The Application Of Diabetes Genetic Loci In Analyses Of Causal Relationship And Gene-diet Interaction

Background The rapid development of the genotyping chip and next generation sequencing technology promoted the discovery of over 100 type 2 diabetes(T2D)and 60 glycated hemoglobin A1c(HbA1c)associated single nucleotide polymorphism(SNP)in genome-wide analysis studies(GWAS).This opportunity propelled the Mendelian Randomization(MR)analysis and gene-diet interaction analysis become the most important research methods of genetic epidemiology in the post-GWAS era.MR analysis is a novel analysis technique for genetic epidemiology by taking SNPs discovered in GWAS as instrumental variables(IVs)to detect causal associations among diseases and phenotypes.Compared with traditional observational study,MR analysis can eliminate the interruption of confounding factors and reverse causality by taking advantage of the random distribution principle of allelic genes.Therefore,MR analysis has been widely adopted in recent years.It has been demonstrated that both T2D and dyslipidemia are the main risk factors of cardiovascular diseases(CVD).While for T2D patients,dyslipidemia also acted as one of the most important risk factors of CVD.However,study for the causal relationship of T2D and HbA1c with lipid profiles in Eastern Asian population remains unestabolished.Meanwhile,T2D is believed an outcome of impact of environment and genetic predisposition.Dietary intake and patterns,such as vegetable and fruit consumption were found to be play pivotal roles in T2D prevention and treatment.Although vegetable and fruit consumption were widely studied to be associated with a lower risk of T2D,the gene-diet interation of the genetic predisposition of T2D and HbA1c with vegetable and fruit consumption hasn't yet been reported.Aims 1.To study the causal association of T2D and HbA1c with serum triglycerides(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C)in a Chinese population.2.To study the gene-diet interaction effect of T2D and HbA1c genetic predisposition and fruit and vegetable consumption on risk of T2D in a Chinese population.Study design and methods We used standard and valided questionnaires to collect demographic,disease and medication history,lifestyle information and diatary intake habits.We measured the systolic blood pressure(SBP)and diastolic blood pressure(DBP),body weight and height,and calculated body mass index(BMI).We measured fasting plasma glucose(FPG),2hpost OGTT plasma glucose(2h-PG),lipid profiles,and HbA1c.We genotyped 34 T2Dand 17 HbA1c-associated SNPs.We created the T2D and HbA1c associated genetic risk scores(GRSs)as the primary Instrumental Variables,to performed(1)MR analysis to evaluate the the causal relationship of T2D and HbA1c with triglycerides(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C),and(2)gene-diet interaction analysis to detect the genediet interaction effect of fruit and vegetable consumption and T2D and HbA1c genetic predisposition on risk of T2D.Results Analyses for HbA1c associated GRS and conservative GRS demonstrated that as the GRSs elevated,Log-TG,TC,and LDL-C increased significantly(all P<0.05);while no significant causal effect was detected for HDL-C.This result remained significant in the three adjustment models.Multiple methods of MR analysis were adopted as sensitivity analyses,and the reuslts did not change appreciably;no significant pleiotropy was detected.There were no significant association of T2D-GRS and conservative GRS with lipid profiles(all P>0.05).Gene-diet interaction analyses demonstrated that under the full adjustment model,the odds ratio(OR)for T2D regarding with the T2D related GRS significantly decreased as fruit consumption frequency increased(all P<0.05).While the protective effect of fruit consumption on T2D risk was significantly enhanced as the tertile of T2D related GRS went up(all P<0.05).However,there was no interactive effect between HbA1c related GRS and fruit consumption;no intereaction of vegetable consumption with neither T2D nor HbA1c GRS was found.Conclusions In a Chinese population,we found causal associations of HbA1c with serum TG,TC,and LDL-c;and a gene-diet interaction effect of fruit consumption and genetic predisposition of T2D on risk of T2D.We did not find intereactions of vegetable consumption with neither T2D nor HbA1c GRS.These results showed that lowing HbA1c level could be helpful in treatment of hyperlipidemia.It should be paid attention to the individual's genetic predisposition while considering the protect effect of higher fruit consumption on the risk of T2D.