title: Identification of a missense variant in LNPEP that confers psoriasis risk.
abstract: Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To further advance gene discovery, we extended our genome-wide association study data set of 1,139 cases and 2,234 controls and replicated two independent cohorts of 7,200 cases and 10,491 controls. We identified the missense variant rs2303138 (p.Ala763Thr) within the LNPEP gene associated with psoriasis (Pcombined=1.83 × 10(-13), odds ratio=1.16) and validated four previously reported genes: IL28RA, NFKBIA, TRAF3IP2, and CARD14 (9.74 × 10(-11)P9.37 × 10(-5)), which confirmed the involvement of the nuclear factor-κB signaling pathway in psoriasis pathogenesis. LNPEP, also named insulin-responsive aminopeptidase, was identified as an angiotensin IV receptor. Protein function prediction suggested that this missense variant of LNPEP was most likely deleterious. Expression analysis showed that LNPEP was significantly downregulated in psoriatic lesions compared with the control skin (P=1.44 × 10(-6)) and uninvolved patient skin (P=2.95 × 10(-4)). Pathway analysis indicated that LNPEP was involved in the renin-angiotensin system, which also has a key role in cardiovascular disease and diabetes. These results provided genetic evidence that psoriasis might share common mechanisms with hypertension and diabetes, which was consistent with clinical observations. Our study identified a genetic susceptibility factor and provided genetic evidence of insight into psoriasis pathogenesis with the involvement of the renin-angiotensin system pathway.
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Xian-Bo
authors.initials: XB
authors.lastname: Zuo
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Hua-Yang
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Xian-Fa
authors.initials: XF
authors.lastname: Tang
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Gao
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Sheng
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Xian-Yong
authors.initials: XY
authors.lastname: Yin
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Zhou
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zheng
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Yan-Tao
authors.initials: YT
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authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Rui-Xue
authors.initials: RX
authors.lastname: Chang
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Gong-Bu
authors.initials: GB
authors.lastname: Pan
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Fan
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Zai-Xing
authors.initials: ZX
authors.lastname: Wang
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: An-Ping
authors.initials: AP
authors.lastname: Zhang
authors.affiliation: School of Life Science, Anhui Medical University, Hefei, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Yang
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China. Electronic address: ahmusld@163.com.
authors.forename: Liang-Dan
authors.initials: LD
authors.lastname: Sun
authors.affiliation: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China; State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China. Electronic address: ayzxj@vip.sina.com.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D010122:Cystinyl Aminopeptidase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D055106:Genome-Wide Association Study; D006162:Guanylate Cyclase / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020125:Mutation, Missense; D000072000:NF-KappaB Inhibitor alpha; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000453:epidemiology* / Q000235:genetics*; D012307:Risk Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D010122:Cystinyl Aminopeptidase; D006162:Guanylate Cyclase; D020672:I-kappa B Proteins; D007378:Interleukins; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C000606204:NFKBIA protein, human; C414202:TRAF3IP2 protein, human; C105964:leucyl-cystinyl aminopeptidase; C426243:CARD14 protein, human
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