Polymorphisms in the Interleukin-1 Receptor Antagonist and Interleukin-6 Genes Affect Risk of Osteolysis in Patients With Total Hip Arthroplasty
Polymorphisms in the Interleukin-1 Receptor Antagonist and Interleukin-6 Genes Affect Risk of Osteolysis in Patients With Total Hip Arthroplasty
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DOI：
10.1002/art.23863
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发表时间：
2008-10-01
影响因子：
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通讯作者：
Wilkinson, J. Mark
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文献类型：
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作者：
Gordon, Andrew;Kiss-Toth, E.;Wilkinson, J. Mark
Objective.确定全髋关节置换术（THA）后骨质溶解是否与白细胞介素-1（IL-1）家族和IL-6编码基因内的常见多态性相关，并确定与骨质溶解相关的多态性是否影响人外周血单核细胞（PBMC）对磨损颗粒反应的体外信使RNA（mRNA）表达。招募了非相关的北欧血统的白色受试者（n = 612），骨水泥型THA治疗原发性骨关节炎后平均IT年。在这些受试者中，272例既往有骨质溶解，340例无骨质溶解的影像学证据（对照组）。对基因组DNA进行以下单核苷酸多态性（SNP）基因分型：IL 1A +4845、IL 1B +3954、IL 1B-3737、IL 1B-511、IL 1 RA +2018、IL 6 - 174、IL 6 - 572和IL 6 - 597。在60名受试者的一个子集中，提取PBMC并用钛颗粒和/或内毒素刺激，并使用定量实时逆转录-聚合酶链反应测定细胞因子mRNA表达。与携带IL 1 RA +2018 C等位基因相关的骨质溶解的比值比（OR）为0.66（95%置信区间[95% CI] 0.48-0.91）（P = 0.012）。其余的SNPs与骨质溶解无关。罕见的IL 6单倍型-174 G/-572 G/-597 A（骨质溶解组频率2.4%，对照组频率0.8%）与骨质溶解相关（P = 0.02，使用Haploview软件计算）。在未刺激和刺激的PBMCs中，与+2018TT基因型相比，IL 1 RA +2018CC基因型与mRNA表达增加相关（经Bonferroni校正后，方差分析P = 0.01）。结论。IL 1 RA +2018 C等位基因与THA后骨质溶解风险降低和体外IL-1受体拮抗剂mRNA表达增加相关。IL-6基因启动子区域内的一种罕见单倍型与骨质溶解正相关。
Objective. To determine whether osteolysis after total hip arthroplasty (THA) is associated with common polymorphisms within the genes encoding the interieukin-1 (IL-1) family and IL-6, and to determine whether polymorphisms that are associated with osteolysis affect in vitro messenger RNA (mRNA) expression in human peripheral blood mononuclear cells (PBMCs) in response to wear particles.Methods. Unrelated white subjects of North European descent (n = 612) were recruited a mean of IT years after cemented THA for primary osteoarthritis. Of these subjects, 272 had previous osteolysis and 340 had no radiographic evidence of osteolysis (control group). Genomic DNA was genotyped for the following single-nucleotide polymorphisms (SNPs): IL1A +4845, IL1B +3954, IL1B -3737, IL1B -511, IL1RA +2018, IL6 -174, IL6 -572, and IL6 -597. In a subset of 60 subjects, PBMCs were extracted and stimulated with titanium particles and/or endotoxin, and cytokine mRNA expression was measured using quantitative real-time reverse transcriptase-polymerase chain reaction.Results. The odds ratio (OR) for osteolysis associated with carriage of the IL1RA +2018C allele was 0.66 (95% confidence interval [95% CI] 0.48-0.91) (P = 0.012). The remaining SNPs were not individually associated with osteolysis. The uncommon IL6 haplotype -174G/-572G/-597A (osteolysis group frequency 2.4%, control group frequency 0.8%) was associated with osteolysis (P = 0.02, calculated using Haploview software). The IL1RA +2018CC genotype was associated with increased mRNA expression compared with the +2018TT genotype in both unstimulated and stimulated PBMCs (P = 0.01 by analysis of variance, after Bonferroni correction).Conclusion. The IL1RA +2018C allele is associated with a decreased risk of osteolysis after THA and with increased IL-1 receptor antagonist mRNA expression in vitro. An uncommon haplotype within the promoter region of the gene for IL-6 is positively associated with osteolysis.