The relationship between genetic and haemodynamic factors in diabetic nephropathy (DN): Case–control study in type 1 diabetes mellitus (T1DM)

Abstract 

The development and progression of diabetic nephropathy shows the significant variation between individuals and different ethnic groups and is known to have multiple risk factors. Chronic hyperglycemia, glomerular and systemic hypertension, hyperlipidemia has been shown to play an important role as well as genetic factors. The relationship between genetically determined polymorphic nature of metabolic and haemodynamic disorders and DN development have been suggested. This case–control study was performed to evaluate gene polymorphisms effect on development and progression of DN in T1DM. Using candidate gene approach we have studied polymorphic markers in genes encoding the potential mediators of renal injury: I/D in ACE gene; A(−1903G) in chymase gene (CMA1); M235T in angiotensinogen gene (AGT); A1166C in the angiotensin II receptor, subtype1 gene (AT2R1) and ecNOS4a/4b in the endothelial NO-synthase gene (NOS3).

To reduce the probable masking effect of non-genetic factors the non-overlapping inclusion criteria for group formation were used: 66 normoalbuminuric patients with long standing T1DM≥20 years (DN“−”); 63 with overt DN and T1DM≤15 years (DN“+”) and 96 healthy subjects. To clarify the factors contributing to DN progression we have segregated DN“+” patients into two subgroups: (1) CRF“−”, n=32 with stable renal function and (2) CRF“+”, n=31 with progression to chronic renal failure during the same period of T1DM duration.

We observed significant differences in allele/genotype frequencies between DN“+” and DN“−” in gene NOS3: 4a/4b (76.2% versus 47.0%, OR=3.61), 4b/4b (22.2% versus 51.5%, OR=0.27) and also in DN“−” compared to DN“+” and healthy subjects in ACE gene: II and DD genotype (36.4% versus 23.8% versus 13.5%, OR=0.55 and 18.2% versus 20.6% versus 41.7%, OR=1.17, respectively). For the CMA1, AGT and AT2R1 genes we have not found significant differences in allele/genotype distribution. CRF“−” and CRF“+” patients were not differed in alleles/genotypes frequencies as well as in sex distribution, age, age at DM onset, DM duration, HbA1c and serum lipids level. GFR decline (1.3(ml/min)/1.73(m²/yr) versus 11.2(ml/min)/1.73(m²/yr)) was strongly associated with blood pressure (124/79 versus 145/93) and use of antihypertensive agents (ACE inhibitors: 84.4% versus 55.2%; other agents: 9.4% versus 13.8%; 6.2% versus 31.0% had no antihypertensive treatment).

We conclude that gene polymorphisms involved in production of angiotensin II and nitric oxide might contribute to the susceptibility to early DN onset, while hypertension is the factor of rapid DN progression.

Abbreviations: DN, diabetic nephropathy, T1DM, type 1 diabetes mellitus, BP, blood pressure, AH, arterial hypertension, GFR, glomerular filtration rate, CRF, chronic renal failure, UAER, urinary albumin excretion rate, RAS, rennin angiotensin system, ACE, angiotensin I converting enzyme, ACEI, ACE inhibitors, AGT, angiotensinogen, NO, nitric oxide, ACE, angiotensin I converting enzyme gene, I/D, insertion/deletion, AGT, angiotensinogen gene, CMA1, chymase gene, AT2R1, angiotensin II receptor, type 1 gene, NOS3, endothelial NO-synthase gene, SNP, single nucleotide polymorphism, PCR, polymerase chain reaction, bp, base pair, CI, confidence interval, OR, odds ratio

Keywords: Type 1 diabetes mellitus, Diabetic nephropathy, Polymorphic markers, Genes ACE, NOS3, Arterial hypertension