Gender-Specific Association of M235T Polymorphism in Angiotensinogen Gene and Diabetic Nephropathy in NIDDM

Abstract

Abstract-This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, nϭ117) and patients without any evidence of nephropathy and Ն10 years of NIDDM (control subjects, nϭ125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women. (Hypertension. 1998;31:896-899.)Key Words: nephropathy Ⅲ angiotensinogen Ⅲ polymorphism Ⅲ diabetes R ecent studies have provided evidence that the development of renal complications in diabetes may be determined by genetic factors.1 The evidence includes clustering of diabetic nephropathy in families, 2-4 as well as an association between predisposition to essential hypertension and the development of diabetic nephropathy. [5][6][7][8] It is hypothesized that DNA sequence differences in regulatory or structural parts of genes encoding for proteins of the RAS may contribute to essential hypertension in nondiabetic persons and to hypertension and renal damage in the presence of diabetes. 9,10 A molecular variant of the AGT gene (with a threonine substituted for methionine at amino acid residue 235) has been associated with elevated levels of serum angiotensinogen and essential hypertension in nondiabetics.11 Recently, this polymorphism has been found to be in complete linkage disequilibrium with a sequence difference at position 6 in the promoter region. The latter affects the expression of the AGT gene, 12 with the highest tissue levels of angiotensinogen being found in homozygotes T235/T235. 12Two case-control studies in IDDM patients have shown that the homozygotes 235T/235T had an elevated risk of developing diabetic nephropathy. 13,14 Recently, this association has been confirmed in our family study using TDT. 15 The 235T effect was found among men but not among women. Other case-control studies have not found any association with M235T polymorphism.16,17 A gender-specific effect of the AGT polymorphism, however, was not examined in those studies.Because these stu...

Combinational effect of genes for the renin–angiotensin system in conferring susceptibility to diabetic nephropathy

“…The M235T polymorphism of the AGT gene was originally reported to be associated with hypertension (Jeunemaitre et al 1992), and the TT genotype of this polymorphism was also shown to confer a risk for the progression of diabetic nephropathy (Freire et al 1998). However, another study failed to identify the distinct role of the AGT gene in conferring susceptibility to the disease (Zychma et al 2000).…”

Diminished Alveolar Microvascular Reserves in Type 2 Diabetes Reflect Systemic Microangiopathy

“…For example, diabetic foot lesion has a poorer prognosis in men than in women (20). The DNA polymorphism that promotes angiotensinogen gene expression increases the risk of nephropathy in diabetic men but not women (21). The risk of cardiovascular disease is higher in diabetic women than in men (22).…”

Angiotensin Converting Enzyme Insertion/Deletion Polymorphism and Renoprotection in Diabetic and Nondiabetic Nephropathies

“…More than 30 AGT genetic variants have been described so far (63,64) and one of them, a T to C base substitution at position 702 on exon 2 with consequent replacement of methionine 235 with threonine (M235T), has been associated with arterial hypertension (63), and with progression of diabetic nephropathy (65,66). Actually, the possibility that different AGT genotypes might result in different AGT bioavailability raised the intriguing hypothesis that RAS activity might be affected not only by ACE I/D genotypes but also by the several variants of the AGT gene.…”