Xiao Huang1, Xianhui Qin1, Wenbin Yang1, Lishun Liu1, Chongfei Jiang1, Xianglin Zhang1, Shanqun Jiang1, Huihui Bao1, Hai Su1, Ping Li1, Mingli He1, Yun Song1, Min Zhao1, Delu Yin1, Yu Wang1, Yan Zhang1, Jianping Li1, Renqang Yang1, Yanqing Wu1, Kui Hong1, Qinhua Wu1, Yundai Chen1, Ningling Sun1, Xiaoying Li1, Genfu Tang1, Binyan Wang1, Yefeng Cai1, Fan Fan Hou1, Yong Huo1, Hong Wang2, Xiaobin Wang2, Xiaoshu Cheng2. 1. From the Department of Cardiology, The Second Affiliated Hospital of Nanchang University, China (X.H., H.B., H.S., P.L., R.Y., Y. Wu, K.H., Q.W., X.C.); National Clinical Research Study Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (X.Q., C.J., X.Z., Y.S., Y. Wang, B.W., F.F.H.); Institute of Biomedicine, Anhui Medical University, Hefei, China (W.Y., S.J.); China Agricultural University, Beijing (L.L.); School of Life Sciences, Anhui University, Hefei, China (S.J., G.T.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y. Cai); Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, China (D.Y.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H.); Department of Cardiology, General Hospital of PLA, Beijing, China (Y. Chen); Department of Cardiology, Peking University People's Hospital, Beijing, China (N.S.); Department of Geriatric Cardiology, the General Hospital of the People's Liberation Army, Beijing, China (X.L.); Centers for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA (H.W.); and Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.). 2. From the Department of Cardiology, The Second Affiliated Hospital of Nanchang University, China (X.H., H.B., H.S., P.L., R.Y., Y. Wu, K.H., Q.W., X.C.); National Clinical Research Study Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (X.Q., C.J., X.Z., Y.S., Y. Wang, B.W., F.F.H.); Institute of Biomedicine, Anhui Medical University, Hefei, China (W.Y., S.J.); China Agricultural University, Beijing (L.L.); School of Life Sciences, Anhui University, Hefei, China (S.J., G.T.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y. Cai); Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, China (D.Y.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H.); Department of Cardiology, General Hospital of PLA, Beijing, China (Y. Chen); Department of Cardiology, Peking University People's Hospital, Beijing, China (N.S.); Department of Geriatric Cardiology, the General Hospital of the People's Liberation Army, Beijing, China (X.L.); Centers for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA (H.W.); and Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.). xwang82@jhu.edu xiaoshumenfan@126.com hongw@temple.edu.
Abstract
OBJECTIVE: This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS: This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS: Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.
RCT Entities:
OBJECTIVE: This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS: This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFRC677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS: Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFRC677T genotype and folate status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.