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- Robinson-Cohen, Cassianne, et al.
(author)
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Genetic Variants Associated with Circulating Parathyroid Hormone.
- 2017
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In: Journal of the American Society of Nephrology : JASN. - 1533-3450. ; 28:5, s. 1553-1565
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Journal article (peer-reviewed)abstract
- Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10(-53)), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10(-17)), rs219779 adjacent to CLDN14 (P=3.5 × 10(-16)), rs4443100 near RTDR1 (P=8.7 × 10(-9)), and rs73186030 near CASR (P=4.8 × 10(-8)). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
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- Vandenput, Liesbeth, et al.
(author)
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A meta-analysis of previous falls and subsequent fracture risk in cohort studies
- 2024
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In: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 35:3, s. 469-494
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Journal article (peer-reviewed)abstract
- SummaryThe relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm.IntroductionPrevious falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD).MethodsThe resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients.ResultsFalls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33–1.51) and men (HR 1.53, 95% CI 1.41–1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27–1.84) in men vs. HR 1.32 (95% CI 1.20–1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men.ConclusionsA previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.
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- Eriksson, Anna-Lena, 1971, et al.
(author)
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Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.
- 2018
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:3, s. 991-1004
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Journal article (peer-reviewed)abstract
- Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.To investigate the genetic regulation of serum E2 and E1 in men.Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Genetic determinants of serum E2 and E1 levels.Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
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- Eriksson, Anna-Lena, 1971, et al.
(author)
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Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men.
- 2009
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:3, s. 1033-41
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Journal article (peer-reviewed)abstract
- CONTEXT: The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids. OBJECTIVE: The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men. DESIGN: Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 +/- 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 +/- 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 +/- 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry. RESULTS: The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 x 10(-6)). This association was confirmed both in the MrOS Sweden study (P = 9 x 10(-7)) and in the MrOS US study (P = 1 x 10(-4)). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 x 10(-14)) and E1 (P = 8 x 10(-19)) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05). CONCLUSIONS: rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.
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- Eriksson, Anna-Lena, 1971, et al.
(author)
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SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.
- 2006
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:12, s. 5029-37
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Journal article (peer-reviewed)abstract
- CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
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- Eriksson, Anna-Lena, 1971, et al.
(author)
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The COMT val158met polymorphism is associated with prevalent fractures in Swedish men.
- 2008
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In: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 42:1, s. 107-12
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Sex steroids are important for growth and maintenance of the skeleton. Catechol-O-methyltransferase (COMT) is an estrogen degrading enzyme. The COMT val158met polymorphism results in a 60-75% difference in enzyme activity between the val (high activity=H) and met (low activity=L) variants. We have previously reported that this polymorphism is associated with bone mineral density (BMD) in young men. The aim of this study was to investigate associations between COMT val158met, BMD and fractures in elderly men. METHODS: Population-based study of Swedish men 75.4, SD 3.2, years of age. Fractures were reported using standardized questionnaires. Fracture and genotype data were available from 2,822 individuals. RESULTS: Total number of individuals with self-reported fracture was 989 (35.0%). Prevalence of >or=1 fracture was 37.2% in COMT(LL), 35.7% in COMT(HL) and 30.4% in COMT(HH) (p<0.05). Early fractures (50 years of age). The OR for fracture of the non-weight bearing skeleton in COMT(HH) compared with COMT(LL+HL) was 0.74 (95% CI 0.59-0.92). No associations between COMT val158met and BMD were found in this cohort of elderly men. CONCLUSIONS: The COMT val158met polymorphism is associated with life time fracture prevalence in elderly Swedish men. This association is mainly driven by early fractures (
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| 9. |
- Mellström, Dan, 1945, et al.
(author)
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Older men with low serum estradiol and high serum SHBG have an increased risk of fractures.
- 2008
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In: Journal of bone and mineral research. - 1523-4681. ; 23:10, s. 1552-60
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Journal article (peer-reviewed)abstract
- Osteoporosis-related fractures constitute a major health concern not only in women but also in men. To study the predictive role of serum sex steroids for fracture risk in men, serum sex steroids were analyzed by the specific gas chromatography-mass spectrometry technique at baseline in older men (n = 2639; mean, 75 yr of age) of the prospective population-based MrOS Sweden cohort. Fractures occurring after baseline were validated (average follow-up of 3.3 yr). The incidence for having at least one validated fracture after baseline was 20.9/1000 person-years. Estradiol (E2; hazard ratio [HR] per SD decrease, 1.34; 95% CI, 1.22-1.49), free estradiol (fE2; HR per SD decrease, 1.41; 95% CI, 1.28-1.55), testosterone (T; HR per SD decrease, 1.27; 95% CI, 1.16-1.39), and free testosterone (fT; HR per SD decrease, 1.32; 95% CI, 1.21-1.44) were all inversely, whereas sex hormone-binding globulin (SHBG; HR per SD increase, 1.41; 95% CI, 1.22-1.63) was directly related to fracture risk. Multivariable proportional hazards regression models, adjusted for age, suggested that fE2 and SHBG (p < 0.001), but not fT, were independently associated with fracture risk. Further subanalyses of fracture type showed that fE2 was inversely associated with clinical vertebral fractures (HR per SD decrease, 1.57; 95% CI, 1.36-1.80), nonvertebral osteoporosis fractures (HR per SD decrease, 1.42; 95% CI, 1.23-1.65), and hip fractures (HR per SD decrease, 1.44; 95% CI, 1.18-1.76). The inverse relation between serum E2 and fracture risk was nonlinear with a strong relation <16 pg/ml for E2 and 0.3 pg/ml for fE2. In conclusion, older Swedish men with low serum E2 and high SHBG levels have an increased risk of fractures.
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| 10. |
- Orwoll, Eric S., et al.
(author)
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The Limited Clinical Utility of Testosterone, Estradiol, and Sex Hormone Binding Globulin Measurements in the Prediction of Fracture Risk and Bone Loss in Older Men
- 2017
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In: Journal of Bone and Mineral Research. - : WILEY. - 0884-0431 .- 1523-4681. ; 32:3, s. 633-640
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Journal article (peer-reviewed)abstract
- Measurement of serum testosterone (T) levels is recommended in the evaluation of osteoporosis in older men and estradiol (E2) and sex hormone binding globulin (SHBG) levels are associated with the rate of bone loss and fractures, but the clinical utility of sex steroid and SHBG measurements for the evaluation of osteoporosis in men has not been examined. To evaluate whether measurements of T, E2, and/or SHBG are useful for the prediction of fracture risk or the rate of bone loss in older men, we analyzed longitudinal data from 5487 community-based men participating in the Osteoporotic Fractures in Men (MrOS) study in the United States, Sweden, and Hong Kong. Serum T, E2, and SHBG levels were assessed at baseline; incident fractures were self-reported at 4-month intervals with radiographic verification (US), or ascertained via national health records (Sweden, Hong Kong). Rate of bone loss was assessed by serial measures of hip bone mineral density (BMD). We used receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to assess improvement in prediction. Mean age at baseline was 72 to 75 years and the prevalence of low T levels (<300 ng/dL) was 7.6% to 21.3% in the three cohorts. There were 619 incident major osteoporotic and 266 hip fractures during follow-up of approximately 10 years. Based on ROC curves, there were no improvements in fracture risk discrimination for any biochemical measure when added to models, including the Fracture Risk Assessment Tool (FRAX) with BMD. Although minor improvements in NRI were observed for the dichotomous parameters low bioavailable E2 (BioE2) (<11.4 pg/mL) and high SHBG(>59.1 nM), neither sex steroids nor SHBG provided clinically useful improvement in fracture risk discrimination. Similarly, they did not contribute to the prediction of BMD change. In conclusion, there is limited clinical utility of serum E2, T, and SHBG measures for the evaluation of osteoporosis risk in elderly men.
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