The genetics of osteoporosis

Abstract

Osteoporosis is a metabolic bone disease with a strong genetic component. In this study both association and linkage approaches were used to identify genes that might be responsible for the disease in the Maltese population. No statistically significant association was found between the studied polymorphisms within candidate genes and bone mineral density (BMD) in a group of postmenopausal women. A statistically significant difference was observed in the distribution of genotype and haplotype frequencies, between women having a normal and a low BMD, of polymorphisms within the promoter region of the osteoprotegerin gene (TNFRSF11B). A genome-wide scan using 400 microsatellite markers was performed in 27 members from two extended families with a high incidence of osteoporosis. Evidence of linkage was observed to a marker at I1p12 where a nonparametric LOD score (NPl) of 5.77 (p=0.0006) was obtained. A maximum heterogeneity LOD (HlOD) score of 2.55 for this region was obtained for the dominant mode of inheritance with 90% penetrance and a phenocopy rate of 1%. Following fine mapping, the critical interval was narrowed to a region that is 52.94cM from IIp-telomere. In this region the gene for TRAF-6 is located approximately 1cM away from the indicated marker. Suggestive linkage was also observed to other chromosomal regions including 5q34, 6q23 and 5p15. Known genes that might be involved in the disease that are found in these regions include those coding for fibroblast growth factor {FGF)-18 (5q34) and interferon gamma receptor {IFNGR)-1 (6q23). The TRAF6 and FGF18 genes were sequenced to try to identify any mutations. No suspected variants were observed in the coding regions of the FGF18 and TRAF6 genes. Sequencing of the promoter region and intron-exon boundaries of the TRAF6 gene revealed three sequence variants, two of which were found in introns and the third one found in the promoter region, at position -721 upstream from the transcriptional start site. Three affected members within one family were heterozygous for this variant in the promoter region while only two heterozygotes for this variant were identified (population frequency 1.1%), when screening the general population (n=175). Studies of this variant on its possible role in gene expression are indicative of an effect on gene expression, possibly by collaboration with other transcriptional factors further upstream in the promoter. An increase in TRAF6 expression can result in increased osteoclastogenesis and therefore an increased risk of osteoporosis.