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

Previous studies have identified an association between osteoporotic fractu re and a polymorphism affecting a Spl binding site in the first intron of t he 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 re lationship 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 stro ng linkage disequilibrium (chi(2)=77.87, p<0.001) and weaker linkage disequ ilibrium was detected between the Sp1 and MnlI polymorphisms (chi(2)=5.54, p<0.025). There was a significant association between COL1A1 haplotypes tha t 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 polymor phisms. This association with fracture was strongest when haplotypes were g rouped by Spl alleles (chi(2)=11.15, d.f. = 1; p = 0.001). Furthermore, log istic regression analysis showed that of all the polymorphisms tested, only the Sp1 binding site polymorphism acted as an independent predictor of fra cture: odds ratio [95% CI] = 2.26 [1.09-4.69]. These data suggest that it i s the Sp1 polymorphism rather than other polymorphisms at the COL1A1 locus which act as a marker for osteoporotic fractures.