Investigation and characterisation of loci influencing the genetic susceptibility to osteoporosis
The main aim of this thesis was to identify novel genes or to further define the role of existing candidate genes in the regulation of BMD. In chapter 3, the role of the oestrogen receptor (ER)- and - genes in BMD regulation was investigated because of the importance of oestrogen deficiency in the pathogenesis of postmenopausal osteoporosis. The results showed that ER- haplotypes defined by two intronic polymorphisms (Pvull and XbaI) were significantly associated with BMD in postmenopausal women from the U.K. No significant association was found between a novel ER- polymorphism and BMD. In chapter 4, linkage analysis was performed on a candidate locus on chromosome 11q12-13 that has previously been found to be linked to a high BMD trait. Although the linkage study was insufficiently powered to detect linkage, analysis of a positional candidate gene (the Fra-1 gene) located in the 11q12-13 region showed a strong association with BMD. Fos related antigen-1 (Fra-1) is important in osteoclast differentiation. In chapter 5, a novel polymorphism was identified in the Fra-1 gene and found to be highly associated with BMD in a study of perimenopausal women from the U.K. In chapter 6, association mapping using DNA pooling was performed on the chromosome 1p36 locus which has previously been found to be linked to hip BMD using sib-pair linkage analysis. Analysis of 17 microsatellite markers from the 1p36 region in a group of individuals with high and low BMD showed five positive markers associated with hip BMD. Analysis of two candidate genes in the 1p36 region (the TNFR2 and NPPB genes) showed significant association between polymorphisms in the TNFR2 gene and BMD.