The Effects Of NRF2Gene Polymorphism In Diabetes And Its Complications

European Association for the Study of Diabetes announces that Diabetes Mellitushas reached366million people worldwide in2011, nearly30%more than in2010when there were285million suffers. The number is increasing year by year.Diabetes become one of the serious diseases all over the world. The patientsare enduring the severe disease and so many complications. At the same time,they have to afford huge medical bills. How to prevent the disease, improvethe patients’living quality and delay the emergence of its complications thatare our common urgent desire. However, since diabetic is a complex polygenichereditary disease, its pathogenesis is not clear now.It is well known that oxidative stress is an important course in diabetes.Recently Nuclear factor erythroid2related factor(NFE2L2,also be known as NRF2)is found to be one of the key genes in oxidative stress and damage repair. Afteroxidative stress stimulation, NRF2which transfers into the nucleus, bandingto the upstream promoter regions of antioxidant response element, startsdownstream protective protein gene’s transcription so as to improve theability of cells against oxidative stress. Then the NRF2gene protects our lung,liver, digestive system, nervous system and cardiovascular system. Yet how doesthe NRF2regulate antioxidant injury pathways in the development of diabetes?Will NRF2gene mutate in diabetes patients? Will these mutations increase personsusceptibility to diabetes? Can these mutations become a forecast index ofdiabetes in the future? All these things are unknown. So we designed andconducted the following study.655samples from north china are studied in the study. It includes344diabetescases and311normal controls. This experiment takes four steps:1. All SNPs alleles in the NRF2gene on human chromosomes are download from the human genomedatabase. Then7tag SNPs (htSNPs) sites from the NRF2gene are selected byhaploview4.2.0.0software.2. Custom probes according to the above siteinformation are provided by ABI company in the United States. Then Taqman probetechnology is be used to type all these7tag SNPs loci of these DNA samples.At the same time,10samples randomly selected from each site are sent forsequence by the biological engineering co. Shanghai.3.82cases of samplesare randomly selected from these classified SNP samples. HO-1in serum isdetected by ELISA and superoxide dismutase (SOD) is detected by chemicalcolorimetry.4. All clinical informations of these SNP samples are collectedto analysis the relationship between the SNP variation, serological indexchanges and clinical symptoms through the statistical analysis.In this experiment,7tag SNPs were screened from intron1area of NRF2gene,and they respectively are rs2364723(G/C), rs10497511(G/A), rs13001694(A/G),rs3731799(G/A), rs1806649(C/T), rs1962142(G/A),and rs672639(G/A).Experimental results show that there is significant difference (P=0.038<0.05) between C (=158) and G (=152) alleles of the rs2364723site in diabetescomplications. From haploid type analysis,22kinds of haploid type can beformed according to these seven SNPS loci. All these haploid’s comparison isfound no significant difference (P>0.05) between the diabetes and non-diabetesgroup, the diabetes group and other diseases group, diabetes group and normalcontrol group, uncomplicated diabetes group and diabetes complications.Correlation analysis of SNP and serological data shows strikingly reducedexpression of HO-1in rs2364723sites GG genotype samples. In overall and thediabetes group samples, HO-1expression at rs10497511sites GG genotype weresignificantly reduced too. The same results are certified in rs1962142andrs6726395loci AA genotype. SOD level of serum in diabetic group wassignificantly lower than normal control group. The mutation of AA (rs6726395)and GG (rs2364723) genotype make SOD less expression. Observation proved that there is a significant difference (P=0.026<0.05)in rs2364723loci between hyperlipidemia patients with243cases (68.6%) andnormal lipidemia (111cases). We also found the association of hypertension(P=0.006<0.05) and overweight (P=0.029<0.05) in rs3731799loci.Through the above experiments, we found that the NRF2gene mutation of G inrs2364723locus increased risk of hyperlipidemia, and also increases the riskof complications in diabetes. rs3731799site have total627cases, includingwide type of612(97.6%), heterozygote of15(2.4%), and no GG genotype, sothat heterozygote increases the risk of high blood pressure and obesity. NRF2gene mutations affect HO-1, SOD expression.This study is one of the important content of disease genomics researchfollowing genome era. Research results will help to elucidate the geneticmechanism of diabetes and its complications. It laid the important experimentalbasis for in forecasting the occurrence of diabetes as early as possible atthe genetic level, establishing diagnosis method, developing new drugs,effectively preventing and controlling diabetes chronic complication.