Effect of the COL1A1 G-1997T variant on osteoporosis and fracture susceptibility in Malta

Abstract

Osteoporosis is a multifactorial metabolic skeletal disorder characterised by low bone mass and microarchitectural deterioration, predisposing to increased fracture risk. Genetic studies have identified several gene variants associated with osteoporosis and fracture risk, particularly those in the collagen type I alpha I (COL1A1) gene. COL1A1 encodes the pro alpha-1(I) chain of type I collagen which is the most abundant protein in bone and found in a 2:1 ratio with pro-alpha-2(I) collagen. The promoter COL1A1 G-1997T (rs1107946) variant is hypothesised to affect transcription factor binding resulting in altered gene expression and protein production, that in turn creates an imbalance in the 2:1 ratio leading to reduced bone strength and increased porosity culminating in higher fracture risk. The aim of the study was to determine whether the COL1A1 G-1997T variant affects spine and hip bone mineral density (BMD), and fracture susceptibility in Maltese postmenopausal women. The variant was genotyped in a case-control collection of 1,045 Maltese postmenopausal women using the TaqMan® fluorogenic 5’ nuclease allelic discrimination assay. The Mann-Whitney and Kruskal Wallis tests were performed to assess genotype phenotype associations, whilst odds ratios (OR) with 95% confidence intervals (CI) were computed using logistic regression analysis adjusted for age computed to determine the effect of the genotyped variant in relation to osteoporosis and fracture risk. Allele frequencies for the wild-type (G) and alternative (T) allele were of 80.2% and 19.8% respectively, and the population was in Hardy-Weinberg equilibrium. Women with the homozygous alternative genotype had a 2-fold (95% CI 1.0-4.5) increased risk of osteoporosis at the lumbar spine relative to women with the homozygous wild-type genotype. No associations were observed with BMD at the femoral neck and total hip, or with fracture risk. Results indicate that the COL1A1 G-1997T variant predisposes to osteoporosis, particularly in trabecular-rich bone, such as the vertebrae.