title: The -1997 G/T and Sp1 polymorphisms in the collagen type I alpha1 (COLIA1) gene in relation to changes in femoral neck bone mineral density and the risk of fracture in the elderly: the Rotterdam study.
abstract: The COLIA1 Sp1 polymorphism has been associated with bone mineral density (BMD) and fracture. A promoter polymorphism, -1997 G/T, also has been associated with BMD. In this study, we examined whether these polymorphisms alone and in the form of haplotypes influence bone parameters and fracture risk in a large population-based cohort of elderly Caucasians. We determined the COLIA1 -1997 G/T (promoter) and Sp1 G/T (intron) polymorphisms in 6,280 individuals and inferred haplotypes. Femoral neck BMD and BMD change were compared across COLIA1 genotypes at baseline and follow-up (mean 6.5 years). We also investigated the relationship between the COLIA1 polymorphisms and incident nonvertebral fractures, which were recorded during a mean follow-up period of 7.4 years. Vertebral fractures were assessed by radiographs on 3,456 genotyped individuals. Femoral neck BMD measured at baseline was 3.8% lower in women carrying two copies of the T-Sp1 allele (P for trend = 0.03). No genotype dependent differences in BMD loss were observed. In women homozygous for the T allele of the Sp1 polymorphism, the risk of fragility fracture increased 2.3 times (95% confidence interval 1.4-3.9, P = 0.001). No such association was observed with the promoter polymorphism. In men, no association with either the Sp1 or the -1997 G/T promoter polymorphism was seen with BMD or fracture. High linkage disequilibrium (LD; D' = 0.99, r (2 )= 0.03) exists between the two studied polymorphisms. We observed three haplotypes in our population: haplotype 1 (G(promoter)-G(intron)) frequency (f) = 69%, haplotype 2 (G(promoter)-T(intron)) f = 17.6%, and haplotype 3 (T(promoter)-G(intron)) f = 13.4%. Haplotype 2 was associated with a 2.1-fold increased risk of fragility fracture in women (95% confidence interval 1.2-3.7, P = 0.001). We confirm that the COLIA1 Sp1 polymorphism influences BMD and the risk of fracture in postmenopausal Caucasian women. In contrast, we found no independent effect of the -1997 G/T promoter polymorphism on BMD or fracture.
authors.affiliation: Netherlands Institute for Health Science, Rotterdam, The Netherlands.
authors.forename: Nahid
authors.initials: N
authors.lastname: Yazdanpanah
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: M Carola
authors.initials: MC
authors.lastname: Zillikens
authors.forename: P
authors.initials: P
authors.lastname: Arp
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Huibert A P
authors.initials: HA
authors.lastname: Pols
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
mesh_terms: D000368:Aged; D015519:Bone Density; D015331:Cohort Studies; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005272:Femur Neck / Q000473:pathology*; D017102:Fracture Healing; D050723:Fractures, Bone / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011110:Polymorphism, Genetic; D012306:Risk; D044465:White People
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain