The promoter polymorphism -301T/C in the sclerosteosis gene that affects C/EBPα and FOXA1 binding is associated with osteoporosis

Abstract

OBJECTIVE: To determine whether the allelic variation in seven monogenic bone disease genes (CLCN7, TCIRGI, SOST, CA2, CSTK, TGFB1 and SLC26A2) contributes to osteoporosis / bone mineral density (BMD) variation in the normal Chinese population. METHODS: We conducted a gene-wide and tag SNP-based association study in 1243 case-control Chinese subjects. The cases were subjects with low BMD (Z-scores≤-1.28) at either the L1-4 lumbar spine or femoral neck. Control subjects had high BMD (Z-score≥+1.0) at the corresponding sites. Twenty-two tag SNPs from seven monogenic bone disease genes were selected based on the CHB panel of the Phase II HapMap Project (r2N0.8 and minor allele frequency N0.2), and were genotyped using the high-throughput sequenom platform. Allelic and haplotype association analyses were conducted by Haploview and binary logistic regression analyses. Gene-gene interactions were investigated using multifactor dimensionality reduction method. AliBaba 2.1 was applied to predict the putative transcription factor binding sites at the promoter polymorphism. RESULTS: The promoter SNP rs1230399 (-301T/C) of SOST showed significant genotypic and allelic associations with BMD at all skeletal sites measured (P=0.04-0.001). The haplotype CC consisting of rs1230399 and rs865429 showed consistent associations with high BMD at femoral neck and spine (P=0.005, 0.002, respectively). Importantly, this association has been replicated in the Caucasian population. Functional analysis showed that the rs1230399 was located at the core consensus recognition site of two important transcription factors C/EBPα and FOXA1 which were involved in the Wnt and estrogen signaling pathway. T→C mutation abolishes the binding of both C/EBPα and FOXA1 to SOST. In addition, significant gene-gene interactions were identified for SOST/CLCN7 and TGFB1. CONCLUSION: The C-allele of -301TNC variant of SOST was associated with high BMD. The variant may mediate BMD by Wnt and estrogen signaling pathways.