Polymorphisms in the 5' flank of COL1A1 gene and osteoporosis: meta-analysis of published studies

Abstract

A meta-analysis of studies was conducted involving 24,511 participants with 7,864 fractures in which polymorphisms in the 5' flank of COL1A1 (rs1107946, rs2412298, and rs1800012) were related to osteoporosis phenotypes. Polymorphisms of all three sites were associated with BMD, and rs1800012 was associated with fracture but effect sizes were modest.

Introduction and hypothesis: Polymorphisms in the 5' flank of COL1A1 gene have been implicated as genetic markers for susceptibility to osteoporosis, but previous studies have yielded conflicting results.

Methods: We conducted a meta-analysis of 32 studies including 24,511 participants and 7,864 fractures in which alleles at the -1997G/T (rs1107946), -1663in/delT (rs2412298), and Sp1 binding site polymorphisms (rs1800012) of COL1A1 had been related to bone mineral density (BMD) or fracture.

Results: For the Sp1 polymorphism, BMD values in TT homozygotes were 0.13 units [95% CI, 0.03 to 0.24] lower at the spine (p = 0.01) and 0.16 units [0.10 to 0.23] lower at the hip (p = 1 x 10⁻⁶) than GG homozygotes. Clinical fractures were 1.31-fold [1.04-1.65] increased in TT homozygotes (p = 0.02) and vertebral fractures were 1.34-fold [1.01-1.77] increased (p = 0.04). We also observed associations between spine BMD and allelic variants at the -1997G/T (p = 0.05) and the -1663indelT (p = 0.009) sites. We found no association between alleles at the -1997G/T or -1663indelT sites and fracture but power was limited.

Conclusions: The COL1A1 Sp1 polymorphism is associated with a modest reduction in BMD and an increased risk of fracture, although we cannot fully exclude the possibility that the results may have been influenced by publication bias. Further studies are required to fully evaluate the contribution of the -1997G/T and -1663in/delT sites to these phenotypes and to determine if they interact with the Sp1 polymorphism to regulate susceptibility to osteoporosis.

Fig. 1

Meta-analysis of Sp1 polymorphism and association with BMD in females. Panel a Sp1 GG homozygotes versus TT homozygotes for lumbar spine BMD. Panel b Sp1 GG homozygotes versus TT homozygotes for femoral neck BMD. Each study is shown as the point estimate of the standardized mean difference with 95% confidence intervals as analyzed using a random effects model. The diamond shows the overall effect. Where the diamond lies to the right of the vertical line this indicates a higher BMD value in the GG genotype compared with the TT genotype group. The p values shown have not been corrected for multiple testing

Fig. 2

Meta-analysis for Sp1 polymorphism and association with fracture in females. Odds ratio (OR) for fracture is reported with 95% confidence intervals as analyzed using a random effects model for a all fractures or b vertebral fracture. The diamond shows the overall risk and where it lies towards the right of the vertical line, this indicates an increased risk of fracture associated with the genotype. The p values shown have not been corrected for multiple testing

Fig. 3

Association between -1997 G/T polymorphism and BMD in females. Comparisons are shown in panel a for lumbar spine BMD and panel b for femoral neck BMD. Each study is shown as the point estimate of the standardized mean difference with 95% confidence intervals as analyzed using a random effects model. Diamonds which lie to the left of the vertical line indicates a reduced BMD in the -1997 GG genotype compared with G/T and TT genotype groups. The p values shown have not been corrected for multiple testing

Fig. 4

Funnel plots of spine and hip BMD in the whole study population. a Funnel plot of lumbar spine BMD in whole study population. b Funnel plot of femoral neck BMD in whole study population. Standardized mean difference is plotted on the horizontal axis and its standard error on the vertical axis