Common variants within the interleukin 4 receptor α gene (IL4R) are associated with susceptibility to osteoarthritis
Common variants within the interleukin 4 receptor α gene (IL4R) are associated with susceptibility to osteoarthritis
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DOI：
10.1007/s00439-004-1083-0
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发表时间：
2004-03-01
期刊：
影响因子：
5.3
通讯作者：
Loughlin, J
中科院分区：
文献类型：
--
作者：
Forster, T;Chapman, K;Loughlin, J
原发性骨关节炎（OA）是一种常见的迟发性关节炎，表现出复杂的传播模式，具有关节部位和性别特异性的异质性。我们之前在通过全髋关节置换术确定的 146 个受影响的女性兄弟姐妹家庭（女性 THR 家庭）中，将 OA 易感性位点连锁映射到染色体 16p12.3-p12.1 处 12 cM 间隔，最大多点 LOD 评分为 1.7。尽管 LOD 评分较低，但在有报告称该区间与患有早发性髋关节 OA 的冰岛家系中的同一区间存在关联后，我们被鼓励进一步研究该区间。使用公共数据库，我们在区间内搜索了可能的候选基因，并得出结论，编码白细胞介素 4 受体 α 链 (IL4R) 的基因是一个特别强大的候选基因，因为它在软骨稳态中的已知作用。我们对来自女性 THR 家族的 146 名先证者（第 1 阶段）和由 310 名女性 THR 病例组成的独立队列（第 2 阶段）中的 IL4R 内的 9 个常见单核苷酸多态性 (SNP) 进行了基因分型，其中包括 6 个非同义 SNP。我们将等位基因频率与 399 名年龄匹配的女性对照进行了比较。所有个人都是英国白人。两个 SNP 的次要等位基因在两个阶段都显示出关联，其中最显着的关联的 P 值为 0.004，比值比 (OR) 为 2.1。这两个 SNP 定义了两个相关的 SNP 组。遗传两组的次要 SNP 等位基因是一个特殊的危险因素（OR=2.4，P=0.0008）。我们的数据表明，IL4R 基因内的功能变异易导致白种女性髋部 OA。
Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor alpha chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.