Interaction between the vitamin D receptor gene and collagen type I alpha 1 gene in susceptibility for fracture

Osteoporosis is a common disease with a strong genetic component. Polymorph isms in the vitamin D receptor (VDR) gene have been implicated in osteoporo sis but explain only a small part of the genetic effect on bone mineral den sity (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Spl site in the collagen type I alpha1 (COLIA1) g ene was found to be associated with reduced BRID and,vith increased fractur e risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fract ure, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constru cted from three adjacent restriction fragment length polymorphisms, was fou nd to be overrepresented among fracture cases (p = 0.009). This corresponde d to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95%CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most impo rtantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotyp e-dependent in the COLIA1 '"reference" group (genotype GG) while in the COL IA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95%CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carrier s of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 p olymorphisms are genetic markers for osteoporotic fracture in women, indepe ndent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.