Midtveisevaluering - Yunpeng Ding
Association Between the MTHFD1 Promoter Polymorphism and Survival in Patients With Acute Myocardial Infarction
The role of one-carbon metabolism in the pathogenesis of cardiovascular disease has not been fully understood yet due to the complexity of folate-associated network. While observational studies showed that elevated plasma level of homocysteine was associated with ischemic heart disease and stroke, randomized clinical trials failed to reduce the risk of cardiovascular diseases by folate/Vitamin B6 supplementary. From this aspect, genetic research may provide more information about the pathology since it is less likely to be affected by traditional confounding. There is one single nucleotide polymorphism (SNP) locates in the promoter region of MTHFD1 gene in one carbon metabolism, which has been showed in vitro experiments that the mutant type could decrease the enzyme activity to only 38.5% comparing with the wild-type. My project mainly focuses on the association between this SNP and the occurrence of myocardial infarction (MI), genetic interaction in folate network as well as the effect modification of dietary supplements and lipid metabolism. We first examine the independent effect of this promoter SNP on the occurrence of fatal and non-fatal MI in tow cohorts: WENBIT and NORVIT. And then we explore the potential causal relations by involving other SNPs and clinical parameters in folate cycle to test their interactions. Data mining approaches, like random survival forests and nest recursive analysis are carried out in this phase. Finally, we will manage to do mediation analysis trying to illustrate the potential mediator(s) between MTHFD1 genetic variants and MI risk. Until now, we have found the significant association between MTHFD1 promoter polymorphism and the occurrence of MI in WENBIT cohort but not in NORVIT. People carrying two mutant alleles of MTHFD 105C>T would have almost 2.2 fold higher risks to have non-fatal MI in our research population. Besides, vitamin B6 is a significant effect modifier to MTHFD1 promoter polymorphism on its relationship with fatal AMI in both WENBIT and NORVIT cohort. Furthermore, results from gene-gene interaction also showed that there are several genes in this network interacting together to mediate the occurrence of MI. This work so far suggests that folate metabolism is closely involved into the pathogenesis of MI, and also showed the intercorrelatedness between folate metabolism and dietary vitamin B6 supplement as well as lipid metabolism.