rs12956925

This association study examined 589 European men to determine whether SNPs in RANKL, RANK, and OPG genes influence volumetric bone mineral density (vBMD) and bone geometry at the radius. The authors identified 12 OPG SNPs associated with vBMD and geometric parameters (e.g., rs10505348 associated with total vBMD β=9.35, P=0.011; rs2073618 associated with cortical vBMD β=-4.30, P=0.015), three RANK SNPs associated with vBMD including rs12956925 associated with trabecular vBMD β=-7.58, P=0.021, and five RANK SNPs associated with geometric parameters including rs8083511 associated with cross-sectional area β=8.90, P=0.029. No significant associations were found with RANKL SNPs, suggesting genetic variation in OPG and RANK influences radius bone density and geometry in men.

This association study identifies genetic variants in the TNFRSF11A gene (encoding RANK) associated with susceptibility to sporadic Paget's disease of bone (PDB) in three European populations. Meta-analysis across Belgian, Dutch, and British cohorts shows rs1805034 (A192V, p=1.27×10⁻⁸, OR=1.627) and rs35211496 (H141Y, p=.002, OR=1.410) are significantly associated with PDB, with strongest effects observed in females. Haplotype analysis in Belgian females identified risk haplotypes CGACGAA and AAAGGG with ORs of 2.808 and 3.462 respectively, though functional studies did not identify a definitive causative variant.

This association study of 1,873 subjects from 405 Caucasian nuclear families examined RANKL/RANK/OPG gene polymorphisms in relation to femoral neck compression strength index (fCSI). Three RANKL SNPs (rs12585014, rs7988338, rs2148073) were significantly associated with fCSI (P = 0.0007, 0.0007, and 0.0005, respectively) after Bonferroni correction, with a haplotype showing even stronger association (P = 0.0003). No significant associations were detected with bone mineral density, femoral neck width, or weight.

This linkage and family-based association study of 4,102 Caucasian subjects examined the RANK gene (chromosome 18q21.33) for association with obesity-related phenotypes. Linkage analysis achieved empirical P=0.004 for BMI at the RANK locus. Association testing of 18 SNPs identified 8 variants associated with obesity phenotypes (P<0.05), with strongest associations at rs11664594/SNP7 (P=0.002-0.003 for BMI, fat mass, lean mass, PFM) and rs4436867/SNP10 (P=0.002 for obesity) and rs4941125/SNP16 (P=0.001 for obesity). Multi-marker analysis showed significant association of the RANK gene with percentage fat mass (P=0.006).