Impact of Folic‐acid Intervention and MTHFRC677T Gene Polymorphism on All‐cause Mortality Associated with Elevated Serum Homocysteine Levels in Chinese Adults with Hypertension

Abstract

BackgroundMortality is one of the most fundamental metrics of population health. The role of nutrition in reducing mortality is of great public health interest. High levels of homocysteine (HHcy, in part, due to low folate intake) are known to increase the risk of cardiovascular diseases. However, data are limited on the longitudinal association of HHcy levels with all‐cause mortality in low folate regions such as China.ObjectiveIn a population with relatively low folate intake and high rate of HHcy, we aimed to test the hypothesis that HHcy is associated with increased mortality and folic acid therapy can reduce the risk of all‐cause mortality associated with HHcy. We also examined whether the effect may be affected by individual MTHFR (a key enzyme involved in Hcy metabolism) gene C677T polymorphism.MethodsWe analyzed the data of 20,702 hypertensive adults (age: 59.6 ± 7.5 years) enrolled in the China Stroke Primary Prevention Trial (CSPPT), with measurements for individual baseline serum total Hcy (tHcy) levels and MTHFR C677T genotypes. These participants were randomized to receive 5‐year, double‐blind daily treatment with 10mg enalapril and 0.8mg folic acid (n=10,348) or 10mg enalapril alone (n=10,354). Kaplan‐Meier survival analysis and Cox proportionate hazard model were used to estimate the effect of tHcy levels on all‐cause mortality and to test effect modification by folic acid intervention and MTHFR C677T genotype.ResultsThere were 622 (3%) all‐cause deaths during a mean treatment period of 4.5 years. There was a dose‐response relationship between tHcy quartiles and all‐cause mortality (P for trend<0.001) after adjusting for pertinent covariables. This relationship was stronger among participants with CC or CT genotypes than among those with TT genotype. Compared to the enalapril alone group, enalapril plus folic acid therapy further lowered the risk of all‐cause mortality associated with increased tHcy levels. The risk reduction was more pronounced in participants with CC or CT genotypes.ConclusionsIn this large‐scale study of population residing in a low folate region, we found that baseline tHcy levels were associated with all‐cause mortality in a dose‐response fashion; and folic acid therapy can lower the all‐cause mortality risk associated with HHcy. Our data suggest that tHcy and MTHFR genotypes may serve as biomarkers for risk stratification and folic acid therapy may offer a simple, inexpensive and safe intervention strategy to reduce mortality among population characterized by low folate intake and high rate of HHcy.