Genome-Wide Analysis of Protein-Coding Variants in Leprosy
Genome-Wide Analysis of Protein-Coding Variants in Leprosy
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麻风病蛋白质编码变异的全基因组分析
DOI：
10.1016/j.jid.2017.08.004
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发表时间：
2017-12-01
影响因子：
6.5
通讯作者：
Zhang, Furen
中科院分区：
文献类型：
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作者：
Liu, Hong;Wang, Zhenzhen;Zhang, Furen
虽然全基因组关联研究极大地推进了我们对常见非编码变异对麻风易感性的贡献的理解，但蛋白质编码变异尚未得到系统的研究。我们在中国汉族人中进行了蛋白质编码变体的三阶段全基因组关联研究，其中包括7，048名麻风患者和14，398名健康对照者。发现了7个具有外显子组意义的编码变体，包括两个罕见的变体：NCKIPSD中的rs 145562243（P = 1.71 x 10（-9），比值比[OR] = 4.35）和CARD 9中的rs 149308743（P = 2.09 x 10（-8），OR = 4.75）;三种低频变异：IL 23 R中的rs76418789（P = 1.03 x 10（-10），OR = 1.36），rs 146466242在FLG中（P = 3.39 x 10（-12），OR = 1.45），TYK 2中rs 55882956（P = 1.04 x 10（-6），OR = 1.30）;两种常见变异：SLC 29 A3中的rs780668（P = 2.17 x 10（-9），OR = 1.14）和IL 27中的rs 181206（P = 1.08 x 10（-7），OR = 0.83）。发现的蛋白质编码变异，特别是低频率和罕见的，表明参与皮肤屏障和内吞/吞噬/自噬，除了已知的先天性和适应性免疫，在麻风病的发病机制，突出了蛋白质编码变异研究的优点复杂的疾病。
Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 x 10(-9), odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 x 10(-8), OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 x 10(-10), OR = 1.36), rs146466242 in FLG (P = 3.39 x 10(-12), OR = 1.45), and rs55882956 in TYK2 (P = 1.04 x 10(-6), OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 x 10(-9), OR = 1.14) and rs181206 in IL27 (P = 1.08 x 10(-7), OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.