Gene-fatty Acids Interactions And Homocysteine Metabolism, Type 2 Diabetes Susceptibility

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases (CVD). It also increases the risk of type 2 diabetes (T2DM). Fatty acids compositions play an important role in prevention of chronic diseases such as CVD, T2DM. Recent studies showed that n-3 polyunsaturated fatty acids (PUFA) were inversely associated with plasma homocysteine (Hcy). However, the potential mechanism by which n-3 PUFA decrease plasma Hcy is not understood. The mechanism by which the genetic variants involved in Hcy metabolism regulate plasma Hcy level and T2DM susceptibility is not understood. Therefore, the objectives of the present study were to investigate:1) the effect of genetic variants involved in fatty acid metabolism on fatty acid composition in Chinese.2) the associations of diet/plasma phospholipids (PL) fatty acids with plasma Hcy.3) the potential mechanism by n-3 PUFA decrease plasma Hcy.4) Diet fatty acids-Hcy related genetic variants interactions and plasma Hcy concentration.5) the associations of plasma PL fatty acids with chronic diseases such as T2DM. metabolic syndrome and hypertension in Chinese.6) effects of plasma Hcy and Hcy related genetic variants on T2DM susceptibility.The main findings were summarized as follows:1. FADS3 genotype (rs174455), FADS1 genotype (rs174537), FADS2 (rs174575) were significantly associated with the metabolism of n-3 PUFA and n-6 PUFA in plasma or erythrocyte phospholipids in Chinese. PEMT genotypes and haplotypes were significantly associated with plasma PL PUFA. PEMT may modulate plasma Hcy level through regulating PL n-3 PUFA in plasma and erythrocyte.2. n-3 PUFA was significantly inversely associated with plasma Hcy. The cancer mortality and ischemic heart disease mortality was significantly lower in vegetarians than that in nonvegetarians, However, all cause morality, circulatory diseases and cerebrovascular disease mortality were not significantly lower in vegetarians. N-3 PUFA has protective effects on T2DM, metabolic syndrome and hypertension. Saturated fatty acids increase the risk of chronic diseases. However, fatty acids may interact with other CVD risk factors in determining chronic diseases.3. n-3 PUFA supplementation significantly improved PL fatty acids compositions in plasma and other tissues. N-3 PUFA modulates plasma Hcy concentration through regulating the critical enzyme activity and gene expression involved in Hcy and phospholipids metabolic pathways. Moreover, DHA, EPA, ALA exert different effects on plasma Hcy metabolism.4. In Boston Puerto Ricans, MAT1A and MTHFR genetic variants directly lead to the increased concentration of plasma Hcy. Diet fatty acids interact with MAT1A and MTHFR genotypes in determining plasma Hcy. Lifestyle factors (smoking, drinking and physical activity) interact with genetic variants involved in methionine metabolic pathway in modulating plasma Hcy. In Chinese, MTHFR, MTR, MTRR, MAT1A,PEMT genetic variants affect the plasma Hcy in Chinese. Erythrocyte phospholipids fatty acid interacts with THFD, MTHFR, PEMT genotype in determining plasma Hcy level in Chinese T2DM.5. MTHFR (rs1801131), MTHFD (rs2236225), PEMT (rs4646356), PEMT (rs4646406) was associated with the risk of Chinese T2DM. MAT1A, MTHFR, PEMT also affect the risk of T2DM. Plasma Hcy level in T2DM was significantly higher than that in healthy subjects. MTHFR 677 TT significantly increased the risk of T2DM. MAT1A_i15752 and MAT1A_d18777 modulate the plasma Hcy concentration and increase the risk of T2DM. In addition, PEMT genotypes and haplotypes were associated with plasma Hey level. Moreover, PEMT T-A significantly increased the risk of T2DM.In conclusion, the results of the present study showed that genetic variants involved in fatty acid metabolism affect the fatty acids composition in Chinese. n-3 PUFA modulating plasma Hcy concentration through regulating the critical enzyme activity and gene expression involved in methionine metabolic pathway. Higher plasma Hcy level and the genetic variants involved in Hcy metabolic pathway increase the risk of T2DM. Fatty acids interact with Hcy related genetic variants in determining plasma Hcy level. Therefore, according to the nutrigenomics, increasing n-3 PUFA intake based on the DNA backup may prevent the Hyperhomocysteinemia and T2DM.