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Identification of C21orf59 and ATG2A as novel determinants of renal function-related traits in Japanese by exome-wide association studies

2017; Impact Journals LLC; Volume: 8; Issue: 28 Linguagem: Inglês

10.18632/oncotarget.16696

1949-2553

Yoshiji Yamada, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai, Masashi Tanaka,

Genetic Associations and Epidemiology

// Yoshiji Yamada 1, 2 , Jun Sakuma 2, 3, 4 , Ichiro Takeuchi 2, 4, 5 , Yoshiki Yasukochi 1, 2 , Kimihiko Kato 1, 6 , Mitsutoshi Oguri 1, 7 , Tetsuo Fujimaki 8 , Hideki Horibe 9 , Masaaki Muramatsu 10 , Motoji Sawabe 11 , Yoshinori Fujiwara 12 , Yu Taniguchi 12 , Shuichi Obuchi 13 , Hisashi Kawai 13 , Shoji Shinkai 14 , Seijiro Mori 15 , Tomio Arai 16 and Masashi Tanaka 17 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi, Japan 3 Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan 4 RIKEN Center for Advanced Intelligence Project, Tokyo, Japan 5 Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan 6 Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan 7 Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan 8 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan 9 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan 10 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 11 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan 12 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 13 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 14 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 15 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 16 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 17 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Correspondence to: Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp Keywords: chronic kidney disease, hyperuricemia, glomerular filtration rate, serum uric acid, exome-wide association study Received: February 12, 2017 Accepted: March 08, 2017 Published: March 30, 2017 ABSTRACT We have performed exome-wide association studies to identify genetic variants that influence renal function-related traits or confer susceptibility to chronic kidney disease or hyperuricemia in Japanese. Exome-wide association studies for estimated glomerular filtration rate and the serum concentration of creatinine were performed with 12,565 individuals, that for the serum concentration of uric acid with 9934 individuals, and those for chronic kidney disease or hyperuricemia with 5161 individuals (3270 cases, 1891 controls) or 11,686 individuals (2045 cases, 9641 controls), respectively. The relation of genotypes of single nucleotide polymorphisms to estimated glomerular filtration rate or the serum concentrations of creatinine or uric acid was examined by linear regression analysis, and that of allele frequencies of single nucleotide polymorphisms to chronic kidney disease or hyperuricemia was examined with Fisher's exact test. The exome-wide association studies revealed that 25, seven, and six single nucleotide polymorphisms were significantly ( P <1.21 × 10 –6 ) associated with estimated glomerular filtration rate or the serum concentrations of creatinine or uric acid, respectively, and that 49 and 35 polymorphisms were significantly associated with chronic kidney disease or hyperuricemia, respectively. Subsequent multivariable logistic regression analysis with adjustment for covariates revealed that four and three single nucleotide polymorphisms were related ( P < 0.05) to chronic kidney disease or hyperuricemia, respectively. Among polymorphisms identified in the present study, rs76974938 [C/T (D67N)] of C21orf59 and rs188780113 [G/A (R478C)] of ATG2A may be novel determinants of estimated glomerular filtration rate and chronic kidney disease or of the serum concentration of uric acid, respectively.