CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B
CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B
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DOI：
10.1093/hmg/ddh318
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Tokunaga, K
中科院分区：
文献类型：
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作者：
Hitomi, Y;Tsuchiya, N;Tokunaga, K
我们先前报道了在三个亚洲人群中FCGR 2B-Ile 232 Thr与系统性红斑狼疮（SLE）的相关性。由于B细胞的另一种抑制性受体CD 72的多态性与小鼠SLE相关，我们鉴定了人CD 72多态性，检测了它们与SLE的相关性，并在日本人（160例SLE，277例对照）、泰国人（87例SLE，187例对照）和高加索人（94个含有SLE成员的家族）中检测了与FCGR 2 B的遗传相互作用。检测到四种多态性和六种罕见变异。前者构成了两种主要的单倍型，在内含子8中含有一个或两个13个核苷酸的重复序列（分别命名为 *1和 *2）。虽然未检测到与SLE易感性的相关性，但 *1等位基因与日本患者的肾炎显著相关（P=0.024）。RT-PCR鉴定了一种新的选择性剪接（AS）转录本，该转录本在COS-7转染子中在蛋白水平上表达。与 *1/*1（P=0.000038）或 *1/*2（P=0.0085）基因型相比，*2/*2基因型个体AS/普通亚型的比例显著增加。使用两个亚洲队列，仅在存在CD 72-*1/*1基因型的情况下观察到FCGR 2B-232 Thr/Thr与SLE显著相关（OR 4.63，95% CI 1.47-14.6，P=0.009，相对于FCGR 2B-232 Ile/Ile + CD 72-*2/*2）。小基因分析表明，内含子8的13个核苷酸重复和同一单倍型内的4个碱基缺失可以调节选择性剪接。AS同种型缺乏外显子8，并推断在胞外结构域的膜远端部分含有49个氨基酸的变化，其中在与鼠SLE相关的CD 72（c）等位基因中已知有相当大的氨基酸变化。这些结果表明，CD 72-*2等位基因的存在降低了FCGR 2B-232 Thr赋予的人SLE的风险，可能是通过增加CD 72的AS同种型。
We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P=0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of AS/common isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P=0.000038) or *1/*2 (P=0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72(c) allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72.