Remmers E F, Longman R E, Du Y, O'Hare A, Cannon G W, Griffiths M M, Wilder R L
Inflammatory Joint Diseases Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland 20892, USA.
Nat Genet. 1996 Sep;14(1):82-5. doi: 10.1038/ng0996-82.
Identification of specific genetic loci that contribute to susceptibility to rheumatoid arthritis (RA) in humans has been hampered by several factors, including: i) multiple interacting genetic loci contributing to susceptibility; ii) complex interactions of environmental and genetic factors; iii) genetic heterogeneity; and iv) low penetrance. We have, therefore, mapped quantitative trait loci (QTLs) that control inflammatory arthritis susceptibility and/or severity in progeny of two inbred rat strains with significantly different susceptibilities to collagen-induced arthritis (CIA), an animal model for RA. Not surprisingly, we identified a major susceptibility factor, Cia1, on chromosome 20 in the vicinity of the rat major histocompatibility complex (MHC). However, by limiting the analysis to animals with arthritis-susceptible MHC genotypes and using genome-wide QTL analytic techniques, we also found four non-MHC QTLs-Cia2, 3, 4 and 5-on chromosomes 1, 4, 7 and 10, that contributed to disease severity. In addition, a QTL on chromosome 8 was suggestive for linkage. Characterization of the genes underlying these QTLs will facilitate the identification of key biochemical pathways regulating experimental autoimmune arthritis in rats and may provide insights into RA and other human autoimmune diseases. These genes may also represent novel targets for therapy.
人类类风湿性关节炎（RA）易感性相关特定基因座的鉴定受到多种因素的阻碍，包括：i）多个相互作用的基因座导致易感性；ii）环境和遗传因素的复杂相互作用；iii）遗传异质性；以及iv）低外显率。因此，我们绘制了数量性状基因座（QTL），这些基因座控制着两种对胶原诱导性关节炎（CIA，一种RA动物模型）易感性显著不同的近交系大鼠后代中的炎性关节炎易感性和/或严重程度。不出所料，我们在大鼠主要组织相容性复合体（MHC）附近的20号染色体上鉴定出一个主要的易感性因子Cia1。然而，通过将分析限制在具有关节炎易感MHC基因型的动物上，并使用全基因组QTL分析技术，我们还在1、4、7和10号染色体上发现了四个非MHC QTL——Cia2、3、4和5，它们影响疾病严重程度。此外，8号染色体上的一个QTL提示存在连锁关系。对这些QTL潜在基因的表征将有助于鉴定调节大鼠实验性自身免疫性关节炎的关键生化途径，并可能为RA和其他人类自身免疫性疾病提供见解。这些基因也可能代表新的治疗靶点。
