Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women.

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.