Association of the G-174C Variant in the Interleukin-6 Promoter Region With Bone Loss and Fracture Risk in Older Women

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Abstract
We analyzed the association between the IL‐6 G‐174C polymorphism and osteoporosis phenotypes in 3376 older women. Women with the C/C genotype had a significantly slower rate of decline in hip BMD and a 33% lower risk of wrist fracture than women with the G/G genotype. Variation at the IL‐6 locus may contribute to the genetic susceptibility to bone fragility. Introduction: Interleukin 6 (IL‐6) promotes osteoclast formation and bone resorption. The C allele of the G‐174C polymorphism in the IL‐6 promoter region has been related to lower gene transcription and plasma IL‐6 levels. Materials and Methods: In this study, we evaluated the relationship between the IL‐6 G‐174C polymorphism and BMD, the rate of decline in BMD, and the risk of fracture in 3376 women 65 years of age and older participating in the Study of Osteoporotic Fractures. BMD was measured at the distal and proximal radius using single photon absorptiometry and at the hip using DXA. Hip BMD was measured again an average of 3.5 years later. Incident fractures over an average of 10.8 years of follow‐up were confirmed by physician adjudication of radiology reports. Results: Distal and proximal radius BMD was lowest among women with the G/G genotype, intermediate in the heterozygotes, and highest in women with the C/C genotype (p = 0.016 and p = 0.049, respectively), although the differences between the genotypes were small. While there were no differences by genotype with initial hip BMD, women with the C/C genotype experienced a slower rate of decline in total hip and femoral neck BMD compared with women with the G/G genotype (p = 0.004 and p = 0.029, respectively). Women with the C/C genotype also had 33% lower risk of wrist fracture compared with women with the G/G genotype, independent of age, body mass index, estrogen use, and study center (RR, 0.67; 95% CI, 0.45, 1.00; p = 0.048), whereas heterozygous women had a more intermediate risk (RR, 0.85; 95% CI, 0.65, 1.12; p = 0.256). No association was found between genotype and risk of hip or all non‐spine fractures. Conclusions: These results suggest that the IL‐6 G‐174C promoter polymorphism may be a genetic marker for bone loss and wrist fracture among older women.

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