Predicting Hyperhomocysteinemia by Methylenetetrahydrofolate Reductase C677T Polymorphism in Chinese Patients With Hypertension

Objective: To evaluate the performance of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in predicting hyperhomocysteinemia (HHcy) in Chinese patients with hypertension. Methods: We measured plasma total homocysteine tHcy level and C677T genotype in 1058 Chinese patients with hypertension from 4 previous studies. We used 10, 15, and 20 μmol/L as cutoff values for the definition of mild, modest, and severe HHcy, respectively. Logistic models for HHcy were built from the study sample using the C677T genotype as well as age and gender as predictors. The receiver–operating characteristics of the models were evaluated. Results: Our major findings are that (1) C677T TT genotype is consistently associated with a higher tHcy across the 4 studies, with an increase in size ranging from 38% to 68% in the 4 studies and 51% overall. The C677T polymorphism independently explained about 14% of the total variance of the normalized tHcy. (2) The TT genotype is associated with a large increase in odds ratio (OR) for HHcy. Overall, the multivariate-adjusted ORs for the TT genotype are 3.9 (95% confidence interval [CI]: 2.4-6.4), 6.5 (95% CI: 4.0-10.6), and 17.9 (95% CI: 8.4-38.1) for mild, modest, and severe HHcy, respectively. (3) Overall, the predicting performance increased with HHcy severity, with sensitivity improving from 31.0% for mild HHcy to 70.3% for severe HHcy, and with specificity slightly decreasing from 85.4% to 80.3%. Inclusion of gender and age as predictors significantly improves the sensitivity, especially for predicting mild HHcy. Conclusion: With an excellent sensitivity and a modest specificity, C677T could be a useful screening marker for severe HHcy.

[1]  Andrew D. Johnson,et al.  Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. , 2013, The American journal of clinical nutrition.

[2]  Yun Li,et al.  Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults. , 2010, Human molecular genetics.

[3]  N. Akar,et al.  Single Nucleotide Polymorphisms That Affect Homocysteine Levels in Turkish Population , 2009, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[4]  S. Chanock,et al.  Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. , 2009, Human molecular genetics.

[5]  X. Qin,et al.  [Efficacy of enalapril combined with folic acid in lowering blood pressure and plasma homocysteine level]. , 2009, Zhonghua yi xue za zhi.

[6]  L. Almasy,et al.  Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study. , 2009, Blood.

[7]  X. Qin,et al.  Efficacy of combined amlodipine/terazosin therapy in male hypertensive patients with lower urinary tract symptoms: a randomized, double-blind clinical trial. , 2009, Urology.

[8]  Toshiko Tanaka,et al.  Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. , 2009, American journal of human genetics.

[9]  R. Collins,et al.  Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women’s Genome Health Study , 2009, Circulation. Cardiovascular genetics.

[10]  Shan-chun Zhang,et al.  Efficacy of folic acid and enalapril combined therapy on reduction of blood pressure and plasma glucose: a multicenter, randomized, double-blind, parallel-controlled, clinical trial. , 2008, Nutrition.

[11]  H. McNulty,et al.  Homocysteine, B-vitamins and CVD , 2008, Proceedings of the Nutrition Society.

[12]  Xiping Xu,et al.  Efficacy of folic acid supplementation in stroke prevention: a meta-analysis , 2007, The Lancet.

[13]  H. Xing,et al.  [Distribution of serum folic acid level of patient suffered mild and moderate hypertension in six cities in China]. , 2007, Wei sheng yan jiu = Journal of hygiene research.

[14]  K. Furie,et al.  Dose-Related Association of MTHFR 677T Allele With Risk of Ischemic Stroke: Evidence From a Cumulative Meta-Analysis , 2005, Stroke.

[15]  L. Smeeth,et al.  For Personal Use. Only Reproduce with Permission from Elsevier Ltd Homocysteine and Stroke: Evidence on a Causal Link from Mendelian Randomisation , 2022 .

[16]  T. Niu,et al.  D919G polymorphism of methionine synthase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients , 2004, Journal of Human Genetics.

[17]  W. Willett,et al.  Geographical, seasonal and gender differences in folate status among Chinese adults. , 2003, The Journal of nutrition.

[18]  H. Blom,et al.  Genetics of hyperhomocysteinaemia in cardiovascular disease , 2003, Annals of clinical biochemistry.

[19]  D. Wald,et al.  Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis , 2002, BMJ : British Medical Journal.

[20]  Petra Verhoef,et al.  MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. , 2002, JAMA.

[21]  J. Loscalzo,et al.  Homocysteine and atherothrombosis. , 1998, The New England journal of medicine.

[22]  V. Gudnason,et al.  C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group. , 1997, Atherosclerosis.

[23]  J. Witteman,et al.  Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. , 1997, JAMA.

[24]  M. Levene,et al.  Determination of plasma total homocysteine and cysteine using HPLC with fluorescence detection and an ammonium 7-fluoro-2, 1, 3-benzoxadiazole-4-sulphonate (SBD-F) derivatization protocol optimized for antioxidant concentration, derivatization reagent concentration, temperature and matrix pH. , 1996, Biomedical chromatography : BMC.

[25]  R. Matthews,et al.  Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification , 1994, Nature Genetics.

[26]  M. Norusis,et al.  Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. , 1991, American journal of human genetics.

[27]  P. Ueland,et al.  Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. , 1989, The Journal of laboratory and clinical medicine.

[28]  S. S. Kang,et al.  Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. , 1988, American journal of human genetics.

[29]  K. Mccully.  Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. , 1969, The American journal of pathology.

[30]  I. Rosenberg,et al.  Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. , 1996, Circulation.

[31]  R. Matthews,et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase , 1995, Nature Genetics.

[32]  J. Selhub,et al.  The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. , 1992, The American journal of clinical nutrition.

[33]  K. Pettigrew,et al.  The natural history of homocystinuria due to cystathionine beta-synthase deficiency. , 1985, American journal of human genetics.