Functional polymorphisms in the P2X7 receptor gene are associated with osteoporosis

The P2X(7) receptor is an ATP-gated cation channel. We investigated the effect of both loss-of-function and gain-of-function polymorphisms in the P2X(7) receptor gene on BMD and risk of vertebral fractures and found that five polymorphisms and haplotypes containing three of these polymorphisms were associated with BMD and fracture risk. The P2X(7) receptor is an ATP-gated cation channel. P2X(7) receptor knockout mice have reduced total bone mineral content, and because several functional polymorphisms have been identified in the human P2X(7) receptor gene, we wanted to investigate the effect of these polymorphisms on BMD and risk of vertebral fractures in a case-control study including 798 individuals. Genotyping was carried out using TaqMan assays. BMD was measured using dual energy X-ray absorptiometry, and vertebral fractures were assessed by lateral spinal X-rays. The rare allele of a splice site polymorphism, 151 + 1: G-T, was associated with increased fracture risk and reduced BMD in women. Two other loss-of-function polymorphisms, Glu496Ala and Gly150Arg, were also associated with BMD. The Glu496Ala variant allele was associated with decreased lumbar spine BMD in women and decreased total hip BMD in men. The 150Arg allele was associated with decreased total hip BMD in women and men combined. The minor allele of the gain-of-function polymorphism, Ala348Thr, was associated with reduced fracture risk and increased BMD at all sites in men. The Gln460Arg variant allele, which has been associated with increased receptor function in monocytes, was associated with increased total hip BMD in women. With the exception of His155Tyr for which we found conflicting results in men and women, our results are consistent with the phenotype of the knockout mouse. Analysis of a haplotype containing Ala348Thr, Gln460Arg, and Glu496Ala showed that the effects of the haplotypes on BMD and fracture were driven by Ala348Thr in men and by Gln460Arg and Glu496Ala in women. In conclusion, we found that functional polymorphisms in the P2X(7) receptor gene and haplotypes containing three of these polymorphisms are associated with osteoporosis.