Association Study Of Angiotensinogen Gene M235T Polymorphism And Type2Diabetic Nephropathy

Background:Genetic background is related to the development and progression of diabetic nephropathy. Renin-angiotensin-system （RAS） plays a key role in the diabetic nephropathy. This study examines a possible association between angiotensinogen M235T polymorphism with the presence and progression of nephropathy in type2diabetic Chinese. This study aims to investigate the association of gene M235T polymorphism and type2diabetic nephropathy.Methods:For the purpose of the study, type2diabetic cases （n=311） and healthy controls （n=203） were randomly selected. Diabetic patients were divided into three groups according to albumin-creatinine-ratio （ACR） levels:the normalbuminuria group （N group, ACR<30mg/g, n=158, duration of disease was over8years,8to36years [median12years]）, the patients was never treated with angiotensin converting enzyme （ACE） inhibitors or angiotensin receptor blockers （ARBs）; microalbuminuria group （M group,30mg/g<ACR<300mg/g, n=111, duration of disease was1to40years [median10years]）; proteinuria group （P group, ACR>300mg/g, n=42, duration of disease was2 to50years [median11years]）. Genotyping was tested by Polymerase Chain Reaction Restriction Fragment Length Polymorphism, PCR-RFLP). The frequency of the genotypes and alleles of AGT-M235T were compared among groups. The relationship of genetic disposition and clinical data collected and tested from type2diabetic patients were analyzed.Results:1. The genotype distributions in control group and type2diabetic group were in hardy-Weinberg equilibrium （P>0.05）.2. The frequencies of MM、MT、TT genotype in control group and diabetic group were2.5%、29.6%、68.0%and2.6%、28.3%、69.1%, the frequencies of M. T allele were17.2%、82.8%and16.7%、83.3%, respectively. No difference of genotype distribution （P=0.962） or allele frequencies （P=0.845） was found between healthy controls and T2DM patients; The two groups were stratified by gender, but still no distortion in distributions of genotypes （Male P=0.056, Female P=0.376） and alleles （Male P=0.302, Female P=0.559） was shown. No difference of genotype distribution （P=0.193） or allele frequencies （P=0.228） was observed between normotensive and hypertensive diabetic patients.3. No difference of genotype distribution （P=0.727） or allele frequencies （P=0.641） was found between diabetic patients with DN or without DN;The study groups were stratified by gender, but no distortion in distributions of genotypes （Male P=0.142, Female P=0.565） and alleles （Male P=0.424, Female P=0.701） was shown.4. No significant difference of genotype distribution （P=0.848） or allele frequencies （P=0.828） was found, among normalbuminuric, micro albuminuric, overt proteinuric cases and controls; The study groups were stratified by gender, still no distortion in distributions of genotypes （Male P=0.282, Female P=0.785） and alleles （Male P=0.634, Female P=0.871） was shown. 5. Type2diabetic subjects were divided into low-eGFR group （eGFR below60ml/min*m2） and high-eGFR group （eGFR above60ml/min*m2）. Although the frequency of TT genotype of low-eGFR group was higher than its of high-eGFR group （77.9%vs65.3%）, the difference was not significant （P=0.084）, the allele frequencies of two groups were different （P=0.041, OR1.676,95%CI₁.018-2.758）. After the exclusion of patients once treated with ACE inhibitors or ARBs, the frequency of TT genotype of low-eGFR group was significantly higher than its of high-eGFR group （81.2%vs64.9%, P=0.012）, and allele frequencies of two groups were also different （P=0.031）, the TT genotype （OR2.328,95%CI₁.188-4.560） and the T allele （OR1.905,95%CI₁.051-3.450） were probably associated with the decline in renal function.6. Multiple linear regression analysis indicated that age, ACE inhibitors or ARBs treatment was independently related to the decline in renal function, TT genotype was not an independent risk factor for the deteriorated renal function.Conclusion:The polymorphism of AGT-M235T in ZheJiang Han population is confirmed. AGT-M235T polymorphism, which is possibly not associated with the type2diabetes mellitus （T2DM） and albumin-creatinine-ratio in T2DM cases, may be associated with the decline in renal function in type2diabetic patients. T allele probably contributes to the diabetic chronic renal insufficiency.