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J Invest Dermatol. 2017 Dec;137(12):2544-2551. doi: 10.1016/j.jid.2017.08.004. Epub 2017 Aug 24.

Genome-Wide Analysis of Protein-Coding Variants in Leprosy.

Author information

1
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China; Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, China; Shandong Provincial Key Lab for Dermatovenereology, Jinan, China; Shandong Provincial Medical Center for Dermatovenereology, Jinan, China.
2
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China; Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, China; Shandong Provincial Key Lab for Dermatovenereology, Jinan, China.
3
Human Genetics, Genome Institute of Singapore, A*STAR, Singapore; Computational Sciences, The Jackson Laboratory, Farmington, Connecticut, USA.
4
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China; Shandong Provincial Key Lab for Dermatovenereology, Jinan, China.
5
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China; Shandong Provincial Key Lab for Dermatovenereology, Jinan, China; School of Medicine, Shandong University, Jinan, China.
6
Human Genetics, Genome Institute of Singapore, A*STAR, Singapore.
7
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China; Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, China.
8
Singapore Immunology Network, Agency for Science, Technology and Research Singapore, Singapore.
9
Biomolecular Function Discovery Division, Bioinformatics Institute, A*STAR, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore.
10
Biomolecular Function Discovery Division, Bioinformatics Institute, A*STAR, Singapore.
11
Computational and Systems Biology, Genome Institute of Singapore, A*STAR, Singapore.
12
Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
13
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China; Shandong Provincial Key Lab for Dermatovenereology, Jinan, China; School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China.
14
Singapore National Eye Centre, Glaucoma Department, Singapore.
15
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, China.
16
Department of Otolaryngology, National University of Singapore, Singapore.
17
Department of Otolaryngology, the Second Affiliated Hospital, Shandong University, Jinan, China.
18
Sichuan Provincial Institute of Dermatology, Sichuan, China.
19
Honghe Institute of Dermatology, Honghe, Yunnan, China.
20
Wenshan Institute of Dermatology, Wenshan, Yunnan, China.
21
Guizhou Provincial Center for Disease Control and Prevention, Guizhou, China.
22
Yunnan Provincial Center for Disease Control and Prevention, Yunnan, China.
23
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China; Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, China; Shandong Provincial Key Lab for Dermatovenereology, Jinan, China; Shandong Provincial Medical Center for Dermatovenereology, Jinan, China; School of Medicine, Shandong University, Jinan, China; School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China; National Clinical Key Project of Dermatology and Venereology, Jinan, China. Electronic address: zhangfuren@hotmail.com.

Abstract

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 × 10-9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 × 10-8, OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 × 10-10, OR = 1.36), rs146466242 in FLG (P = 3.39 × 10-12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 × 10-6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 × 10-9, OR = 1.14) and rs181206 in IL27 (P = 1.08 × 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.

PMID:
28842327
DOI:
10.1016/j.jid.2017.08.004
[Indexed for MEDLINE]
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