ACEVariants Interact with the RAS Pathway to Confer Risk and Protection against Type 2 Diabetic Nephropathy

Abstract

Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Among candidate genes examined for susceptibility to diabetic nephropathy, angiotensin-converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic nephropathy. However, the role of other renin-angiotensin system (RAS) polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Recent studies also show that ACE haplotypes may be better predictors to disease susceptibility. Thus, in the present study, we evaluated the association of ACE haplotypes and the interactions of ACE, angiotensinogen (AGT), and angiotensin II receptor type I (AGTR1) gene polymorphisms with DNP in Asian Indians. We genotyped seven variants of the RAS pathway genes (ACE, AGT, and AGTR1) in type 2 diabetic cohorts without nephropathy (DM) and with nephropathy (DNP), using allele-specific oligonucleotide-PCR, and PCR-restriction fragment length polymorphism assays. We studied the interaction of these variants with each other and ACE I/D polymorphism. Frequency of ACE D allele and DD genotype (ACE I/D) was significantly higher in DNP (p < 0.005) and was associated with increased risk of nephropathy. The frequency of T allele, MT/TT genotypes (AGT: M235T), and C allele 1166CC genotype (AGTR1: A1166C) was higher and associated with increased risk of DNP (235T, p < 0.0001; 235TT/MT, p < 0.01; 1166C, p < 0.007; 1166CC, p < 0.0001). The ACE locus revealed a near doubling in the prevalence of T-D-G risk haplotype (odds ratio, 1.76) in DNP (0.13) compared to DM (0.08; p < 0.02). ACE haplotypes carrying the I allele were associated with a lower risk of DNP (C-I-A, p < 0.04; C-I-G, p < 0.008). ACE ID/DD genotypes in combination with ACE rs4311, rs4343, and AGT rs699 mutant genotypes increased the risk of DNP development fourfold (p < 0.01). This study provides the first evidence for a disease haplotype for DNP at the ACE locus in Asian Indians. The study further indicates that ACE D allele individually and in interaction with other RAS single-nucleotide polymorphisms significantly increases the risk of nephropathy in type 2 diabetic patients of Asian Indian origin.

Genetic Predisposition to Diabetic Nephropathy: Evidence for a Role of ACE (I/D) Gene Polymorphism in Type 2 Diabetic Population from Kutch Region

“…Therefore, we suggest that the genetic variation at the ACE locus as D/D variant in intron 16, contribute to an increased risk of nephropathy in T2DM patients, but not extent of DN severity (as the allelic or genotypic distribution was comparable between the two DN groups) in studied population. Our findings were in conformity with other studies [26][27][28][29][30][31] but not all [32,55,56]. This difference may possibly be due to different races, methods of quantitation and patient selection; as proteinuria in adults is a multifactorial condition frequently linked with diabetes, the issue of whether proteinuria is due to diabetes or some other etiology remains debatable, but there was no uncertainty in our group of patients on the role of T2DM in diabetic nephropathy constitution as we excluded the patients who had proteinuria/renal disorders before their diabetes was diagnosed, thus we confined our study to diabetic kidney diseases.…”

“…This polymorphism was associated with circulating ACE levels [23][24][25] and owing to its central role in the regulation of blood pressure, sodium metabolism and renal hemodynamics [16,17], it is reasonable to hypothesize that genetic variation of ACE I/D contributes to the development of DN and numerous studies have addressed the role of this polymorphism in the complex etiology of DN, albeit with conflicting results i.e. several studies have demonstrated [26][27][28][29][30][31] or refuted [32][33][34] the role of ACE D variant as candidates for the development of DN. The discrepant finding among studies is attributed to genetic and environmental heterogeneity among different populations.…”

ACE insertion/deletion (I/D) polymorphism and diabetic nephropathy

“…In T2DM patients from Tehran the presence of the D allele of ACE was associated with higher ACE activity and increasing severity of albuminurea (11,20). Further, in Asian Indian and Tunisian patients with diabetic nephropathy the frequency of the D allele and the DD genotype was significantly increased compared with diabetic without nephropathy (21,22). In a metaanalysis by Staessen et al (23) it was reported that DD genotype of ACE I/D polymorphism versus II genotype is associated with 1.56-fold increased risk of diabetic nephropathy.…”

Association of the Angiotensinogen M235T and APO E Gene Polymorphisms in Turkish Type 2 Diabetic Patients with and without Nephropathy

“…In the presence of AGT M235T gene polymorphism, elevated plasma AGT concentration is seen. 18,35 TT homozygote genotype results in the highest AGT elevation, which in turn increases angiotensin II level. 36 Such high angiotensin II levels may cause glomerular injury due to both systemic and glomerular pressure increase.…”

“…16,17 Therefore, the main genes whose DN associations are most commonly studied are angiotensinogen-converting enzyme, angiotensinogen (AGT), and angiotensin II Type 1 receptor genes, which code parts of the RAS system. 18 AGT M235T gene polymorphism in RAS is related to elevated AGT levels and hypertension. [19][20][21] Due to the association between this gene polymorphism and hypertension it has also been linked to DN.…”