Polymorphisms in genes involved in the NF-κB signalling pathway are associated with bone mineral density, geometry and turnover in men

<p><b>Introduction:</b> In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-kappa B cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover.</p> <p><b>Methods:</b> Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r<sup>2</sup> ≥= 0.8) within MAP3K14 (±10 kb) were genotyped in 2359 men aged 40-79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS). Measurement of bone turnover markers (PINP and CTX-I) in the serum and quantitative ultrasound (QUS) at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA), at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT), at the distal and midshaft radius, were performed in a subsample (2 centres). Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre.</p> <p><b>Results:</b> We validated the associations between SNPs in GPR177 and BMD<sub>a</sub> previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMD<sub>a</sub>, increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMD<sub>a</sub>, vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS.</p> <p><b>Conclusion:</b> Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-kappa B signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.</p&gt