PLD4 as a Novel Susceptibility Gene for Systemic Sclerosis in a Japanese Population
PLD4 as a Novel Susceptibility Gene for Systemic Sclerosis in a Japanese Population
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DOI：
10.1002/art.37777
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发表时间：
2013-02-01
影响因子：
--
通讯作者：
Mimori, Tsuneyo
中科院分区：
文献类型：
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作者：
Terao, Chikashi;Ohmura, Koichiro;Mimori, Tsuneyo
客观的。系统性硬化症（SSc）是一种自身免疫性疾病，已报道有多种易感基因。全基因组关联研究表明，自身免疫性疾病共有大量易感基因。最近，我们的研究小组在日本人群中发现了 9 个与类风湿性关节炎 (RA) 相关的新易感基因。本研究的目的是阐明我们之前的研究中显示与 RA 相关或暗示相关的 18 个基因是否与日语中的 SSc 相关。方法。我们进行了一项关联研究，其中包括 415 名 SSc 患者和 16,891 名对照受试者，随后进行了一项包括 315 名患者和 21,054 名对照受试者的复制研究。在第一项研究中，对报告显示与 RA 相关的 18 个标记物与 SSc 的相关性进行了分析，并在重复研究中进一步分析了 5 个标记物。在一项联合研究中，使用逆方差法来评估这些标记物与 SSc 的关联。结果。在磷脂酶 D4 基因 (PLD4) 中，rs2841277 显示与日本患者的 SSc 显着相关 (P = 0.00017)。我们观察到PLD4外显子2中的rs2841280与rs2841277存在强连锁不平衡，并引入了氨基酸改变。我们还观察到 SSc 与 TNFAIP3 中的 rs6932056 和 IRF8 中的 rs2280381 之间的关联（分别为 P = 0.0000095 和 P = 0.0030），两者均显示与欧洲人群中的 SSc 相关。结论。我们确定PLD4是日本人SSc的新易感基因，从而证实PLD4参与自身免疫。在我们的日本人群中也检测到了 SSc 与 TNFAIP3 或 IRF8 之间的关联。 SSc 和 RA 似乎具有相对较大比例的遗传背景。
Objective. Systemic sclerosis (SSc) is an autoimmune disease for which multiple susceptibility genes have been reported. Genome-wide association studies have shown that large numbers of susceptibility genes are shared among autoimmune diseases. Recently, our group identified 9 novel susceptibility genes associated with rheumatoid arthritis (RA) in a Japanese population. The aim of this study was to elucidate whether the 18 genes that displayed associations or suggestive associations for RA in our previous study are associated with SSc in Japanese.Methods. We performed an association study that included 415 patients with SSc and 16,891 control subjects, followed by a replication study that included 315 patients and 21,054 control subjects. The 18 markers reported to display association with RA were analyzed for their associations with SSc in the first study, and 5 markers were further analyzed in the replication study. The inverse variance method was used to evaluate the associations of these markers with SSc in a combined study.Results. In the phospholipase D4 gene (PLD4), rs2841277 displayed a significant association with SSc in Japanese patients (P = 0.00017). We observed that rs2841280 in exon 2 of PLD4 was in strong linkage disequilibrium with rs2841277 and introduced an amino acid alteration. We also observed associations between SSc and rs6932056 in TNFAIP3 and rs2280381 in IRF8 (P = 0.0000095 and P = 0.0030, respectively), both of which displayed associations with SSc in a European population.Conclusion. We determined that PLD4 is a novel susceptibility gene for SSc in Japanese, thus confirming the involvement of PLD4 in autoimmunity. Associations between SSc and TNFAIP3 or IRF8 were also detected in our Japanese population. SSc and RA appear to share relatively large proportions of their genetic backgrounds.