Individual And Interactive Effects Of MTHFR And COMT Gene Polymorphisms On Baseline Blood Pressure Levels And Antihypertensive Efficacy Of Irbesartan In Chinese Hypertensive Population

Background:At present,cardiovascular disease(CVD)is a leading cause of death worldwide.The number of deaths from CVD is 17 million,which accounting for approximately 30%of mortality.Moreover,the mortality rate caused by CVD accounts for over 40%of the total death rate in China.CVD has become the primary risk factors affecting the health of Chinese residents.Interestingly,genetic variants are considered to play an important role in the occurrence and development of CVD.It may be an effective way to reduce the risk of hypertension by digging out the susceptible genes and then provide a targeted/personalized treatment in patients with hypertension.Objective:(1)To investigate the effect of MTHFR C677T polymorphism,COMT Val158Met polymorphism and environmental factors on baseline DBP and SBP in Chinese population with essential hypertension.(2)To further investigate the effect of the COMT Val158Met polymorphism on antihypertensive efficacy of irbesartan in Chinese population with essential hypertension.Methods:A total of 1094 patients were enrolled from the Anhui Province,China.They received 150mg of irbesartan daily for twenty eight consecutive days.Baseline blood pressures and post-medication blood pressure were measured using a standardized mercury-gravity monometer.The polymorphism of the MTHFR C677T and COMT Val158Met gene were detected using high-throughput TaqMan allelic discrimination assay.Plasma irbesartan concentrations were measured using high-performance liquid chromatography(HPLC)with fluorescent detection.Result:(1)The frequencies of MTHFR 677CC,677CT and 677TT genotype were 38.6%,48.1%and 13.3%,respectively.In a recessive model(CC+CT versus TT genotypes),compared with CT or CC genotype carriers,TT genotype carriers have higher DBP levels(P=0.013).Furthermore,based on the tertiles of baseline DBP and SBP distribution,we divided all patients into three groups.Compared to subjects in the lowest tertile of DBP,the adjusted odds of having the TT genotype among subjects in the highest tertile was 2.6(95%CI,1.1-6.2).However,we did not find significant association between baseline SBP and MTHFR C677T polymorphism.(2)The genotype distribution of the COMT Val158Met polymorphism conformed to the Hardy-Weinberg equilibrium.Despite no significant associations were found between COMT Val158Met polymorphism and baseline blood pressure(BP)in the all participants,our results showed that patients carrying the AA genotype of the COMT Val158Met gene had significantly higher SBP than those with the G allele among the most severe SBP group(P=0.021)after stratifying by severity status of hypertension.Moreover,significant effect of interactions between environmental factors and the polymorphism were found on the antihypertensive efficacy.Compared with the COMT Val158Met G allele carriers,female subjects and smokers with the AA genotype having higher SBP response after irbesartan treatment for 28 days(P=0.011 and P=0.014,respectively).Conclusion:(1)MTHFR C677T and COMT Val158Met gene polymorphisms could be important genetic determinant of BP levels in Chinese essential hypertensive patients.(2)COMT Val158Met gene mutations could be further predictive of antihypertensive efficacy of irbesartan in Chinese hypertensive patients.