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-1beta gene.
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
B L
BL
Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus Amtssygehus, Denmark.
Løkke
E
E
Carstens
M
M
Stenkjaer
L L
LL
Eriksen
E F
EF
D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers; D015519:Bone Density / Q000235:genetics; D016723:Bone Remodeling / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics / Q000503:physiopathology; D016022:Case-Control Studies; D003094:Collagen / Q000032:analysis; D024042:Collagen Type I; D005091:Exons / Q000235:genetics; D005260:Female; D005598:Fractures, Spontaneous / Q000453:epidemiology / Q000209:etiology; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D008297:Male; D008593:Menopause; D008875:Middle Aged; D018598:Minisatellite Repeats; D016017:Odds Ratio; D010024:Osteoporosis / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D010052:Ovariectomy; D010455:Peptides / Q000032:analysis; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D012306:Risk; D012795:Sialoglycoproteins / Q000235:genetics*
D015415:Biomarkers; D024042:Collagen Type I; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010455:Peptides; D012795:Sialoglycoproteins; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen; D006909:Hydroxyproline