Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study

Abstract

Background: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.

Methods and findings: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.

Conclusions: Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

Figure 1. Association between COLIA1 Alleles and BMD

Differences in BMD (in mg/cm ²) for the contrasts of GG homozygotes versus GT heterozygotes are shown in the top panel and those for GG and GT combined versus TT homozygotes in the bottom panel. For each study, the point estimates and 95% CIs for the differences in BMD in the lumbar spine (blue) and femoral neck (green) are shown. The figures are purposely drawn putting data on the two skeletal sites side by side in each center for comparison. Summary estimates of the differences and their 95% CIs are given by random effects models for male (M), female (F), and all participants (total). Fixed effects estimates are very similar (not shown). Filled circles represent summary estimates.

Figure 2. Association between COLIA1 Alleles and Fractures

OR for fractures in co-dominant models (per T allele) for (A) fracture at any site; (B) vertebral fracture; and (C) incident vertebral fracture. Point estimates and 95% CIs are shown for the ORs in each study. Summary estimates of the ORs and their 95% CIs (diamonds) are given by random effects models per gender and for the total database.