Dataset Information

Sex-specific association of the glucocorticoid receptor gene with extreme BMD.

ABSTRACT: To study the role of the GR gene on BMD regulation in the Chinese, a sex-specific association study was performed. The results indicated that GR variation contributed to the extreme BMD variation in the Chinese.The glucocorticoid (GC) receptor (GR) gene is an important candidate gene for BMD regulation in GC-induced osteoporosis (GIO). However, no study has explored the genetic effects of the GR gene on BMD variation in the Chinese population.Our sample consisted of 800 unrelated subjects (400 women and 400 men) with extreme age-adjusted hip BMD Z-scores selected from a population composed of 1988 normal adult Chinese Han. Four single nucleotide polymorphisms (SNPs) in the GR gene were genotyped. Both single SNP and haplotype association analyses were conducted.SNP rs1866388 (p(c) = 0.028) was found to be significantly associated with extreme BMD only in men. In both sexes, haplotypes involving rs1866388 and rs2918419 were found to have different frequency distributions in extremely low and high BMD groups (p(p) = 0.024, 0.001, and 0.002 in women and 0.002, 0.003, and 0.003 in men for window sizes of two, three, and four SNPs, respectively). Most shared haplotypes showed opposite effects between women and men.For the first time, our study suggested the possible role of the GR gene on BMD regulation and sex specificity in the association of GR with extreme BMD in the Chinese.

SUBMITTER: Peng YM

PROVIDER: S-EPMC2665695 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Sex-specific association of the glucocorticoid receptor gene with extreme BMD.

Peng Yu-Mei YM Lei Shu-Feng SF Guo Yan Y Xiong Dong-Hai DH Yan Han H Wang Liang L Guo Yan-Fang YF Deng Hong-Wen HW

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20080201 2

<h4>Unlabelled</h4>To study the role of the GR gene on BMD regulation in the Chinese, a sex-specific association study was performed. The results indicated that GR variation contributed to the extreme BMD variation in the Chinese.<h4>Introduction</h4>The glucocorticoid (GC) receptor (GR) gene is an important candidate gene for BMD regulation in GC-induced osteoporosis (GIO). However, no study has explored the genetic effects of the GR gene on BMD variation in the Chinese population.<h4>Materials ...[more]

PMID: 17937535

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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:Glucocorticoids are a class of steroid hormones that bind to and activate the glucocorticoid receptor (GR), which then positively or negatively regulates transcription of many genes that govern multiple important physiological pathways such as inflammation and metabolism of glucose, fat and bone. The remodeling of chromatin and regulated assembly or disassembly of active transcription complexes by GR and other DNA-binding transcription factors is mediated and modulated by several hundred transcriptional coregulator proteins. Previous studies focusing on single coregulators demonstrated that each coregulator is required for regulation of only a subset of all the genes regulated by a steroid hormone. We hypothesized that the gene-specific patterns of coregulators may correspond to specific physiological pathways such that different coregulators modulate the pathway-specificity of hormone action, thereby providing a mechanism for fine tuning of the hormone response. We tested this by direct comparison of multiple coregulators, using siRNA to deplete the products of four steroid hormone receptor coregulator genes (CCAR1, CCAR2, CALCOCO1 and ZNF282). Global analysis of glucocorticoid-regulated gene expression after siRNA mediated depletion of coregulators confirmed that each coregulator acted in a selective and gene-specific manner and demonstrated both positive and negative effects on glucocorticoid-regulated expression of different genes. We identified several classes of hormone-regulated genes based on the effects of coregulator depletion. Each coregulator supported hormonal regulation of some genes and opposed hormonal regulation of other genes (coregulator-modulated genes), blocked hormonal regulation of a second class of genes (coregulator-blocked genes), and had no effect on hormonal regulation of a third gene class (coregulator-independent genes). In spite of previously demonstrated physical and functional interactions among these four coregulators, the majority of the several hundred modulated and blocked genes for each of the four coregulators tested were unique to that coregulator. Finally, pathway analysis on coregulator-modulated genes supported the hypothesis that individual coregulators may regulate only a subset of the many physiological pathways controlled by glucocorticoids. We conclude that gene-specific actions of coregulators correspond to specific physiological pathways, suggesting that coregulators provide a potential mechanism for physiological fine tuning in vivo and may thus represent attractive targets for therapeutic intervention.

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Sex-specific association of the glucocorticoid receptor gene with extreme BMD.

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Sex-specific association of the glucocorticoid receptor gene with extreme BMD.

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