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

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

doi:10.18632/oncotarget.16696

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.

Highlights

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease as well as end-stage renal disease [1,2,3,4,5,6]
We examined the relation of genotypes for 41,352 single nucleotide polymorphisms (SNPs) that passed quality control to estimated glomerular filtration rate (eGFR) or the serum concentration of creatinine in 12,565 subjects by linear regression analysis
We examined the relation of genotypes for 41,372 SNPs that passed quality control to the serum concentration of uric acid in 9934 subjects not taking uric acid-lowering medications by linear regression analysis

Summary

Introduction

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease as well as end-stage renal disease [1,2,3,4,5,6]. Multiple renal transporters contribute to the maintenance of normal circulating uric acid levels by mediating the excretion or reabsorption of uric acid in the proximal kidney tubules, the underlying mechanisms of such homeostasis have not been fully elucidated [20]. The heritability of the serum concentration of uric acid has been estimated to be 40% [21], suggesting that genetic variants contribute to regulation of this parameter by influencing uric acid synthesis, excretion, or reabsorption [21, 22]. Previous GWASs have identified single nucleotide polymorphisms (SNPs) significantly associated with the serum uric acid concentration or the prevalence of gout [23,24,25,26,27,28,29]. A large-scale GWAS in European ancestry populations identified 28 loci that influence the serum concentration of uric acid [30]

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Conclusion