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Interleukin-1beta (IL-1beta) is a potent stimulator of bone resorption, and has been implicated in the pathogenesis of high bone turnover and osteoporosis. IL-1 receptor antagonist (IL-1ra) is a competitive inhibitor of IL-1beta effects and the biological effects of IL-1beta are therefore proportional to the ratio IL-1beta/IL-1ra. The coding regions of IL-1beta were examined for sequence variations by SSCP and sequencing after polymerase chain reaction (PCR) of genomic DNA. Three previously described polymorphisms (C(-511)-T, G(3877)-A and C(3954)-T) in the IL-1beta gene were determined by restriction fragment length polymorphism (RFLP) using Ava I, Aci I, and Taq I after PCR. The 86-base pair repeat polymorphism in IL-1ra was examined by PCR and electrophoresis and the T11100-C polymorphism in the IL-1ra gene was examined by RFLP using MspA1I after PCR. All polymorphisms were related to bone mass, biochemical markers of bone turnover, and presence of fracture in a study including 389 osteoporotic patients with vertebral fractures and normal controls. Two normal women were heterozygous for a shift from cytosine to thymine (C3263-T) in exon 4 of the IL-1beta gene. This substitution did not affect the amino acid sequence. We did not find other sequence variations in the IL-1beta gene apart from the already known polymorphisms. The distribution of C(-511)-T, G(3877)-A, and C(3954)-T genotypes was similar in the osteoporotic and the normal controls. No significant differences could be shown in bone mass or bone turnover. In the IL-1ra gene almost complete linkage was confirmed between the already known polymorphisms: G(1731)-A, G(1821)-A, A(1868)-G, G(1887)-C, T(8006)-C, C(8061)-T, 86 base pair variable number tandem repeat (VNTR), A(9589)-T, and a new polymorphism: T(1934)-C. The A1A1/A3 genotypes of the IL-1ra VNTR polymorphism were significantly more frequent in osteoporotic patients (56.2%) compared with age-matched normal controls (43.3%) (chi2 = 4.09; p = 0.043). The relative risk of osteoporotic fractures was increased to 1.68 (95% CI, 1.01-2.77) in individuals with A1A1/A3 genotypes. Bone mineral density (BMD) of the lumbar spine was reduced in individuals with A1A1/A3 genotypes (p = 0.014, analysis of variance ANOVA). The difference in bone mass between A1A1/A3 and A2A1/A2 tended to increase with increasing age. T1100-C genotypes were distributed similarly in osteoporotic patients and normal controls and the polymorphism was without effect on bone mass and biochemical markers of bone turnover. In conclusion, an 86-base pair repeat polymorphism in the IL-lra gene is associated with increased risk of osteoporotic fractures. Other polymorphisms in the IL-1ra and the IL-1beta genes are not associated with osteoporotic fractures or alterations in bone mass or bone turnover.
Langdahl et al. (Wed,) studied this question.