Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis
Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis
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DOI：
10.1086/516736
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发表时间：
2007-05-01
影响因子：
9.8
通讯作者：
Alfredsson, Lars
中科院分区：
文献类型：
--
作者：
Kallberg, Henrik;Padyukov, Leonid;Alfredsson, Lars
基因基因和基因环境相互作用是类风湿关节炎（RA）和其他复杂疾病发展的关键特征。这项研究的目的是在三个大病例对照研究中使用和比较RA的两个主要遗传风险因素之间的相互作用的三个不同定义 - HLA -DRB1共享表位（SE）等位基因（SE）等位基因（SE）等位基因 - PTPN22 R620W等位基因 - 瑞典类风湿关节炎（EIRA）研究，北美RA联盟（NARAC）研究和荷兰莱顿早期关节炎诊所研究（总共1,977例和2,405例对照）的瑞典流行病学研究。 EIRA研究还用于分析吸烟与两个基因之间的相互作用。 “相互作用”被定义为偏离添加性，在乘法模型中的相互作用，或者是在连锁不平衡方面的互动 - 例如，与两个未连接基因座的渗透性的独立性偏离。 Hla-drb1 Se等位基因和PTPN22 R620W等位基因之间的一致相互作用在抗CCP阳性RA的所有三项研究中都可以看到，而定义为偏离添加性。对乘法相互作用的测试证明，仅当三个研究合并时，这两个基因之间存在相互作用。连锁不平衡方法表明EIRA和NARAC以及合并分析中的基因 - 基因相互作用。吸烟与PTPN22 R620W之间没有相互作用。在两个主要已知的遗传危险因素和有关发展抗CCP阳性RA的风险的主要环境风险因素之间描述了一种新的相互作用模式。数据扩展了涉及遗传和环境因素的RA的致病假设的基础。该研究还提出并说明了有关定义复杂疾病相互作用的方法的主要问题。
Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis ( RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA - the HLA-DRB1 shared epitope ( SE) alleles and the PTPN22 R620W allele - in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study ( in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. "Interaction" was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium - for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA- DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP-positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP - positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.