1. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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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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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:3, s. 991-1004
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Tidskriftsartikel (refereegranskat)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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2. |
- Harvey, N. C., et al.
(författare)
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Greater pQCT Calf Muscle Density Is Associated with Lower Fracture Risk, Independent of FRAX, Falls and BMD: A Meta-Analysis in the Osteoporotic Fractures in Men (MrOS) Study
- 2022
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Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the predictive performance of peripheral quantitative computed tomography (pQCT) measures of both calf muscle density (an established surrogate for muscle adiposity, with higher values indicating lower muscle adiposity and higher muscle quality) and size (cross-sectional area [CSA]) for incident fracture. pQCT (Stratec XCT2000/3000) measurements at the tibia were undertaken in Osteoporotic Fractures in Men (MrOS) United States (US), Hong Kong (HK), and Swedish (SW) cohorts. Analyses were by cohort and synthesized by meta-analysis. The predictive value for incident fracture outcomes, illustrated here for hip fracture (HF), using an extension of Poisson regression adjusted for age and follow-up time, was expressed as hazard ratio (HR) per standard deviation (SD) increase in exposure (HR/SD). Further analyses adjusted for femoral neck (fn) bone mineral density (BMD) T-score, Fracture Risk Assessment Tool (FRAX) 10-year fracture probability (major osteoporotic fracture) and prior falls. We studied 991 (US), 1662 (HK), and 1521 (SW) men, mean +/- SD age 77.0 +/- 5.1, 73.9 +/- 4.9, 80 +/- 3.4 years, followed for a mean +/- SD 7.8 +/- 2.2, 8.1 +/- 2.3, 5.3 +/- 2.0 years, with 31, 47, and 78 incident HFs, respectively. Both greater muscle CSA and greater muscle density were associated with a lower risk of incident HF [HR/SD: 0.84; 95% confidence interval [CI], 0.72-1.0 and 0.78; 95% CI, 0.66-0.91, respectively]. The pattern of associations was not materially changed by adjustment for prior falls or FRAX probability. In contrast, after inclusion of fn BMD T-score, the association for muscle CSA was no longer apparent (1.04; 95% CI, 0.88-1.24), whereas that for muscle density was not materially changed (0.69; 95% CI, 0.59-0.82). Findings were similar for osteoporotic fractures. pQCT measures of greater calf muscle density and CSA were both associated with lower incidence of fractures in older men, but only muscle density remained an independent risk factor for fracture after accounting for fn BMD. These findings demonstrate a complex interplay between measures of bone, muscle size, and quality, in determining fracture risk. (C) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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3. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:8, s. 753-60
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
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4. |
- Mellström, Dan, 1945, et al.
(författare)
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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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Ingår i: J Bone Miner Res. - : Wiley. - 1523-4681 .- 0884-0431. ; 23:10, s. 1552-60
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Tidskriftsartikel (refereegranskat)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
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5. |
- Nielson, Carrie M., et al.
(författare)
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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2
- 2016
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 31:12, s. 2085-2097
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n=15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n=21,701) and clinical vertebral fracture (n=5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]=3%) was associated with higher vBMD (β=0.22, p=1.9×10-8) and decreased risk of radiographic vertebral fracture (odds ratio [OR]=0.75; false discovery rate [FDR] p=0.01). In 1p36.12, rs12742784 (MAF=21%) was associated with higher vBMD (β=0.09, p=1.2×10-10) and decreased risk of clinical vertebral fracture (OR=0.82; FDR p=7.4×10-4). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β=0.28, FDR p=0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β=0.12, FDR p=1.7×10-3, functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence.
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6. |
- Ohlsson, Claes, 1965, et al.
(författare)
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Low Serum DHEAS Predicts Increased Fracture Risk in Older Men: The MrOS Sweden Study
- 2017
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 32:8, s. 1607-1614
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Tidskriftsartikel (refereegranskat)abstract
- 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. (C) The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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7. |
- Ohlsson, Claes, 1965, et al.
(författare)
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Serum DHEA and Its Sulfate Are Associated With Incident Fall Risk in Older Men: The MrOS Sweden Study
- 2018
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 33:7, s. 1227-1232
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Tidskriftsartikel (refereegranskat)abstract
- The adrenal-derived hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the most abundant circulating hormones and their levels decline substantially with age. Many of the actions of DHEAS are considered to be mediated through metabolism into androgens and estrogens in peripheral target tissues. The predictive value of serum DHEA and DHEAS for the likelihood of falling is unknown. The aim of this study was, therefore, to assess the associations between baseline DHEA and DHEAS levels and incident fall risk in a large cohort of older men. Serum DHEA and DHEAS levels were analyzed with mass spectrometry in the population-based Osteoporotic Fractures in Men study in Sweden (n=2516, age 69 to 81 years). Falls were ascertained every 4 months by mailed questionnaires. Associations between steroid hormones and falls were estimated by generalized estimating equations. During a mean follow-up of 2.7 years, 968 (38.5%) participants experienced a fall. High serum levels of both DHEA (odds ratio [OR] per SD increase 0.85; 95% CI, 0.78 to 0.92) and DHEAS (OR 0.88, 95% CI, 0.81 to 0.95) were associated with a lower incident fall risk in models adjusted for age, BMI, and prevalent falls. Further adjustment for serum sex steroids or age-related comorbidities only marginally attenuated the associations between DHEA or DHEAS and the likelihood of falling. Moreover, the point estimates for DHEA and DHEAS were only slightly reduced after adjustment for lean mass and/or grip strength. Also, the addition of the narrow walk test did not substantially alter the associations between serum DHEA or DHEAS and fall risk. Finally, the association with incident fall risk remained significant for DHEA but not for DHEAS after simultaneous adjustment for lean mass, grip strength, and the narrow walk test. This suggests that the associations between DHEA and DHEAS and falls are only partially mediated via muscle mass, muscle strength, and/or balance. In conclusion, older men with high DHEA or DHEAS levels have a lesser likelihood of a fall. (c) 2018 American Society for Bone and Mineral Research.
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8. |
- Orwoll, Eric S., et al.
(författare)
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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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Ingår i: Journal of Bone and Mineral Research. - : WILEY. - 0884-0431 .- 1523-4681. ; 32:3, s. 633-640
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Tidskriftsartikel (refereegranskat)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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9. |
- Vandenput, Liesbeth, 1974, et al.
(författare)
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Low Testosterone, but Not Estradiol, Is Associated With Incident Falls in Older Men: The International MrOS Study
- 2017
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 32:6, s. 1174-1181
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Tidskriftsartikel (refereegranskat)abstract
- Fracture risk is determined by bone strength and the risk of falls. The relationship between serum sex steroids and bone strength parameters in men is well known, whereas the predictive value of sex steroids for falls is less studied. The aim of this study was to assess the associations between serum testosterone (T) and estradiol (E2) and the likelihood of falls. Older men (aged > 65 years) from the United States (n = 1919), Sweden (n = 2495), and Hong Kong (n = 1469) participating in the Osteoporotic Fractures in Men Study had baseline T and E2 analyzed by mass spectrometry. Bioavailable (Bio) levels were calculated using mass action equations. Incident falls were ascertained every 4 months during a mean follow-up of 5.7 years. Associations between sex steroids and falls were estimated by generalized estimating equations. Fall rate was highest in the US and lowest in Hong Kong (US 0.50, Sweden 0.31, Hong Kong 0.12 fall reports/person/year). In the combined cohort of 5883 men, total T (odds ratio [OR] per SD increase = 0.88, 95% confidence interval [CI] 0.86-0.91) and BioT (OR = 0.86, 95% CI 0.83-0.88) were associated with incident falls in models adjusted for age and prevalent falls. These associations were only slightly attenuated after simultaneous adjustment for physical performance variables (total T: OR = 0.94, 95% CI 0.91-0.96; BioT: OR = 0.91, 95% CI 0.89-0.94). E2, BioE2, and sex hormone-binding globulin (SHBG) were not significantly associated with falls. Analyses in the individual cohorts showed that both total T and BioT were associated with falls in MrOS US and Sweden. No association was found in MrOS Hong Kong, and this may be attributable to environmental factors rather than ethnic differences because total T and BioT predicted falls in MrOS US Asians. In conclusion, low total T and BioT levels, but not E2 or SHBG, are associated with increased falls in older men. (C) 2017 American Society for Bone and Mineral Research.
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