Gene Polymorphisms in the RANKL/RANK/OPG Pathway Are Associated with Type 2 Diabetes Mellitus in Southern Han Chinese Women

Aims: Receptor activator of nuclear factor-kappa B ligand (RANKL), its receptor activator of nuclear factor-kappa B (RANK), and decoy receptor osteoprotegerin (OPG) are three major proteins of the RANKL/RANK/OPG signaling pathway encoded by TNFSF11, TNFRSF11A, and TNFRSF11B, respectively. This pathway plays a critical role in bone remodeling and may have a role in the pathogenesis of type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the relationship between gene polymorphisms in the RANKL/RANK/OPG pathway and T2DM in Southern Han Chinese women. Methods: A total of 1233 participants, including 514 T2DM patients and 719 healthy control subjects, were enrolled in this case-control study. Twenty-one single-nucleotide polymorphisms (SNPs) of TNFSF11, TNFRSF11A, and TNFRSF11B were genotyped using an improved multiplex ligation detection reaction technique. Results: Two SNPs of TNFRSF11B (rs11573819 and rs2073618) were significantly associated with T2DM (p = 0.04 and p = 0.009, respectively). Subjects with the GA genotype of rs11573819 had a lower risk of T2DM (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.51-0.88, p = 0.005) compared with subjects with the GG genotype. The GG genotype of rs2073618 was associated with increased risk for T2DM (OR = 1.94, 95% CI = 1.14-3.30, p = 0.01) compared with the CC genotype. Conclusions: This study suggests that TNFRSF11B but not TNFSF11 and TNFRSF11A genetic polymorphisms are associated with T2DM in Southern Han Chinese women. These findings provide preliminary support for the potential role of the RANKL/RANK/OPG pathway in T2DM.