title: Haplotypes of promoter and intron 1 polymorphisms in the COLIA1 gene are associated with increased risk of osteoporosis.
abstract: 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/cm(2), in individuals with the del/del genotype versus 0.83 +/- 0.18 and 0.85 +/- 0.18 g/cm(2) 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/cm(2), respectively, versus 0.78 +/- 0.15 g/cm(2) 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/cm(2), versus 0.85 +/- 0.18 and 0.82 +/- 0.18 g/cm(2), 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.
authors.affiliation: Department of Endocrinology and Metabolism, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus C, Denmark.
authors.forename: L B
authors.initials: LB
authors.lastname: Husted
authors.forename: T
authors.initials: T
authors.lastname: Harsløf
authors.forename: N
authors.initials: N
authors.lastname: Gonzalez-Bofill
authors.forename: A
authors.initials: A
authors.lastname: Schmitz
authors.forename: M
authors.initials: M
authors.lastname: Carstens
authors.forename: L
authors.initials: L
authors.lastname: Stenkjaer
authors.forename: B L
authors.initials: BL
authors.lastname: Langdahl
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000235:genetics; D016022:Case-Control Studies; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D050723:Fractures, Bone / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics*; D015810:Linkage Disequilibrium; D010024:Osteoporosis / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain