| 1. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 2. |
- Jiang, Jieying, et al.
(författare)
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Association of genetic variations in aromatase gene with serum estrogen and estrogen/testosterone ratio in Chinese elderly men.
- 2010
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Ingår i: Clinica chimica acta. - : Elsevier BV. - 1873-3492 .- 0009-8981. ; 411:1-2, s. 53-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Single nucleotide polymorphism (SNP) rs2470152 of the gene CYP19A1 is associated with serum estradiol (E2) levels in Caucasian men. However, it remains to be verified if rs2470152 is the sole determinant accounting for the association. We determined whether 2 CYP19A1 SNPs tagging different haploblocks (rs2470152 and rs2899470) are associated with sex steroid levels in Chinese men. METHOD: Serum sex steroid level including E2, estrone (E1) and testosterone (T), of 1402 Chinese men aged > or = 65 years were analyzed. Genotyping of the two CYP19A1 SNPs was performed using Tm-shift allele-specific PCR. RESULTS: SNP rs2899470 was significantly associated with serum E2, E1 levels and E2/T ratio (p<0.001). However, SNP rs2470152 was only modestly associated with E2/T ratio (p=0.023). Analysis of haplotype showed a significant association between C-G, T-T haplotype with serum E2/T ratio (p=0.019 and p=1 x 10(-5), respectively). Similarly, E2 levels was also associated the T-T and T-G haplotypes (p=1 x 10(-5)). CONCLUSION: The genetic variation of CYP19A1 was associated with circulating estrogen levels in Chinese elderly men. In addition, it revealed that haplotype of rs2899470 and rs2470152, rather than rs2899470 alone, was a better indicator for the serum E2/T ratio and E2 levels.
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| 3. |
- Jiang, Jieying, et al.
(författare)
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Association of SRD5A2 variants and serum androstane-3alpha,17beta-diol glucuronide concentration in Chinese elderly men.
- 2010
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Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 56:11, s. 1742-9
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Tidskriftsartikel (refereegranskat)abstract
- Results of recent studies have demonstrated that genetic variants of the enzyme steroid 5α reductase type II (SRD5A2) are associated with serum concentrations of major androgen metabolites such as conjugates of androstane-3α,17β-diol-glucuronide (3α-diol-G). However, this association was not consistently found among different ethnic groups. Thus, we aimed to determine whether the association with SRD5A2 genetic variations exists in a cohort of healthy Chinese elderly men, by examining 2 metabolite conjugates: androstane-3α,l7β-diol-3-glucuronide (3α-diol-3G) and androstane-3α,17β-diol-17-glucuronide (3α-diol-17G).
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| 4. |
- Kwok, T, et al.
(författare)
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ACE inhibitor use was associated with lower serum dehydroepiandrosterone concentrations in older men.
- 2010
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Ingår i: Clinica chimica acta. - : Elsevier BV. - 1873-3492 .- 0009-8981. ; 411:15-16, s. 1122-5
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Angiotensin converting enzyme (ACE) activity may influence the production of adrenal androgen precursors and testosterone. Use of ACE inhibitors may therefore have an influence on serum sex hormone concentrations in older men. DESIGN AND METHODS: 1486 out of 2,000 community-dwelling Chinese men aged 65years who participated in a cohort study were randomly selected to have archived fasting morning serum analyzed for androgen precursors and sex hormones. DNA was extracted from whole blood and analyzed for ACE gene I/D polymorphism. RESULTS: Subjects with the ACE gene D allele (higher ACE activity) had higher serum dehydroepiandrosterone (DHEA) sulphate and DHEA than those with I/I genotype (P=0.014 and 0.018 respectively, Mann Whitney test). These differences were not significant after Bonferroni correction. Among those with history of hypertension, but without diabetes mellitus or cardiac failure, users of ACE inhibitors had significantly lower serum DHEA (median 1.78 versus 1.49ng/ml in non-users, P=0.0074, Mann Whitney test) and also tended to have lower serum androstenedione and androst-5-ene-3beta,17beta-diol (0.68 versus 0.72ng/ml in non-users; 552.4 versus 624.1pg/ml respectively, both P values <0.05). Serum testosterone and estradiol were not significantly changed. CONCLUSIONS: ACE inhibitor use was associated with lower serum DHEA in older men.
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| 5. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 6. |
- Ohlsson, Claes, 1965, et al.
(författare)
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Low Serum Levels of Dehydroepiandrosterone Sulfate Predict All-Cause and Cardiovascular Mortality in Elderly Swedish Men
- 2010
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:9, s. 4406-4414
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Tidskriftsartikel (refereegranskat)abstract
- Context: The age-related decline in dehydroepiandrosterone (DHEA) levels is thought to be of importance for general and vascular aging. However, data on the association between DHEA and mortality are conflicting. Objectives: We tested the hypothesis that low serum DHEA and DHEA sulfate (DHEA-S) levels predict all-cause and cardiovascular disease (CVD) death in elderly men. Design, Setting, and Participants: We used gas/liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based MrOS Sweden study (2644 men, aged 69-81 yr). Mortality data were obtained from central registers and analyzed using Cox proportional hazards regressions. Main Outcome Measures: All-cause and CVD mortality by serum DHEA(-S) levels. Results: During a mean 4.5-yr follow-up, 328 deaths occurred. Low levels of DHEA-S (quartile 1 vs. quartiles 2-4), predicted death from all causes [hazard ratio (HR) 1.54,95% confidence interval (CI) 1.21-1.96; adjusted for traditional cardiovascular risk factors], from CVD (n = 123 deaths; HR 1.61, 95% CI 1.10-2.37) and ischemic heart disease (n = 73; HR 1.67, 95% CI 1.02-2.74) but not cancer. Analyses with DHEA gave similar results. The association between low DHEA-S and CVD death remained after adjustment for C-reactive protein and circulating estradiol and testosterone levels. When stratified by the median age of 75.4 yr, the mortality prediction by low DHEA-S was more pronounced among younger (age adjusted HR for CVD death 2.64, 95% CI 1.37-5.09) than older men (HR 1.30, 95% CI 0.83-2.04). Conclusions: Low serum levels of DHEA(-S) predict death from all causes, CVD, and ischemic heart disease in older men.
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| 7. |
- Orwoll, Eric S., et al.
(författare)
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Evidence for Geographical and Racial Variation in Serum Sex Steroid Levels in Older Men
- 2010
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:10, s. E151-E160
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite considerable racial and geographical differences in human phenotypes and in the incidence of diseases that may be associated with sex steroid action, there are few data concerning variation in sex steroid levels among populations. We designed an international study to determine the degree to which geography and race influence sex steroid levels in older men. Methods: Using mass spectrometry, concentrations of serum androgens, estrogens, and sex steroid precursors/metabolites were measured in 5003 older men from five countries. SHBG levels were assessed using radioimmunoassay. Results: There was substantial geographical variation in the levels of sex steroids, precursors, and metabolites, as well as SHBG. For instance, Asian men in Hong Kong and Japan, but not in the United States, had levels of total testosterone approximately 20% higher than in other groups. Even greater variation was present in levels of estradiol, SHBG, and dihydrotestosterone. Group differences in body mass index did not explain most geographical differences. In addition, body mass index-independent racial differences were present; Black men had higher levels of estrogens (estradiol, estrone), and Asian men had lower levels of glucuronidated androgen metabolites. Conclusions: On a global scale, there are important geographical and racial differences in the concentrations of serum sex steroids and SHBG in older men.
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| 8. |
- Paternoster, Lavinia, et al.
(författare)
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Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the RANKL Locus and Potential Pleiotropic Effects on Bone
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:11, s. e1001217-
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMDC) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMDC, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged similar to 15 years and GOOD n = 935, aged similar to 19 years), we attempted to replicate the BMDC associations that had p<1 x 10(-5) in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMDC in all cohorts (overall p = 2 x 10(-14), n = 5739). Each minor allele was associated with a decrease in BMDC of similar to 0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males -6.77mg/cm(3) per C allele, p = 2 x 10(-6); females -2.79 mg/cm(3) per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development.
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| 9. |
- Paternoster, L, et al.
(författare)
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OPG and RANK Polymorphisms Are Both Associated with Cortical Bone Mineral Density: Findings from a Metaanalysis of the Avon Longitudinal Study of Parents and Children and Gothenburg Osteoporosis and Obesity Determinants Cohorts.
- 2010
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Ingår i: The journal of clinical endocrinology and metabolism. - 1945-7197. ; 95:8, s. 3940-3948
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Tidskriftsartikel (refereegranskat)abstract
- Context: Several single-nucleotide polymorphisms (SNPs) have been reliably associated with areal bone mineral density (aBMD) in genome-wide association studies of mostly older subjects. Objective: We aimed to test those SNPs for an association with peripheral quantitative computed tomography (pQCT) bone measures in two young cohorts. Design and Study Participants: We genotyped nine SNPs from the most promising aBMD candidates in a cohort of 15-yr-olds [in the Avon Longitudinal Study of Parents and Children (ALSPAC)] and carried out association analysis with several tibial pQCT measures to determine whether these candidates were important during adolescent growth and which particular skeletal parameters each of the candidates were acting upon. We also carried out a metaanalysis of the SNPs for association with cortical bone mineral density (BMDC) in ALSPAC and a similar male-only study (Gothenburg Osteoporosis and Obesity Determinants). Results: In the ALSPAC cohort, we found a significant association between RANK SNP (rs3018362) and BMDC but not any of the other pQCT bone measures. In the metaanalysis, we found the OPG SNP (rs4355801) and the RANK SNP (rs3018362) to be significantly associated with BMDC. We also found suggestive evidence of an association between the MARK3 SNP (rs2010281) and BMDC but with a direction of effect opposite to that previously reported. Conclusion: The association of genes from the RANK/RANKL/OPG pathway and BMDC provides new insight into how this system might affect the skeleton, confirming it to be associated with volumetric cortical bone density but observing no relationship with bone size.
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| 10. |
- Song, Xin-Yuan, et al.
(författare)
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A semiparametric Bayesian approach for structural equation models.
- 2010
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Ingår i: Biometrical journal.. - : Wiley. - 1521-4036 .- 0323-3847. ; 52:3, s. 314-32
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Tidskriftsartikel (refereegranskat)abstract
- In the development of structural equation models (SEMs), observed variables are usually assumed to be normally distributed. However, this assumption is likely to be violated in many practical researches. As the non-normality of observed variables in an SEM can be obtained from either non-normal latent variables or non-normal residuals or both, semiparametric modeling with unknown distribution of latent variables or unknown distribution of residuals is needed. In this article, we find that an SEM becomes nonidentifiable when both the latent variable distribution and the residual distribution are unknown. Hence, it is impossible to estimate reliably both the latent variable distribution and the residual distribution without parametric assumptions on one or the other. We also find that the residuals in the measurement equation are more sensitive to the normality assumption than the latent variables, and the negative impact on the estimation of parameters and distributions due to the non-normality of residuals is more serious. Therefore, when there is no prior knowledge about parametric distributions for either the latent variables or the residuals, we recommend making parametric assumption on latent variables, and modeling residuals nonparametrically. We propose a semiparametric Bayesian approach using the truncated Dirichlet process with a stick breaking prior to tackle the non-normality of residuals in the measurement equation. Simulation studies and a real data analysis demonstrate our findings, and reveal the empirical performance of the proposed methodology. A free WinBUGS code to perform the analysis is available in Supporting Information.
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