{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:21:36Z","timestamp":1791206496302,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2015,8,10]],"date-time":"2015-08-10T00:00:00Z","timestamp":1439164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2013CB835100"],"award-info":[{"award-number":["2013CB835100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31123005"],"award-info":[{"award-number":["31123005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31401142"],"award-info":[{"award-number":["31401142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28\u201375 were enrolled in this study from September 2005\u2013December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p &lt; 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk.<\/jats:p>","DOI":"10.3390\/nu7085303","type":"journal-article","created":{"date-parts":[[2015,8,10]],"date-time":"2015-08-10T11:15:00Z","timestamp":1439205300000},"page":"6670-6687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency"],"prefix":"10.3390","volume":"7","author":[{"given":"Wen-Xing","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Health Sciences, Anhui University, Hefei 230601, Anhui, China"},{"name":"State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Xing","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Juan","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Fei","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China"},{"name":"KIZ-SU Joint Laboratory of Animal Models and Drug Development, College of Pharmaceutical Sciences, Soochow University, Kunming 650223, Yunnan, China"},{"name":"Collaborative Innovation Center for Natural Products and Biological Drugs of Yunnan, Kunming 650223, Yunnan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1001\/jama.2015.2274","article-title":"Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: The CSPPT randomized clinical trial","volume":"313","author":"Huo","year":"2015","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/S0140-6736(11)60872-6","article-title":"Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: A meta-analysis of genetic studies and randomised trials","volume":"378","author":"Holmes","year":"2011","journal-title":"The Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/S0140-6736(05)70152-5","article-title":"Homocysteine and stroke: Evidence on a causal link from mendelian randomisation","volume":"365","author":"Casas","year":"2005","journal-title":"The Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.arcmed.2007.07.009","article-title":"The 677 C\/T MTHFR polymorphism is associated with essential hypertension, coronary artery disease, and higher homocysteine levels","volume":"39","author":"Ilhan","year":"2008","journal-title":"Arch. Med. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1017\/S0007114512003157","article-title":"Prevalence of hyperhomocysteinaemia and its major determinants in rural Chinese hypertensive patients aged 45\u201375 years","volume":"109","author":"Wang","year":"2013","journal-title":"Br. J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1017\/S0029665109991728","article-title":"Postgraduate Symposium: The MTHFR C677T polymorphism, B-vitamins and blood pressure","volume":"69","author":"Wilson","year":"2010","journal-title":"Proc. Nutr. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/sj.ejcn.1602810","article-title":"Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women","volume":"62","author":"Barbosa","year":"2008","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.3390\/nu5051531","article-title":"Homocysteine lowering by folate-rich diet or pharmacological supplementations in subjects with moderate hyperhomocysteinemia","volume":"5","author":"Zappacosta","year":"2013","journal-title":"Nutrients"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ejcn.2011.152","article-title":"Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population","volume":"66","author":"Sukla","year":"2012","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e33222","DOI":"10.1371\/journal.pone.0033222","article-title":"Polymorphisms in MTHFR, MS and CBS genes and homocysteine levels in a Pakistani population","volume":"7","author":"Yakub","year":"2012","journal-title":"PloS ONE"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1007\/s00394-014-0659-2","article-title":"MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification","volume":"53","author":"Husemoen","year":"2014","journal-title":"Eur J. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4760","DOI":"10.3390\/nu5114760","article-title":"Folate deficiency and folic acid supplementation: The prevention of neural-tube defects and congenital heart defects","volume":"5","author":"Czeizel","year":"2013","journal-title":"Nutrients"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1475-2891-11-2","article-title":"MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults","volume":"11","author":"Qin","year":"2012","journal-title":"Nutr. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e1003530","DOI":"10.1371\/journal.pgen.1003530","article-title":"Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets","volume":"9","author":"Grarup","year":"2013","journal-title":"PLoS Genet."},{"key":"ref_15","first-page":"987","article-title":"Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes: Is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?","volume":"140","author":"Perez","year":"2006","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1590\/S0100-879X2006005000195","article-title":"The MTR A2756G polymorphism is associated with an increase of plasma homocysteine concentration in Brazilian individuals with Down syndrome","volume":"41","author":"Biselli","year":"2008","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1073\/pnas.95.6.3059","article-title":"Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria","volume":"95","author":"Leclerc","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s11239-009-0321-7","article-title":"Genetic polymorphisms involved in folate metabolism and concentrations of methylmalonic acid and folate on plasma homocysteine and risk of coronary artery disease","volume":"29","author":"Biselli","year":"2010","journal-title":"J. Thromb. Thrombolysis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.clon.2011.03.005","article-title":"Methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C and G1793A polymorphisms: Association with risk for clear cell renal cell carcinoma and tumour behaviour in men","volume":"24","author":"Safarinejad","year":"2012","journal-title":"Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s12263-012-0321-7","article-title":"Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness","volume":"8","author":"Jackson","year":"2013","journal-title":"Genes. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/ajmg.a.30108","article-title":"Polymorphisms in the methylenetetrahydrofolate reductase and methionine synthase reductase genes and homocysteine levels in Brazilian children","volume":"128","author":"Alessio","year":"2004","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1086\/301825","article-title":"A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?","volume":"62","author":"Gabreels","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","first-page":"286","article-title":"Correlation between low folate levels and hyperhomocysteinemia, but not with vitamin B12 in hypertensive patients","volume":"44","author":"Scazzone","year":"2014","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.nut.2008.05.009","article-title":"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","volume":"24","author":"Mao","year":"2008","journal-title":"Nutrition"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/15648265080292S110","article-title":"The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status","volume":"29","author":"Selhub","year":"2008","journal-title":"Food. Nutr. Bull."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.ajp.2012.03.002","article-title":"Association between MTHFR C677T and A1298C, and MTRR A66G polymorphisms and susceptibility to schizophrenia in a Syrian study cohort","volume":"5","author":"Lajin","year":"2012","journal-title":"Asian. J. Psychiatr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/ajh\/hps015","article-title":"Folate deficiency is associated with oxidative stress, increased blood pressure, and insulin resistance in spontaneously hypertensive rats","volume":"26","author":"Pravenec","year":"2013","journal-title":"Am. J. Hypertens."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.nut.2012.09.015","article-title":"Elderly women: Homocysteine reduction by short-term folic acid supplementation resulting in increased glucose concentrations and affecting lipid metabolism (C677T MTHFR polymorphism)","volume":"29","author":"Chmurzynska","year":"2013","journal-title":"Nutrition"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Santilli, F., Davi, G., and Patrono, C. (2015). Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective. Vascul Pharmacol.","DOI":"10.1016\/j.vph.2015.06.009"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1160\/TH11-12-0899","article-title":"Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C-->T polymorphism","volume":"108","author":"Dragani","year":"2012","journal-title":"Thromb. Haemost."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1177\/1741826711424568","article-title":"Serum homocysteine and folate but not vitamin B12 are predictors of CHD mortality in older adults","volume":"19","author":"Gopinath","year":"2012","journal-title":"Eur. J. Prev. Cardiolog."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e71587","DOI":"10.1371\/journal.pone.0071587","article-title":"Low birthweight (LBW) and neonatal hyperbilirubinemia (NNH) in an Indian cohort: association of homocysteine, its metabolic pathway genes and micronutrients as risk factors","volume":"8","author":"Sukla","year":"2013","journal-title":"PloS ONE"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/ijlh.12158","article-title":"Vitamin B12 and folate deficiency: should we use a different cutoff value for hematologic disorders?","volume":"36","author":"Toprak","year":"2014","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1006\/mgme.2000.3034","article-title":"A polymorphism (80G- > A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia","volume":"70","author":"Chango","year":"2000","journal-title":"Mol. Genet. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng0595-111","article-title":"A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase","volume":"10","author":"Frosst","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"929","DOI":"10.6026\/97320630009929","article-title":"A structured-based model for the decreased activity of Ala222Val and Glu429Ala methylenetetrahydrofolate reductase (MTHFR) mutants","volume":"9","author":"Shahzad","year":"2013","journal-title":"Bioinformation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13217","DOI":"10.1073\/pnas.95.22.13217","article-title":"A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells","volume":"95","author":"Bagley","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","first-page":"1259","article-title":"Impact of MTHFR C677T gene polymorphism and vitamins intake on homocysteine concentration in the Polish adult population","volume":"69","author":"Waskiewicz","year":"2011","journal-title":"Kardiologia. Polska."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13378","DOI":"10.1021\/bi020536s","article-title":"Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase","volume":"41","author":"Olteanu","year":"2002","journal-title":"Biochemistry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/(SICI)1098-2272(199911)17:4<298::AID-GEPI5>3.0.CO;2-V","article-title":"Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations","volume":"17","author":"Harmon","year":"1999","journal-title":"Genet. Epidemiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11895","DOI":"10.1007\/s13277-014-2456-1","article-title":"Association of methylenetetrahydrofolate reductase and methionine synthase polymorphisms with breast cancer risk and interaction with folate, vitamin B6, and vitamin B12 intakes","volume":"35","author":"Qiao","year":"2014","journal-title":"Tumour. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.atherosclerosis.2003.12.036","article-title":"Methionine synthase reductase MTRR 66A > G has no effect on total homocysteine, folate, and Vitamin B12 concentrations in renal transplant patients","volume":"174","author":"Feix","year":"2004","journal-title":"Atherosclerosis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/ng0694-195","article-title":"Human methylenetetrahydrofolate reductase: Isolation of cDNA, mapping and mutation identification","volume":"7","author":"Goyette","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1074\/jbc.272.6.3628","article-title":"Human methionine synthase. cDNA cloning, gene localization, and expression","volume":"272","author":"Chen","year":"1997","journal-title":"J. Biol. Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/7\/8\/5303\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:50:29Z","timestamp":1760215829000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/7\/8\/5303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,10]]},"references-count":44,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2015,8]]}},"alternative-id":["nu7085303"],"URL":"https:\/\/doi.org\/10.3390\/nu7085303","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,10]]}}}