Genetic polymorphisms of the wint receptor LRP5 are differentially associated with trochanteric and cervical hip fractures

Abstract

Purpose. Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We planned to test the hypothesis that genetic factors have different influences on both types of fractures. Methods. Ten polymorphisms of genes known to play an important role in skeletal homeostasis (estrogen receptor alpha [ESR1], aromatase [CYP19A1], type I collagen [COL1A1], and lipoprotein receptor-related protein 5 [LRP5]) were analyzed in 471 Spanish patients with fragility hip fractures. Results. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (p-value 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci, in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with 1 or 2 rare alleles, and 7.5 in those with 3 or 4 rare alleles (p-value for trend 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1 and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or in an extended group of 818 patients. Conclusions. These results suggest LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies.