Susceptibility to osteoporotic fracture is determined by allelic variation at the Sp1 site, rather than other polymorphic sites at the COL1A1 locus

Previous studies have identified an association between osteoporotic fracture and a polymorphism affecting a Spl binding site in the first intron of the collagen type I alpha 1 gene (COL1A1). It is currently unclear, however, whether this association is direct or the result of linkage disequilibrium with other polymorphisms situated nearby. In this study we analyzed the relationship between four well-characterized single-nucleotide polymorphisms at the COL1A1 locus and osteoporotic fracture in 93 patients with vertebral fracture and 88 age-matched controls randomly selected from the community. We studied a MspI polymorphism 26 kb upstream of the COL1A1 gene, the Spl binding site polymorphism in intron I, a RsaI polymorphism in intron 5 and a MnlI polymorphism in exon 52. The Sp1 and RsaI polymorphisms were in strong linkage disequilibrium (chi(2)=77.87, p<0.001) and weaker linkage disequilibrium was detected between the Sp1 and MnlI polymorphisms (chi(2)=5.54, p<0.025). There was a significant association between COL1A1 haplotypes that included the Sp1 and RsaI polymorphisms and fracture (p<0.05-0.001), but no association with haplotypes that included only the MspI and MnlI polymorphisms. This association with fracture was strongest when haplotypes were grouped by Spl alleles (chi(2)=11.15, d.f. = 1; p = 0.001). Furthermore, logistic regression analysis showed that of all the polymorphisms tested, only the Sp1 binding site polymorphism acted as an independent predictor of fracture: odds ratio [95% CI] = 2.26 [1.09-4.69]. These data suggest that it is the Sp1 polymorphism rather than other polymorphisms at the COL1A1 locus which act as a marker for osteoporotic fractures.