Wu Hui, Boackle Susan A, Hanvivadhanakul Punchong, Ulgiati Daniela, Grossman Jennifer M, Lee Youngho, Shen Nan, Abraham Lawrence J, Mercer Timothy R, Park Elly, Hebert Lee A, Rovin Brad H, Birmingham Dan J, Chang Deh-Ming, Chen Chung Jen, McCurdy Deborah, Badsha Humeira M, Thong Bernard Y H, Chng Hiok H, Arnett Frank C, Wallace Daniel J, Yu C Yung, Hahn Bevra H, Cantor Rita M, Tsao Betty P
Division of Rheumatology, University of California-Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3961-6. doi: 10.1073/pnas.0609101104. Epub 2007 Feb 22.
A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23-42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21-43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P = 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P = 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5' untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus.
小鼠1号染色体远端的一个基因组区域及其在人类中的同线性对应区域1q23 - 42，有强有力的证据表明含有狼疮易感基因。在对126个狼疮多发家系（包含151对患病同胞对）进行的1q21 - 43靶向基因组扫描中，我们在1q32.2发现了连锁证据（非参数连锁分数2.52，P = 0.006）。位于1q32.2的一个位置候选基因，补体受体2（CR2），也是小鼠Sle1c狼疮易感位点的一个候选基因。为了探究其在人类疾病中的作用，我们分析了来自258个白种人和142个中国狼疮单发家系的1416名个体，结果表明一种常见的三单核苷酸多态性CR2单倍型（rs3813946、rs1048971、rs17615）与狼疮易感性相关（P = 0.00001），疾病发生风险增加1.54倍。位于CR2基因5'非翻译区的单核苷酸多态性1（rs3813946）改变了转录活性，提示了CR2可能导致狼疮发生的潜在机制。我们的研究结果表明，CR2是1q32.2处人类狼疮的一个可能的易感基因，扩展了先前提示CR2参与系统性红斑狼疮发病机制的研究。
