Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta‑analysis of 10,415 subjects

Yang,Ke‑Ming; Jia,Jian; Mao,Li‑Na; Men,Chen; Tang,Kang‑Ting; Li,Yan‑Yan; Ding,Hai‑Xia; Zhan,Yi‑Yang

doi:10.3892/br.2014.302

Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta‑analysis of 10,415 subjects

Authors:
- Ke‑Ming Yang
- Jian Jia
- Li‑Na Mao
- Chen Men
- Kang‑Ting Tang
- Yan‑Yan Li
- Hai‑Xia Ding
- Yi‑Yang Zhan
View Affiliations

Affiliations: Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P.R. China, Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P.R. China
Published online on: June 25, 2014 https://doi.org/10.3892/br.2014.302
Pages: 699-708

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been suggested to be associated with the risk of essential hypertension (EH), however, results remain inconclusive. To investigate this association, the present meta‑analysis of 27 studies including 5,418 cases and 4,997 controls was performed. The pooled odds ratio (OR) and its corresponding 95% conﬁdence interval were calculated using the random‑effects model. A significant association between the MTHFR C677T gene polymorphism and EH was found under the allelic (OR, 1.32; 95% CI, 1.20‑1.45; P=0.000), dominant (OR, 1.39; 95% CI, 1.25‑1.55; P=0.000), recessive (OR, 1.38; 95% CI, 1.18‑1.62; P=0.000), homozygote (OR, 1.59; 95% CI, 1.32‑1.92; P=0.000), and heterozygote (OR, 1.32; 95% CI, 1.20‑1.45; P=0.000) genetic models. A strong association was also revealed in subgroups, including Asian, Caucasian and Chinese. The Japanese subgroup did not show any significant association under all models. Meta‑regression analyses suggested that the study design was a potential source of heterogeneity, whereas the subgroup analysis additionally indicated that the population origin may also be an explanation. Another subgroup analysis revealed that hospital‑based studies have a stronger association than population‑based studies, however, the former suffered a greater heterogeneity. Funnel plot and Egger's test manifested no evidence of publication bias. In conclusion, the present study supports the evidence for the association between the MTHFR C677T gene polymorphism and EH in the whole population, as well as in subgroups, such as Asian, Caucasian and Chinese. The carriers of the 677T allele are susceptible to EH.

View Figures

View References

1	Mein CA, Caulfield MJ, Dobson RJ and Munroe PB: Genetics of essential hypertension. Hum Mol Genet. 13:R169–R175. 2004. View Article : Google Scholar : PubMed/NCBI
2	Dominiczak AF, Negrin DC, Clark JS, Brosnan MJ, McBride MW and Alexander MY: Genes and hypertension: from gene mapping in experimental models to vascular gene transfer strategies. Hypertension. 35:164–172. 2000. View Article : Google Scholar : PubMed/NCBI
3	Lupton SJ, Chiu CL and Lind JM: A hypertension gene: are we there yet? Twin Res Hum Genet. 14:295–304. 2011. View Article : Google Scholar : PubMed/NCBI
4	Men C, Tang K, Lin G, Li J and Zhan Y: ENOS-G894T polymorphism is a risk factor for essential hypertension in China. Indian J Biochem Bio. 48:154–157. 2011.PubMed/NCBI
5	Goyette P, Pai A, Milos R, et al: Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome. 9:652–656. 1998. View Article : Google Scholar
6	Frosst P, Blom HJ, Milos R, et al: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 10:111–113. 1995. View Article : Google Scholar : PubMed/NCBI
7	Tawakol A, Omland T, Gerhard M, Wu JT and Creager MA: Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation. 95:1119–1121. 1997. View Article : Google Scholar : PubMed/NCBI
8	Heux S, Morin F, Lea RA, Ovcaric M, Tajouri L and Griffiths LR: The methylentetrahydrofolate reductase gene variant (C677T) as a risk factor for essential hypertension in Caucasians. Hypertens Res. 27:663–667. 2004. View Article : Google Scholar : PubMed/NCBI
9	Li YY: Methylenetetrahydrofolate reductase C677T gene polymorphism and coronary artery disease in a Chinese Han population:a meta-analysis. Metabolism. 61:846–852. 2012. View Article : Google Scholar : PubMed/NCBI
10	Alam MA, Husain SA, Narang R, Chauhan SS, Kabra M and Vasisht S: Association of polymorphism in the thermolabile 5, 10-methylene tetrahydrofolate reductase gene and hyperhomocysteinemia with coronary artery disease. Mol Cell Biochem. 310:111–117. 2008. View Article : Google Scholar : PubMed/NCBI
11	Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 288:2015–2022. 2002. View Article : Google Scholar : PubMed/NCBI
12	Rodríguez-Esparragón F, Hernández-Perera O, Rodríguez- Pérez J, et al: The effect of methylenetetrahydrofolate reductase C677T common variant on hypertensive risk is not solely explained by increased plasma homocysteine values. Clin Exp Hypertens. 25:209–220. 2003.PubMed/NCBI
13	Lin PT, Cheng CH, Wei JC and Huang YC: Low plasma pyridoxal 5′-phosphate concentration and MTHFR 677C-->T genotypes are associated with increased risk of hypertension. Int J Vitam Nutr Res. 78:33–40. 2008.
14	Yin RX, Wu JZ, Liu WY, et al: Association of several lipid-related gene polymorphisms and blood pressure variation in the Bai Ku Yao population. Am J Hypertens. 25:927–936. 2012. View Article : Google Scholar : PubMed/NCBI
15	Fowdar JY, Lason MV, Szvetko AL, Lea RA and Griffiths LR: Investigation of homocysteine-pathway-related variants in essential hypertension. Int J Hypertens. 2012:1909.232012.PubMed/NCBI
16	Nakata Y, Katsuya T, Takami S, et al: Methylenetetrahydrofolate reductase gene polymorphism relation to blood pressure and cerebrovascular disease. Am J Hypertens. 11:1019–1023. 1998. View Article : Google Scholar : PubMed/NCBI
17	Liu HY, Ma P and Xu QB: The correlation between polymorphisms of N5,10 methylenetetrahydrofolate reductase and essential hypertension in Han population in Ningxia. Guangdong Med J. 32:1977–1980. 2011.
18	Liu H, Chen S, Ma P and Xu Q: The association between gene polymorphisms of N5,10-methylenetetrahydrofolate reductase and essential hypertension in patients of Ningxia Hui nationality. Tianjin Med J. 39:1095–1098. 2011.
19	Cai YM and Gong WX: Linkage study on methylenetetrahydrofolate reductase single nucleotide polymorphisms and hypertension in the elderly with rheumatoid arthritis. Chin J Birth Health and Heredity. 17:14–17. 2009.
20	Luo JW, Tang Y, Chen H, Wu XY, Wu YN and Deng YL: Study on MTHFR C677T polymorphism in hypertensive subjects with blood stasis syndrome. J Beijing Univ Tradit Chin Med. 31:351–354. 2008.
21	Xing X and Hua Q: Relationships between the polymorphism of methylenetetrahydrofolate reductase gene C677T and hypertension, cardiac structure and function. Med J Chin PLA. 32:741–744. 2007.
22	Tang Y, Chen H, Wu XY and Luo JW: The C677T point mutation of N5,10-methylenetetrahydrofolate reductase (MTHFR) and essential hypertension. Mol Cardiol China. 7:205–207. 2007.
23	Wang L, Guo H and Li Y: MTHFR gene C 677 T polymorphisms and variation of plasma homocysteine level in primary hypertension. Tianjin Med J. 30:579–582. 2002.
24	Ilhan N, Kucuksu M, Kaman D, Ilhan N and Ozbay Y: The 677 C/T MTHFR polymorphism is associated with essential hypertension, coronary artery disease, and higher homocysteine levels. Arch Med Res. 39:125–130. 2008. View Article : Google Scholar : PubMed/NCBI
25	Markan S, Sachdeva M, Sehrawat BS, Kumari S, Jain S and Khullar M: MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians. Mol Cell Biochem. 302:125–131. 2007. View Article : Google Scholar : PubMed/NCBI
26	Ng X, Boyd L, Dufficy L, et al: Folate nutritional genetics and risk for hypertension in an elderly population sample. J Nutrigenet Nutrigenomics. 2:1–8. 2009. View Article : Google Scholar : PubMed/NCBI
27	Fridman O, Porcile R, Vanasco V, Junco MN, Gariglio L, et al: Study on homocysteine levels and methylenetetrahydrofolate reductase gene variant (C677T) in a population of Buenos Aires City. Clin Exp Hypertens. 30:574–584. 2008. View Article : Google Scholar : PubMed/NCBI
28	Zhan S, Gao YY, Yin X, et al: Elevated serum homocysteine, MTHFR gene mutataion and essential hypertension in Chinese. Chin J Hypertens. 8:21–25. 2000.
29	Lwin H, Yokoyama T, Yoshiike N, et al: Polymorphism of methylenetetrahydrofolate reductase gene (C677T MTHFR) is not a confounding factor of the relationship between serum uric acid level and the prevalence of hypertension in Japanese men. Circ J. 70:83–87. 2006. View Article : Google Scholar : PubMed/NCBI
30	Zhang Y, Wang H, Zhang X, Wang L and Wu G: Relationship between homocysteine, methylene tetrahydrofolate reductase C677T polymorphisms and essential hypertension in Kazak nationality in Xinjiang. J Clin Cardiol (China). 28:570–573. 2012.
31	Cao Z: The Association between methylenetetrahydrofolate reductase gene polymorphism and hypertensive elderly patient with acute myocardial infarction. Chin J Gerontol. 32:5118–5120. 2012.
32	Li X and Huang W: The analysis of MTHFR gene polymorphism in patients with renal damage caused by hypertension and patients with renal parenchymal hypertension. J Capital Univ Med Sci. 27:497–500. 2006.
33	Hu R, Niu GM, Zhao SG, Zhang CY, Hu RL, Wang ZG and Jiang MF: The association between gene polymorphisms of N5, 10-methylenetetrahydrofolate reductase and Mongolian patients with drimary hypertension. Chin J Hypertension. 14:274–276. 2006.
34	Liu JW, Ye L, Liu J and Li XY: Study on homocysteine metabolism-related enzymes gene polymorphisms in elderly essential hypertension patients with peripheral arterial occlusive disease. Chin J Geriatr. 24:332–335. 2005.
35	Hui P, Nakayama T, Morita A, et al: Common single nucleotide polymorphisms in Japanese patients with essential hypertension: aldehyde dehydrogenase 2 gene as a risk factor independent of alcohol consumption. Hypertens Res. 30:585–591. 2007. View Article : Google Scholar
36	Tylicki L, Födinger M, Puttinger H, et al: Methylenetetrahydrofolate reductase gene polymorphisms in essential hypertension. Am J Hypertens. 18:1442–1448. 2005. View Article : Google Scholar : PubMed/NCBI
37	Benes P, Kanková K, Muzík J, Groch L and Benedik J: Methylenetetrahydrofolate reductase polymorphism, type II diabetes mellitus, coronary artery disease, and essential hypertension in the Czech population. Mol Genet Metab. 73:188–195. 2001. View Article : Google Scholar
38	Li YY: α-Adducin Gly460Trp gene mutation and essential hypertension in a Chinese population: a meta-analysis including 10,960 subjects. PLoS One. 7:e302142012.
39	Li Y: Plasminogen activator inhibitor-1 4G/5G gene polymorphism and coronary artery disease in the Chinese Han population: a meta-analysis. PLoS One. 7:e335112012. View Article : Google Scholar : PubMed/NCBI
40	Ruano-Ravina A, Pérez-Ríos M and Barros-Dios JM: Population-based versus hospital-based controls: are they comparable? Gac Sanit. 22:609–613. 2008. View Article : Google Scholar : PubMed/NCBI
41	Qian X, Lu Z, Tan M, Liu H and Lu D: A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. Eur J Hum Genet. 15:1239–1245. 2007. View Article : Google Scholar : PubMed/NCBI
42	Niu WQ, You YG and Qi Y: Strong association of methylenetetrahydrofolate reductase gene C677T polymorphism with hypertension and hypertension-in-pregnancy in Chinese: a meta-analysis. J Hum Hypertens. 26:259–267. 2012. View Article : Google Scholar : PubMed/NCBI
43	Higgins J, Thompson S, Deeks J and Altman D: Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice. J Health Serv Res Policy. 7:51–61. 2002. View Article : Google Scholar : PubMed/NCBI