Association of Variant Interactions in RANK, RANKL, OPG, TRAF6, and NFATC1 Genes with the Development of Osteonecrosis of the Femoral Head.

Multiple gene polymorphisms have been demonstrated to correlate with the susceptibility to osteonecrosis of the femoral head (ONFH). However, as a complex disease induced by multiple genes, the development of ONFH has rarely been reported to involve in gene interaction. In this study, we first explored the association of 10 variants interactions in receptor activator of nuclear factor-kappa B (RANK), RANK ligand (RANKL), osteoprotegerin (OPG), tumor necrosis factor receptor-associated factor 6 (TRAF6), and nuclear factor of activated T cells cytoplasmic 1 (NFATC1) genes with the development and clinical phenotypes of ONFH in a 377 ONFH case-control study with using Mass ARRAY® platform. Our results showed that not only a total of 6 interactional variants in the paired 10 variants interactions were significantly associated with the development of ONFH (OPG rs2073617 and NFATC1 rs754093, p < 0.019; OPG rs2073618 and NFATC1 rs754093, p < 0.008; OPG rs2073617 and RANKL rs1054016, p < 0.039, respectively) but also a total of 4 paired interactional variants were found to involve significantly in the increased risk of bilateral hip lesions in ONFH (OPG rs2073617 and TRAF6 rs5030411, p = 0.044; RANK rs884205 and TRAF6 rs5030411, p = 0.045, respectively). Moreover, the results from generalized multifactor dimensionality reduction also showed that the five best models were identified and associated significantly with ONFH risk, p = 0.001, 0.01, 0.01, 0.01, and 0.01, respectively. Our results first suggest that the variants in RANK/RANKL/OPG pathway genes affected the development of ONFH in gene interaction manner through the interaction of the paired variants and multiple variants.