Combinational effect of genes for the renin-angiotensin system in conferring susceptibility to diabetic nephropathy.
To elucidate the role of the renin-angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the genes that encode angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy (P<0.05), including five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron (P=0.01, odds ratio =1.34, 95% CI 1.07-1.69). Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59-0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allele in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value =0.00005). We concluded that RAS gene polymorphisms may contribute to the susceptibility to diabetic nephropathy in type 2 diabetes.
Osawa
Norihisa
N
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.|Laboratory for Diabetic Nephropathy, SNP Research Center, The Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Koya
Daisuke
D
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Araki
Shin-Ichi
SI
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Uzu
Takashi
T
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Tsunoda
Tatsuhiko
T
Laboratory for Medical Informatics, SNP Research Center, The Institute of Physical and Chemical Research, Yokohama, Kanagawa, 230-0045, Japan.
Kashiwagi
Atsunori
A
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Nakamura
Yusuke
Y
Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
Maeda
Shiro
S
Laboratory for Diabetic Nephropathy, SNP Research Center, The Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. smaeda@src.riken.jp.
D000808:Angiotensinogen / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D003929:Diabetic Neuropathies / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*
D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A