Association Analyses of RANKL/RANK/OPG Gene Polymorphisms with Femoral Neck Compression Strength Index Variation in Caucasians

Abstract

Femoral neck compression strength index (fCSI), a novel phenotypic parameter that integrates bone density, bone size, and body size, has significant potential to improve hip fracture risk assessment. The genetic factors underlying variations in fCSI, however, remain largely unknown. Given the important roles of the receptor activator of the nuclear factor-κB ligand/receptor activator of the nuclear factor-κB/osteoprotegerin (RANKL/RANK/OPG) pathway in the regulation of bone remodeling, we tested the associations between RANKL/RANK/OPG polymorphisms and variations in fCSI as well as its components (femoral neck bone mineral density [fBMD], femoral neck width [FNW], and weight). This was accomplished with a sample comprising 1873 subjects from 405 Caucasian nuclear families. Of the 37 total SNPs studied in these three genes, 3 SNPs, namely, rs12585014, rs7988338, and rs2148073, of RANKL were significantly associated with fCSI (P = 0.0007, 0.0007, and 0.0005, respectively) after conservative Bonferroni correction. Moreover, the three SNPs were approximately in complete linkage disequilibrium. Haplotype-based association tests corroborated the single-SNP results since haplotype 1 of block 1 of the RANKL gene achieved an even more significant association with fCSI (P = 0.0003) than any of the individual SNPs. However, we did not detect any significant associations of these genes with fBMD, FNW, or weight. In summary, our findings suggest that the RANKL gene may play an important role in variation in fCSI, independent of fBMD and non-fBMD components. KeywordsFemoral neck compression strength index; Femoral neck bone mineral density; Femoral neck width; RANKL/RANK/OPG gene; Quantitative transmission disequilibrium test Osteoporosis is a systemic skeletal disorder characterized by impaired bone strength and an elevated risk of osteoporotic fractures. Osteoporosis represents a major health problem throughout the world and the most serious consequence of osteoporosis is hip fracture, which has a high associated morbidity and mortality [1]. Currently, measurements of bone mineral density (BMD) are widely used to assess hip fracture risk [2,3]. However, BMD alone can only account for about 50-70% of total bone strength variation [4]. Among other risk factors of hip fracture, femoral neck width (FNW) and body weight have been repeatedly reported to be correlated with hip fracture risk [5][6][7][8][9][10]. Femoral neck compression strength index (fCSI) [11], a function of femoral neck BMD (fBMD), FNW, and weight based on structural engineering principles, may have the potential to improve hip fracture risk assessment. Karlamangla et al. [11] observed that a 1-standard-deviation (SD) decrease in fCSI was associated with an approximately 2.56-fold increase in hip fracture risk (P < 0.0001), while a 1-SD decrease in fBMD was associated with only a 1.96-fold increase in hip fracture (P = 0.0013). [18][19][20]. In the current study, for the first time, we comparatively examined the influence of RANKL/RANK/OPG gene variant...

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