Common variants in FLNB/CRTAP, not ARHGEF3 at 3p, are associated with Osteoporosis in southern Chinese women

Abstract

We performed an association study of five candidate genes within chromosome 3p14-25 in 1,080 Chinese female subjects. Polymorphisms in FLNB/CRTAP are associated with bone mineral density (BMD) in Chinese. Introduction: Chromosomal region 3p14-25 has shown strong evidence of linkage to BMD in genome-wide linkage scans. The variants responsible for this linkage signal, nonetheless, remain obscure. Methods: Thirty SNPs in five positional and functional candidate genes within 3p14-25 (PPARG, CRTAP, TDGF1, PTHR1, and FLNB) and rs7646054 in the ARHGEF3 gene were genotyped in a case-control cohort of 1,080 Chinese females. Allelic and haplotypic association were tested using logistic regression analysis implemented in PLINK software. Potential transcription factor binding sites were predicted with Mat Inspector. Results: Multiple SNPs and haplotypes in FLNB were significantly associated with BMDs, with the strongest association between lumbar spine BMD and rs9828717 (p=0.005). SNP rs7623768 and the haplotype G-C of rs4076086-rs7623768 in CRTAP were associated with femoral neck BMD (p=0.009 and p=0.003, respectively). PTHR1 showed haplotypic associations with lumbar spine and femoral neck BMD (p=0.02 and p=0.044, respectively). Nevertheless, the association between rs7646054 in ARHGEF3 and BMD observed in Caucasians was not replicated in our samples. Comparative genomics analysis indicated that rs9828717 is located within a highly conserved region. The minor T allele at rs9828717 may lead to loss of binding site for nuclear factor of activated T cells which binds and triggers the transcriptional program of osteoblasts. Conclusions: Our data suggest that variants in FLNB and CRTAP at 3p are involved in BMD regulation in southern Chinese. © International Osteoporosis Foundation and National Osteoporosis Foundation 2009.