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Contribution of myostatin gene polymorphisms to normal variation in lean mass, fat mass and peak BMD in Chinese male offspring.

ABSTRACT: AIM: Myostatin gene is a member of the transforming growth factor-? (TGF-?) family that negatively regulates skeletal muscle growth. Genetic polymorphisms in Myostatin were found to be associated with the peak bone mineral density (BMD) in Chinese women. The purpose of this study was to investigate whether myostatin played a role in the normal variation in peak BMD, lean mass (LM), and fat mass (FM) of Chinese men. METHODS: Four hundred male-offspring nuclear families of Chinese Han ethnic group were recruited. Anthropometric measurements, including the peak BMD, body LM and FM were measured using dual-energy X-ray absorptiometry (DXA). The single nucleotide polymorphisms (SNPs) studied were tag-SNPs selected by sequencing. Both rs2293284 and +2278GA were genotyped using TaqMan assay, and rs3791783 was genotyped with PCR-restriction fragment length polymorphism (RFLP) analysis. The associations of the SNPs with anthropometric variations were analyzed using the quantitative transmission disequilibrium test (QTDT). RESULTS: Using QTDT to detect within-family associations, neither single SNP nor haplotype was found to be associated with peak BMD at any bone site. However, rs3791783 was found to be significantly associated with fat mass of the trunk (P<0.001). Moreover, for within-family associations, haplotypes AGG, AAA, and TGG were found to be significantly associated with the trunk fat mass (all P<0.001). CONCLUSION: Our results suggest that genetic variation within myostatin may play a role in regulating the variation in fat mass in Chinese males. Additionally, the myostatin gene may be a candidate that determines body fat mass in Chinese men.

SUBMITTER: Yue H

PROVIDER: S-EPMC4010361 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Contribution of myostatin gene polymorphisms to normal variation in lean mass, fat mass and peak BMD in Chinese male offspring.

Yue Hua H He Jin-wei JW Zhang Hao H Wang Chun C Hu Wei-wei WW Gu Jie-mei JM Ke Yao-hua YH Fu Wen-zhen WZ Hu Yun-qiu YQ Li Miao M Liu Yu-juan YJ Wu Song-hua SH Zhang Zhen-lin ZL

Acta pharmacologica Sinica 20120319 5

<h4>Aim</h4>Myostatin gene is a member of the transforming growth factor-β (TGF-β) family that negatively regulates skeletal muscle growth. Genetic polymorphisms in Myostatin were found to be associated with the peak bone mineral density (BMD) in Chinese women. The purpose of this study was to investigate whether myostatin played a role in the normal variation in peak BMD, lean mass (LM), and fat mass (FM) of Chinese men.<h4>Methods</h4>Four hundred male-offspring nuclear families of Chinese Han ...[more]

PMID: 22426697

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Project description:BACKGROUND:Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. METHODS:We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n?=?240) from the UK with BMD Z-scores ?+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n?=?1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n?=?900), with Z-scores -1.5 to -4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. RESULTS:We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF]?=?0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF?=?0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-? regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n?=?32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable. CONCLUSION:We report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.

Project description:BackgroundLittle is known about the association of changes in two body components, muscle and fat mass, with the risk of cardiovascular disease (CVD) among young adults. We investigated the association of changes in predicted lean body mass index (LBMI), appendicular skeletal muscle mass index (ASMI), and body fat mass index (BFMI) with the development of CVD among young adults.MethodsThis nationwide, population-based cohort study included 3 727 738 young adults [2 406 046 (64.5%) men and 1 321 692 (35.5%) women] aged 20-39 years without a previous history of CVD who underwent two health screening examinations during 2009-2010 and 2011-2012. Using validated and robust prediction equations, we calculated the changes in predicted LBMI, ASMI, and BFMI from the first to the second examinations.ResultsThe mean (SD) age was 32.2 (4.9) years, and 2 406 046 (64.5%) of the participants were men. A total of 23 344 CVD events were detected during 22 257 632 person-years of follow-up. Each 1 kg/m2 increase in predicted LBMI and ASMI change was associated with a reduced risk of CVD among men [adjusted hazard ratio (aHR): 0.86, 95% confidence interval (CI) 0.82-0.91; aHR: 0.76, 95% CI 0.69-0.82, respectively] and women (aHR: 0.77, 95% CI 0.63-0.95; aHR: 0.75, 95% CI 0.59-0.96). Each 1 kg/m2 increase in predicted BFMI change was associated with an increased risk of CVD among men (aHR: 1.16, 95% CI 1.10-1.22) and women (aHR: 1.32, 95% CI 1.06-1.65). In both sexes, decreases in predicted LBMI and ASMI were associated with greater CVD risk, and decreased predicted BFMI was associated with a reduced CVD risk. Those who maintained their BMI between -1 and +1 kg/m2 also had a decreased risk of CVD per 1 kg/m2 increase in predicted LBMI and ASMI change among men (aHR: 0.86, 95% CI 0.80-0.92; aHR: 0.85, 95% CI 0.76-0.95) and women (aHR: 0.62, 95% CI 0.47-0.83; aHR: 0.59, 95% CI 0.44-0.80) and had a greater risk of CVD per 1 kg/m2 increase in predicted BFMI change among men (aHR: 1.17, 95% CI 1.10-1.25) and women (aHR: 1.64, 95% CI 1.20-2.23). Regardless of changes in weight, such as from normal to obese or vice versa, these results were consistent.ConclusionsAmong young adults, increased predicted muscle mass or decreased predicted fat mass were associated with a reduced risk of development of CVD. Decreased predicted muscle mass or increased predicted fat mass were associated with an elevated risk of development of CVD.

Project description:BackgroundRecent studies suggest that adjustment of measures of lean mass for adiposity improves associations with physical function. Our objective was to develop and test a method to adjust appendicular lean mass for adiposity.MethodsWhole-body DXA data in 14,850 adults in the National Health and Nutrition Examination Survey were used to generate sex-, and race-specific standard deviation scores (Z-Scores relative to age and T-scores relative to 25 year-olds) for appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Correlations between ALMI and FMI Z- and T-Scores were assessed within demographic categories. Fat-adjusted ALMI (ALMIFMI) scores were determined using residual methods. Sarcopenia was defined as a T-Score <-2.0 and low lean for age as a Z-Score <-1.0. Correlations with physical function were assessed in an at-risk population.ResultsPositive associations between ALMI and FMI Z- and T-Scores were significant (R >0.50; p<0.001) within all demographic categories. The impact of a unit greater FMI Z-score on ALMI Z-score was less in the elderly, men, white subjects, and among individuals with lower FMI (all tests for interaction p<0.001). There was fair agreement between ALMI and ALMIFMI estimates of sarcopenia and low lean for age [Kappa: 0.46, 0.52, respectively (p<0.0001)]. Elderly subjects were likely to be re-classified as sarcopenic while young subjects were likely to be re-classified as normal using ALMIFMI. ALMIFMI T-scores resulted in approximately twice the number of subjects defined as sarcopenic, compared with ALMI T-Scores. (1299 v. 534). Among rheumatoid arthritis patients, ALMIFMI Z-scores correlated with physical function (Health Assessment Questionnaire: rho = -0.22, p = 0.04; Short Physical Performance Battery: rho = 0.27, p = 0.01); however, the ALMI Z-Score did not.ConclusionsAdjustment of ALMI for the confounding association with FMI impacts the definition of lean mass deficits. These methods provide a practical tool for investigators and clinicians based on population-based reference data.

Dataset Information

Contribution of myostatin gene polymorphisms to normal variation in lean mass, fat mass and peak BMD in Chinese male offspring.

Publications

Contribution of myostatin gene polymorphisms to normal variation in lean mass, fat mass and peak BMD in Chinese male offspring.

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