期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 134, 期 2, 页码 359-365出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2013.317
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资金
- National Science Foundation of China for Excellent Young Scholars [81222022]
- National Natural Science Foundation of China [81130031, 81072461, 30971644, 81071285, 81172866, 81273301, 81271747]
- Program for New Century Excellent Talents in University [NCET-11-0889]
- Local Universities Characteristics and Advantages of Discipline Development Program of Ministry of Finance of China
- Youth Project [31200939, 31000528, 81000692, and 81101186]
- Pre-National Basic Research Program of China (973 Plan) [2012CB722404]
- Youth Project of Anhui Province Natural Science Foundation [1208085QH145]
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 (P-combined = 1.83 x 10(-13), odds ratio = 1.16) and validated four previously reported genes: IL28RA, NFKBIA, TRAF3IP2, and CARD14 (9.74 x 10(-11) <= P <= 9.37 x 10(-5)), which confirmed the involvement of the nuclear factor-kappa B 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 x 10(-6)) and uninvolved patient skin (P = 2.95 x 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.
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