A Real World Study On The Relationship Between ATM And SLC47A2 Genotypes And Clinical Outcomes In Metformin Treated Patients

Background:Metformin is one of the oral antidiabetic drugs for the first line treatment of Type II diabetes mellitus(T2DM).But in the clinic,the effect of metformin among different individual show many differences;Ataxia-telangiectasia,mutatedgene(ATM)is the pathogenic gene of ataxia telangiectasia;recent research show that ATM maybe relate to the cause of diabetes,ATM respond encoding the phosphoinositide 3-kinase(PI3K)family;which participate in the pathway of AMPK,cause the alternative effect of metformin;Solution carrier family 47 member 2(SLC47A2)respond encoding multidrug and toxin exotoxin 2K(MATE2K),which play a role in eliminate metformin in the kidney,alter the pharmacokinetics and plasma concentration of metformin,lead to affect the efficacy.Objective:To investigated the realtionship between the SNP of ATM and SLC47A2 genes and clinic outcomes of metformin treated patients with type 2 diabetes mellitus in the real world,to provide basis for the clinical application of gene detection,so as the individualized treatment and precise treatment of T2 DM patients.Materials and Methods:Included 118 patients with type 2 diabetes mellitus in our hospital;which take metformin daily for basic treatment;PCR was used to amplify the target fragment DNA in patients’ blood,to detect the genotype of SNP rs11212617 in ATM and SNP rs12934590 in SLC47A2;According to their genotype of SNP rs11212617,divide the patient into CC(57cases),AC(49cases),and AA(12cases),and the SNP rs12934590 for GG(36cases),AG(56cases)and AA(26cases);to analysis the biochemical indexes,blood glucose control and clinical phenotype in different genotype.Result:In 118 included patients,58 males and 60 females;the average age is 64.07±11.70 years;The allele distribution frequency of SNP rs11212617 and SNP rs12943590 is similar to the frequency of Asia population in accordance with the Hardy-Weinberg equilibrium;the statistics show similar in the average age,sociology,lifestyle BMI,CHO,TG,Cr,and the adverse reaction,no significant in statistical difference(p>0.05);In the analysis of SNP rs11212617,the patients with genotype CC has lower level of HbA1 c than genotype AC and AA(7.0±1.3)% vs(7.6±1.5)% vs(7.5±1.2)%,the difference between the CC and AC is significant in statistics(p<0.05*).Genotype CC has a higher ratio in HbA1c<7.0% than AC and AA(52.6%)vs(32.7%)vs(25.0%),the difference between the CC and AC is significant in statistics(p<0.05),and the statistics show the polymorphism of SNP rs11212617 is relevant to the HbA1 c level and ratio in HbA1c<7.0%;Statistics show the ratio of oligodrug group in the patient with genotype CC is higher than AC and AA(73.3%vs37.5%vs66.6%);the difference between the CC and AC has significant in statistics(p<0.05);Genotype CC has a lower ratio of combination Hypertension(36.8%vs59.2%vs50.0%),the difference between the CC and AC has significant in statistics(p<0.05);In the analysis of SNP rs12934590,the patients with genotype AC has a higher ratio in HbA1c<7.0% than GG and AA(50.0%vs27.8%vs42.3%),and show significant in statistical difference between the AG and GG(p<0.05).The genotype AA show a lower ratio of combination Hyperlipidemia than AG and GG(GG:44.4%;AG:55.4%;AA:30.8%);and show significant in statistical difference between the AA and AG(p<0.05).In the analysis of the alleles of SNP rs11212617 and rs12934590,the the patients with alleles C+A show a lower HbA1 c level and a higher ratio in HbA1c<7.0% than other Alleles,and show significant in statistical difference between the C+A and A+G(p<0.05).In the analysis of relationship between the two SNPs and adverse effect of metformin,SNP rs-11212617 genotype CC show a higher rate of adverse reaction than AC and AA(24.5%vs20.4%vs16.6%),and SNP rs-12943590 genotype GG show a lower rate of adverse reaction than AG and AA(19.4%vs23.2%vs23.0%),but no significant in statistical difference between the three genotypes in the two SNP.Conclusion:1.The genotype of SNP rs11212617 has relationship with the blood sugar control of the metformin treated T2 DM patient.The patient with genotype CC,so as the carryer of alleles C,is trend to has more benefits during the treatment than other genotypes.2.The genotype of SNP rs12943590 has relationship with the clinic phenotype of the metformin treated T2 DM patient.The patient with genotype CC is trend to has less benefits during the treatment than other genotypes.3.The SNP rs11212617 and SNP 12943590 maybe have relationship with the adverse reaction of metformin.The SNP rs11212617 genotype CC maybe have more possibilities of adverse reaction.In the other hand,the SNP 12943590 genotype GG maybe have less possibilities of adverse reaction.