Genetic Variants in GREM2 Are Associated With Bone Mineral Density in a Southern Chinese Population

Context: Gremlin 2 (GREM2) is a regulator of osteoblast differentiation and osteogenesis. A recent genome-wide association study identified GREM2 as a novel susceptibility gene for trabecular volumetric bone mineral density (BMD). Objective: We investigated whether GREM2 gene variants were associated with areal BMD in southern Chinese people. Research Design and Methods: We genotyped 108 single-nucleotide polymorphisms (SNPs) in 417 cases (defined as BMD Z-score <-1.28)and 359 controls (defined as BMD Z-score >+1). Multi-variable logistic regression using an additive model was used to evaluate the association. The most associated SNPs of BMD at the spine, femoral neck, and total hip was then replicated in an additional 454 cases and 401 controls. Results: Twelve, 13, and 14 SNPs showed nominal association with BMD at the spine, femoral neck, and total hip, respectively. The minor alleles of rs9728351 (odds ratio [OR] = 2.56; 95% confidence interval [CI] = 1.33-4.92), rs11588607 (OR = 1.65; 95% CI = 1.14-2.4), and rs4454537 (OR = 1.87; 95% CI = 1.22-2.86) were associated with the low BMD at the spine, femoral neck, and total hip, respectively. Among these SNPs most associated with BMD, rs4454537 was successfully replicated in an independent cohort (OR = 1.59; 95% CI = 1.05-2.4). Meta-analysis showed that the minor allele of rs4454537 was associated with low total hip BMD with an OR of 1.72 (95% CI = 1.28-2.31) (P = 3.2 x 10(-4); P-corrected = .043). Conclusions: The minor allele of rs4454537 is significantly associated with low BMD at the total hip of southern Chinese people. Our study further suggests GREM2 as a novel susceptibility gene for osteoporosis.