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Haplotypes Defined by Promoter and Intron 1 Polymorphisms of the COLIA1 Gene Regulate Bone Mineral Density in Women

Department of Medicine and Therapeutics (T.L.S., H.J., F.E.A.M., A.B., D.M.R., S.H.R.), University of Aberdeen Medical School, Aberdeen AB25 2ZD, United Kingdom; Rheumatic Diseases Unit (H.J., O.M.E.A., S.H.R.), School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom; and University of Barcelona (N.G.-G., D.G., S.B.), Barcelona, Spain

Address all correspondence and requests for reprints to: Professor Stuart H. Ralston, Rheumatic Diseases Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. E-mail: stuart.ralston{at}ed.ac.uk.

Context: 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.

Design: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program.

Main Outcome Measures: 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.

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