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Gout and Hyperuricemia March 2017
Gout and Hyperuricemia. 2017; 4(1): 12-20
DOI: 10.3966/GH1703040103
Abstract  |  Full Text (HTML)  |  Full Text (PDF)
Genetic variants associated with tophi occurrence by a genome wide association study of 1888 gout patients
Changgui Li1,#,*, Chung-Jen Chen2,*, Wei-Ting Liao3,*, Ya-Ting Chan4, Can Wang1, Tien-Tsai Cheng5, Lingling Cui1, Xinde Li1, Shun-Jen Chang1,4,#, Yongyong Shi1,6,7,#
1Shandong Provincial Key Laboratory of Metabolic Disease, the Affiliated Hospital of Qingdao University, Qingdao 266003, P.R. China. 2Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung city, Taiwan. 3Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan. 4Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Taiwan. 5Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 6Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China. 7Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai 200240, P. R. China. *These authors contributed equally to this study.

*Corresponding authors:
Dr. Changgui Li
Affiliated Hospital of Qingdao University.16 Jiangsu Road, Qingdao 266003, PR China.

Dr. Shun-Jen Chang
National University of Kaohsiung, Taiwan. No. 700, Kaohsiung University Rd, Nanzih District, 811, Kaohsiung, Taiwan.

Dr. Yongyong Shi
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China.

Submitted on Apr. 27, 2017; accepted on May. 8, 2017.
©2017, Gout and Hyperuricemia. Published by Dong Fong Health Co. LTD in Taiwan. All right reserved.
Objective:Gouty tophi are nodular mass deposits of monosodium urate (MSU) under the skin. Although environmental factors such as age and disease duration are considered as the major risks for gouty tophi, the genetic factors remain unclear. This study intended to explore the genetic risk components related to tophus occurrence using a genome-wide association study (GWAS).
Methods:Male gout patients were recruited with the tophus status recorded as a major outcome. Each tophaceous patient was matched to four non-tophus controls by their age and gouty disease duration. Affymetrix CHB SNP arrays were used to genotype the DNA samples and analyze associations with tophus occurrence.
Results:A total of 1888 male gout patients were included. Age and disease duration were the significant risk factors related to tophus occurrence. After matching by age and disease duration, 713 patients, composed of 145 gout patients with tophi and 568 without tophus, were included for further analysis. The GWAS results showed 12 SNPs that had significant associations with tophi occurrence (p<1×10-7), which were located in or near MSX2, CXCR5, PRKCE, MARCKS, PTPRD, DIRC3, TTLL7, KRT39, POLA2, PITX2, PITX1 and ADAM20 genes. By signaling pathway analysis, four SNPs near PKC-epsilon, MARCKS, PITX2, and MSX2 showed most significantly associations with each other, and were found to be associated with the process of tophi formation.
Conclusion:We concluded PKC-epsilon, MARCKS, Pitx2, and MSX2 were strongly associated with tophi occurrence via a potential role in the phagocytosis of MSU, NETosis, osteoblast retraction, and fibroblast formation of tophus, respectively.

Key words:Tophi; GWAS; Gout; PRKCE; MARCKS; PITX2; MSX2