Methylenetetrahydrofolate reductase C677T polymorphism, hypertension and risk of stroke: a prospective, nested case-control study

Abstract

Background: Hyperhomocysteinemia is a risk factor for cardiovascular disease. To date, limited prospective studies have examined the joint effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, hyperhomocysteinemia and conventional vascular risk factors on risk of stroke and stroke death. Methods: A total of 39 165 subjects from nine communities within Anqing, Anhui Province, China were prospectively followed from March 1995 to April 2005, with an average follow-up period of 6.2 years. None of the subjects had any history of vascular events at baseline. At follow-up, 251 incident stroke cases were identified. Using a nested, case-control study design, this analysis includes 106 cases with complete MTHFR C677T genotyping data and plasma samples. We selected 106 controls without vascular events matched for age, sex, community and years of plasma storage. Plasma total homocysteine (tHcy) level was measured by high-performance liquid chromatography. Results: Hypertension was independently associated with incident stroke and stroke death after adjusting for important covariates including plasma log-transformed Hcy level. Relative to non-carriers of the MTHFR 677TT genotype with no hypertension, the adjusted odds ratio (95% confidence interval) of stroke and stroke death among hypertensive carriers of the MTHFR 677TT genotype was 10.6 (3.2 to 34.8), 5.8 (1.6 to 21.3), respectively. After excluding subjects with plasma Hcy above 20 μmol/L, the relative odds for stroke, but not for stroke death, was more significantly pronounced (OR = 24.1, 95% CI: 2.3 to 246.1) among subjects with moderate plasma Hcy levels. However, there was no significant interactive effect between hypertensive status and the MTHFR C677T variant on the odds of the two outcomes as estimated by interaction models. Conclusions: Our major findings suggest that joint effects of the MTHFR C677T polymorphism and hypertension are consistent in predicting a significantly high risk of stroke. In addition for moderate plasma levels of Hcy, the predicted effects on the risk for the primary end point of stroke were more pronounced. These results may help to modify current approaches to vascular disease prevention in Chinese hypertensive patients.

KEYWORDS:

• MTHFR C677T polymorphism
• stroke
• nested case-control study

Acknowledgements

We gratefully acknowledge the assistance and cooperation of the faculty and staff of the Anhui Medical University and thank all of the participants in our study. This study was conducted in accordance with the current regulations of the People's Republic of China.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. Investigators were not allowed to ask patients about reasons for non-participation during the first and second follow-up.

Declaration of Interest

The authors declare no conflict of interest. This study was supported by the National Science and Technology Major Projects Specialized for “Major New Drugs Innovation and Development” during the 12th Five-Year Plan Period [grant number zx09101105]; the National Natural Science Foundation of China [grant number 81473052], grant number [81373484], [grant number 81141116]; [grant number 30700454].

Additional information

Funding

the National Natural Science Foundation of China, the National Science and Technology Major Projects