Osteoporotic Fractures Are Associated with an 86‐Base Pair Repeat Polymorphism in the Interleukin‐1‐Receptor Antagonist Gene But Not with Polymorphisms in the Interleukin‐1β Gene

• Published in: Journal of bone and mineral research 2000-03, Vol.15 (3), p.402-414
• Main Authors: Langdahl, Bente L., Løkke, Elsebet, Carstens, Mette, Stenkjær, Lise Lotte, Eriksen, Erik Fink
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; bone mass; bone turnover; Diseases of the osteoarticular system; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Human; IL‐1β; IL‐1‐receptor antagonist; Medical sciences; osteoporosis; Osteoporosis. Osteomalacia. Paget disease; polymorphism; Population genetics, reproduction patterns
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.2000.15.3.402

Interleukin‐1β (IL‐1β) 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‐1β effects and the biological effects of IL‐1β are therefore proportional to the ratio IL‐1β/IL‐1ra. The coding regions of IL‐1β were examined for sequence variations by SSCP and sequencing after polymerase chain reaction (PCR) of genomic DNA. Three previously described polymorphisms (C−511‐T, G3877‐A and C3954‐T) in the IL‐1β 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‐1β gene. This substitution did not affect the amino acid sequence. We did not find other sequence variations in the IL‐1β gene apart from the already known polymorphisms. The distribution of C−511‐T, G3877‐A, and C3954‐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: G1731‐A, G1821‐A, A1868‐G, G1887‐C, T8006‐C, C8061‐T, 86 base pair variable number tandem repeat (VNTR), A9589‐T, and a new polymorphism: T1934‐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 (433%) (χ2 = 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. T11100‐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 conclusi