Collagen and osteoporosis

Common conditions such as osteoporosis often show clear evidence for a genetic component, but pinning the risk of disease on a specific genetic polymorphism is notoriously tricky in these cases: Biologically plausible candidates abound, and evidence implicating a particular mutation in the disease process can be difficult to reproduce. In the case of osteoporosis, one candidate that has been tested repeatedly is a single nucleotide polymorphism in the collagen gene COL1A1 in a sequence that interacts with the transcription factor Sp1. Now, Mann et al. have revisited the vexed question of whether this polymorphism is indeed associated with fragile bones and frequent fractures. First, they performed meta-analysis on 15 studies reported over the last 5 years, dealing with the effects of the Sp1 site polymorphism. In aggregate, they find that carrying one of the two alleles, termed "s", in homozygous form correlates with a loss of bone mass density. The ss genotype predicts a nearly twofold greater risk of vertebral fractures relative to SS homozygotes, with Ss heterozygotes experiencing intermediate effects. Turning to the molecular effects of this polymorphism, they show that, at least in cultured human osteoblasts, the s allele generates higher steady state levels of COL1A1 mRNA than does the S allele, perhaps as a result of more efficient Sp1-dependent transcription. This difference in transcript level further correlates with an increase in the relative amount of the a1(I) collagen chain, the product of this mRNA, in the mature collagen produced by cultured osteoblasts. The authors argue that differences in collagen trimer subunit composition may explain the mechanical and biochemical features they see in the bones of individuals carrying the s allele.