Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms

Abstract

BackgroundRenal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects.MethodsTwelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes.ResultsOf the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34–3.17) were also observed.ConclusionSNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising.

Microalbuminuria Reduction with Telmisartan in Normotensive and Hypertensive Japanese Patients with Type 2 Diabetes: A Post-Hoc Analysis of the Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) Study

“…In Japan, type 2 diabetic nephropathy is the main cause of chronic kidney disease (1,13). Furthermore, nephropathy accounts for a greater propor- tion of deaths in Japanese patients with type 2 diabetes than in their Caucasian counterparts (11)(12)(13)(14)(15). In the present post-hoc analysis of the INNOVATION study, we investigated whether or not treatment with telmisartan elicits beneficial effects on the progression of microalbuminuria in Japanese normotensive patients with type 2 diabetes.…”

“…Although epidemiological and familial studies indicate that there are obvious different genetic susceptibilities to endstage renal disease among ethnic groups (11)(12)(13)(14)(15), most national guideline groups have recommended ARBs or ACEIs instead of other antihypertensive agents in hypertensive patients with diabetic nephropathy (16)(17)(18)(19). Recent studies also provide evidence that treatment with ARBs or ACEIs results in long-term stabilization or normalization of albuminuria in normotensive type 2 diabetic patients (8-10, 20, 21).…”

“…However, no comprehensive largescale study has investigated whether or not angiotensin blockade prevents the progression of albuminuria in normotensive Japanese patients with type 2 diabetes. This investigation should be particularly important because it has been revealed that Japanese diabetic patients are much more susceptible than Caucasians to end-stage renal disease (11)(12)(13)(14)(15). We recently reported on the Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study to examine the effect of telmisartan, an ARB, on the progression of microalbuminuria in Japanese patients with type 2 diabetes (22,23).…”

The Combined Effect of ACE, TCF7L2, and PPARGC1A Gene Polymorphisms in Diabetic Nephropathy

“…There were conflicting results in Iranian population regarding the association of ACE polymorphism; Nikzamir [28] demonstrated strong relation between the homozygous DD and nephropathy while Rahimi [29] showed no significant association. Furthermore, the statistics from India also showed opposing results by Viswanathan [30], Naresh [31], and Bhavani [32] who reported a positive association for D allele and diabetic nephropathy in South Indian population, whereas Bhaskar [33] in South Indian and Prasad [34] and Kumar [35] in North Indian populations not found this association. These incompatible results may be due to numerous factors, mostly ethnicity.…”

Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis

“…The structure of the primers and PCR conditions for genotyping the DNA polymorphisms are described in detail elsewhere (Agerholm-Larsen et al, 2000;Asai et al, 2001;Jalilian et al, 2008;Lanfear et al, 2005;Picard et al, 2007;Prasad et al, 2006;Yazdanpanah et al, 2007).…”