title: Homocysteine and all-cause mortality in hypertensive adults without pre-existing cardiovascular conditions: Effect modification by MTHFR C677T polymorphism.
abstract: BACKGROUND
  Previous studies support an association between elevated total homocysteine (tHcy) levels and increased all-cause mortality. However, few prospective studies have examined this association in hypertensive patients, and/or tested any effect modification by the methylene tetrahydrofolate reductase (MTHFR) C677T genotype.
  
  
  METHODS
  This was a post hoc analysis of the China Stroke Primary Prevention Trial. Serum tHcy and folate were measured at baseline. Individual MTHFR C677T genotype (CC, CT, and TT) was determined. Evidence for death included death certificates or home visits. Cumulative hazards of all-cause mortality by tHcy quartiles were estimated using the Kaplan-Meier method, and group differences were compared by log-rank tests. Hazard ratios (HRs) and 95% confidence intervals were estimated by Cox proportional-hazard regression models, adjusting for age, sex, baseline folate, vitamin B12, blood pressure, body mass index, smoking and alcohol drinking status, study center, total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting glucose, creatinine, and treatment group. Potential effect modification by the MTHFR genotype on the relationship between tHcy and all-cause mortality was tested.
  
  
  RESULTS
  The analyses included 20,424 hypertensive patients (41% males) without a history of myocardial infarction or stroke. Baseline mean age (SD) was 60 ± 7.5 years and mean (SD) serum tHcy was 14.5 ± 8.4 μmol/L. After a mean follow-up period of 4.5 years, there were 612 (3%) all-cause deaths. Kaplan-Meier survival curves revealed a graded relationship between tHcy quartiles and all-cause mortality. The HRs, using the lowest quartile as the reference, were 1.2, 1.2, and 1.5 in Q2, Q3, and Q4, respectively. A linear trend test, using natural log-transformed tHcy, resulted in an HR of 1.5 (95% confidence interval 1.2-1.9, P < .001) after adjustment for lifestyle and health-related variables. Whereas the MTHFR genotype alone had little effect on mortality, it significantly modified the tHcy-mortality association, which was much stronger in the CC/CT genotype than in the TT genotype (P for interaction < 0.05).
  
  
  CONCLUSIONS
  Among Chinese hypertensive patients without cardiovascular comorbidities, elevated tHcy was a significant risk marker for death from all causes, and the association was subject to effect modification by MTHFR genotypes. If confirmed that tHcy and MTHFR genotypes may serve as useful biomarkers for mortality risk assessment and targeted intervention.
authors.affiliation: Department of Cardiology, Peking University First Hospital, Beijing National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou Institute for Biomedicine, Anhui Medical University Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Jiangxi Department of Neurology, First People's Hospital, Lianyungang Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing School of Health Administration, Anhui Medical University, Hefei Department of Cardiology, Chinese People's Liberation Army General Hospital, Beijing Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Department of Cardiology, Peking University People's Hospital Department of Pharmacy, Peking University First Hospital, Beijing, China.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Xu
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Kong
authors.forename: Richard
authors.initials: R
authors.lastname: Xu
authors.forename: Yun
authors.initials: Y
authors.lastname: Song
authors.forename: Lishun
authors.initials: L
authors.lastname: Liu
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Zhou
authors.forename: Rui
authors.initials: R
authors.lastname: Gu
authors.forename: Xiuli
authors.initials: X
authors.lastname: Shi
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Xiao
authors.initials: X
authors.lastname: Huang
authors.forename: Mingli
authors.initials: M
authors.lastname: He
authors.forename: Jia
authors.initials: J
authors.lastname: Fu
authors.forename: Yefeng
authors.initials: Y
authors.lastname: Cai
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Xiaoshu
authors.initials: X
authors.lastname: Cheng
authors.forename: Changyan
authors.initials: C
authors.lastname: Wu
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Genfu
authors.initials: G
authors.lastname: Tang
authors.forename: Xianhui
authors.initials: X
authors.lastname: Qin
authors.forename: Binyan
authors.initials: B
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Xue
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Ningling
authors.initials: N
authors.lastname: Sun
authors.forename: Yimin
authors.initials: Y
authors.lastname: Cui
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Huo
mesh_terms: D002681:China / Q000453:epidemiology; D005260:Female; D005492:Folic Acid / Q000097:blood; D005500:Follow-Up Studies; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics* / Q000401:mortality*; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D006710:Homocysteine; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)