title: Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women.
abstract: BACKGROUND
  The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1.
  
  
  OBJECTIVE
  The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women.
  
  
  METHODS
  This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program.
  
  
  METHODS
  BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298).
  
  
  RESULTS
  The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LS-BMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/+1245G) had increased BMD (P = 0.007 for LS-BMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype.
  
  
  CONCLUSIONS
  Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.
authors.affiliation: Rheumatic Diseases Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Stewart
authors.forename: Huilin
authors.initials: H
authors.lastname: Jin
authors.forename: Fiona E A
authors.initials: FE
authors.lastname: McGuigan
authors.forename: Omar M E
authors.initials: OM
authors.lastname: Albagha
authors.forename: Natalia
authors.initials: N
authors.lastname: Garcia-Giralt
authors.forename: Amelia
authors.initials: A
authors.lastname: Bassiti
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.forename: Susana
authors.initials: S
authors.lastname: Balcells
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
mesh_terms: D015502:Absorptiometry, Photon; D015519:Bone Density / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D006113:United Kingdom
chemical_list: D024042:Collagen Type I; D004247:DNA