James L, Onambele G, Woledge R, Skelton D, Woods D, Eleftheriou K, Hawe E, Humphries SE, Haddad F, Montgomery H. IL-6-174G/C genotype is associated with the bone mineral density response to oestrogen replacement therapy in post-menopausal women. Eur J Appl Physiol. 2004;92(1-2):227-30.

A reduction in interleukin-6 (IL-6) activity may contribute to the beneficial effects of hormone replacement therapy (HRT) on the menopausal decline in bone mineral density (BMD). We have examined this hypothesis using a genetic strategy. The -174C (rather than G) IL-6 gene variant is associated with lower IL-6 expression. As such, we might anticipate the C allele to be associated with a greater response to HRT. We have tested this hypothesis. Mean three-site [spine (L1-L4), neck of femur, and Ward's triangle] BMD was measured in 65 women in a 1-year randomised controlled trial of HRT with 0.625 mg oestrogen/day and 0.15 mg norgestrel (n=30). Baseline BMD was genotype-independent for both the control and HRT group. In the control group, the percentage change in BMD after 1 year was similar between genotypes (P=0.45). In contrast, in the HRT group, the rise was genotype-dependent. Those homozygous for the G allele showed a 3.62 (2.14)% increase in BMD compared with 10.44 (4.68)% for the C-homozygous group. Heterozygotes had an intermediate BMD increase of 5.6 (2.82)% [ P=0.006 ( P value for interaction between HRT and genotype was 0.04)] Although the study was limited by its small sample size, these are the first data to demonstrate the importance of IL-6 genotype in determining response to oestrogen therapy, rather than its physiological withdrawal.

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