Association analysis of estrogen receptor α gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families

Bone geometry is a key factor in bone strength, which is the ultimate intrinsic determinant of fracture risk. Though the heritability of bone geometry is high, little effort has been spent on searching for the underlying genes. In this study, employing a sample of 1,873 subjects from 405 Caucasian nuclear families, we studied seven single nucleotide polymorphisms (SNPs) and their haplotypes of the ER-α gene for association with six hip geometric variables, namely, cross-sectional area (CSA), cortical thickness (CT), endocortical diameter (ED), subperiosteal width (W), sectional modulus (Z) and buckling ratio (BR). The major method used was the quantitative transmission disequilibrium test (QTDT). Our major findings were summarized below. The within-family association between SNP4 (rs1801132) in exon 4 with endocortical diameter and subperiosteal width was detected in single locus analyses (P = 0.008 and 0.021, respectively) and verified in haplotype analyses (P = 0.034 and 0.058, respectively). The total association of SNP4 with these two diameters was also observed in both single locus and haplotype analyses (P = 0.005 and 0.031 for ED, plus P = 0.003 and 0.070 for W). In addition, the total association between SNP5 (rs932477) in intron 4 with cortical thickness and buckling ratio was detected (single locus analyses: P = 0.035 and 0.041, respectively). Haplotype analyses further supported the above association (P = 0.010 and 0.004, respectively). Similar patterns of associations with the studied SNPs and their haplotypes were present in subsamples stratified by sex, too. However, after permutation tests, the empirical significance level was set as P < 0.011, which renders most associations insignificant. Therefore, we concluded that polymorphisms in the ER-α gene were nominally associated with femoral neck (FN) geometry variables estimated from DXA. Such genetic effects on hip geometry were not sex specific.