16. |
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| 17. |
- Farahmand, Bahman Y., et al.
(författare)
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Socioeconomic status, marital status and hip fracture risk : a population-based case-control study
- 2000
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 11:9, s. 803-8
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Tidskriftsartikel (refereegranskat)abstract
- Socioeconomic status and social support have been identified as important determinants of several diseases and overall mortality, but these factors have not been adequately examined in relation to hip fracture risk. The aim of this study was to determine the relationship of socioeconomic status and marital status to hip fracture risk. We used data from a population-based case-control study in postmenopausal women aged 50-81 years during 1993-1995 who resided in six counties in Sweden. The analysis was based on 1327 incident cases of hip fracture and 3262 randomly selected controls. Socioeconomic and marital status were obtained by record linkage with census data in 1960, 1970, 1980 and 1990. Information on other possible risk factors for hip fracture was collected by a mailed questionnaire. Women who were gainfully employed in 1990 had an odds ratio (OR) of 0.74 [95% confidence interval (CI) 0.56-0.96] compared with those not gainfully employed; those in the highest tertile of household income had an OR of 0.74 (95% CI 0.60-0.90) compared with those in the lowest tertile of income. Women who lived in a one-family house had an OR of 0.85 (95% CI 0.72-0.99) compared with those living in an apartment. Divorced, widowed or unmarried women had a higher risk of hip fracture than married or cohabiting women; the OR was 1.40 (95% CI 1.06-1.85). Married women who were both gainfully employed and were living in a one-family house had a substantially decreased risk of hip fracture compared with unemployed women living without a partner in an apartment (OR 0.39; 95% CI 0.22-0.71). Occupational affiliation among women ever employed, and educational level, were not associated with hip fracture risk. We conclude that employment, household income, type of housing and marital status seem to be risk indicators of hip fracture risk independent of known osteoporotic risk factors.
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| 24. |
- Larsson, S. C., et al.
(författare)
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Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study
- 2019
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Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 92:9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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| 25. |
- Levin, G. P., et al.
(författare)
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Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes
- 2012
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 308:18, s. 1898-1905
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Tidskriftsartikel (refereegranskat)abstract
- Context Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.Objective To investigate whether common variation within genes encoding the vitamin D–binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.Design, Setting, and Participants Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.Main Outcome Measure Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.Results Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.Conclusion Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.
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