Standard color scheme is displayed: bright red (D′ = 1; LOD ≥ 2), blue (D′ = 1; LOD < 2), shade of pink/red (D′ < 1; LOD ≤ 2), white (D′ < 1; LOD < 2) The most frequent haplotype was the P2X7-1 variant, accounting

for 37.4 % of the alleles. This haplotype was defined as wild-type. The P2X7-2 and P2X7-4 variants contained the variant allele of the Ala348Thr polymorphism and accounted for 24.9 and 15.7 % of the alleles, respectively. Besides the Ala348Thr polymorphism, the P2X7-4 variant also contained the variant allele of the Gln460Arg polymorphism. The P2X7-3 and P2X7-5 variants contained the loss-of-function polymorphisms Thr357Ser and Glu496Ala, respectively. Strong linkage disequilibrium buy 3-deazaneplanocin A was found between the Bafilomycin A1 purchase Glu496Ala polymorphism and the null allele (D′ = 0.90; Fig. 3). Furthermore, linkage disequilibrium was observed between the Gln460Arg polymorphism and the His155Tyr gain-of-function polymorphism (D′ = 0.86). Association

of P2RX7 haplotypes with bone mineral density Haplotype analysis of the association between BMD and haplotypes showed decreased BMD values in subjects with haplotype P2X7-3. Assuming an additive model this decrease was significant at the lumbar spine (p = 0.035). The proportional odds model showed a significantly increased odds of a lower T-score (OR = 2.09 [95%CI, 1.06–4.11]) for subjects with haplotype P2X7-3 compared to wild-type subjects (i.e. subjects Combretastatin A4 price having haplotype P2X7-1). Gender-stratified analyses showed no association of any of the haplotypes with BMD. Discussion Within a cohort of Dutch fracture patients we investigated 15 non-synonymous SNPs within the P2RX7 in association with osteoporosis. Results showed that the Ala348Thr gain-of-function polymorphism in the P2RX7 was associated with increased lumbar spine BMD values. We also observed significant associations between BMD values and two loss-of-function SNPs in the P2RX7, that is,

decreased hip BMD values were found in subject homozygous for the Glu496Ala polymorphism 4-Aminobutyrate aminotransferase as well as subjects carrying at least one variant allele of the Gly150Arg polymorphism. In men we found that subjects either heterozygous or homozygous for the Gln460Arg gain-of-function polymorphism in the P2RX7 had a significantly decreased risk of osteoporosis. The Glu186Lys, Leu191Pro and the Arg270Cys polymorphisms were not present in the studied population. The allele frequencies for the remaining 12 SNPs in our population were almost identical to previously published data [17, 19]. In non-osteoporotic subjects, SNPs were shown to be in HWE, except the Ala348Thr and Val76Ala polymorphisms which showed significant deviation from HWE. Since the internal validation study, in which we repeated the genotyping in a random sub-sample of our study population, indicated adequate accuracy for subjects with <2 missing SNPs in the P2RX7, genotyping errors are a very unlikely explanation for the observed deviation from HWE.