Haplotypes of Promoter and Intron 1 Polymorphisms in the COLIA1 Gene Are Associated with Increased Risk of Osteoporosis
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- Husted, L.B., Harsløf, T., Gonzalez-Bofill, N. et al. Calcif Tissue Int (2009) 84: 85. doi:10.1007/s00223-008-9199-1
Osteoporosis is a common age-related disease with a strong genetic influence. COLIA1 is one of the most extensively studied candidate genes and has consistently been associated with BMD and fracture. We examined the effects of the polymorphisms –1997G>T, –1663indelT, and +1245G>T and their haplotypes on vertebral fractures and bone mineral density (BMD) in a case-control study comprising 462 osteoporotic patients and 336 controls. The −1663indelT polymorphism was associated with a decreased lumbar spine (ls) BMD, 0.75 ± 0.14 g/cm2, in individuals with the del/del genotype versus 0.83 ± 0.18 and 0.85 ± 0.18 g/cm2 in individuals with the ins/del and ins/ins genotypes, respectively (p = 0.02). The T-allele of the +1245G>T polymorphism, which was in strong linkage disequilibrium (LD) with –1663indelT, was also associated with a decreased lsBMD (p = 0.02). –1997G>T was not significantly associated with lsBMD. The three most common haplotypes accounted for 98.5% of the alleles. Individuals with one or two copies of haplotype 1 (–1997G/–1663ins/+1245G) had a significantly higher lsBMD, 0.84 ± 0.18 and 0.85 ± 0.15 g/cm2, respectively, versus 0.78 ± 0.15 g/cm2 in noncarriers (p = 0.01). Individuals with two copies of haplotype 2 (–1997G/–1663del/+1245T) had a significantly lower lsBMD, 0.76 ± 0.14 g/cm2, versus 0.85 ± 0.18 and 0.82 ± 0.18 g/cm2, respectively, in individuals with zero or one copy (p = 0.03). The odds ratio for vertebral fracture in individuals carrying the variant T-allele of the –1997G>T polymorphism was 1.49 (CI, 1.03–2.16; p = 0.03). Logistic regression revealed that this effect was partly independent of BMD. In conclusion, the −1663del and +1245T alleles influence BMD negatively, whereas the –1997T-allele has a minor effect on BMD but increases the risk of vertebral fractures. These findings are in agreement with functional studies showing that these polymorphisms influence gene expression.