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Association of Genetic Variants with Chronic Kidney Disease in Japanese Individuals

Tetsuro Yoshida^*, Kimihiko Kato, Tetsuo Fujimaki, Kiyoshi Yokoi, Mitsutoshi Oguri, Sachiro Watanabe, Norifumi Metoki^||, Hidemi Yoshida^¶, Kei Satoh^¶, Yukitoshi Aoyagi^**, Yutaka Nishigaki^**, Masashi Tanaka^**, Yoshinori Nozawa, Genjiro Kimura, and Yoshiji Yamada

^* Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan; Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan; Department of Cardiology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan; Department of Cardiology, Gifu Prefectural General Medical Center, Gifu, Japan; ^|| Department of Internal Medicine, Hirosaki Stroke Center, Hirosaki, Japan; ^¶ Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; ^** Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; Gifu International Institute of Biotechnology, Kakamigahara, Japan; Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Japan

Correspondence: Dr. Yoshiji Yamada, Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurima-machiya, Tsu, Mie 514-8507, Japan. Phone.: +81-59-231-5387; Fax: +81-59-231-5388; E-mail: yamada{at}gene.mie-u.ac.jp

Background and objectives: Although genetic linkage analyses and association studies have implicated several loci and candidate genes in predisposition to chronic kidney disease (CKD), the genes that underlie genetic susceptibility to this condition have remained uncharacterized. The purpose of the present study was to identify genetic variants that confer susceptibility to CKD in Japanese individuals.

Design, setting, participants, & measurements: The study population comprised 5217 Japanese individuals (2955 men, 2262 women), including 778 subjects (480 men, 298 women) with CKD [estimated GFR (eGFR), <50 ml min^–1 1.73 m^–2] and 4439 controls (2475 men, 1964 women; eGFR, 60 ml min^–1 1.73 m^–2). The genotypes for 40 polymorphisms of 32 candidate genes were determined.

Results: The chi-square test and multivariable logistic regression analysis with adjustment for covariates revealed that the –219GT polymorphism of APOE, the –519AG of MMP1, the –866GA of UCP2, the –1607/1G2G of MMP1, the AG (Lys45Glu) of MMP3, the GA (Ala163Thr) of AGTR1, the GA (Gly670Arg) of PECAM1, and the –55CT of UCP3 were significantly (false discovery rate <0.05) associated with CKD. Comparison of allele frequencies of these polymorphisms by the chi-square test between subgroups of CKD and control subjects individually matched for covariates revealed that the –519AG of MMP1 and the –866GA of UCP2 were significantly (P < 0.05) associated with CKD.

Conclusions: MMP1 and UCP2 may be susceptibility loci for CKD in Japanese individuals. Determination of genotypes for these polymorphisms may prove informative for prediction of genetic risk for CKD.