亚甲基四氢叶酸脱氢酶1基因多态性在WENBIT（挪威西部B族维生素干预试验）中改变了稳定型心绞痛患者血浆甘氨酸和丝氨酸水平与急性心肌梗死风险之间的关联。
Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial).
作者信息
Ding Yunpeng, Pedersen Eva R, Svingen Gard F T, Helgeland Øyvind, Gregory Jesse F, Løland Kjetil H, Meyer Klaus, Tell Grethe S, Ueland Per M, Nygård Ottar K
机构信息
From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
出版信息
Circ Cardiovasc Genet. 2016 Dec;9(6):541-547. doi: 10.1161/CIRCGENETICS.116.001483. Epub 2016 Nov 21.
BACKGROUND
Serine and glycine interconversion and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)-mediated 1-carbon transfer are the major sources of methyl groups for 1-carbon metabolism. Recently, plasma glycine and a common polymorphism in MTHFD1 have been associated with risk of acute myocardial infarction (AMI). It is, therefore, of interest to explore if these 2 pathways interact in relation to AMI.
METHODS AND RESULTS
A total of 2571 participants in the WENBIT (Western Norway B Vitamin Intervention Trial) undergoing coronary angiography for stable angina pectoris were studied. Associations of plasma serine and glycine concentrations with risk of AMI across 2 common and functional MTHFD1 polymorphisms (rs2236225 and rs1076991) were explored in Cox regression models. During a median follow-up of 4.7 years, 212 patients (8.2%) experienced an AMI. In age- and sex-adjusted analyses, plasma glycine (P<0.01), but not serine (P=0.52), showed an overall association with AMI. However, interactions of MTHFD1 rs2236225 polymorphism with both plasma serine and glycine were observed (P=0.03 for both). Low plasma serine and glycine were associated with an increased risk of AMI among patients carrying the rs2236225 minor A allele. Similarly, low plasma glycine showed stronger risk relationship with AMI in the rs1076991 CC genotype carriers but weaker associations in patients carrying the minor T allele (P=0.02).
CONCLUSIONS
Our results showed that 2 common and functional polymorphisms in the MTHFD1 gene modulate the risk associations of plasma serine and glycine with AMI. These findings emphasize the possible role of the MTHFD1 in regulating serine and glycine metabolism in relation to atherosclerotic complications.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00354081.
背景
丝氨酸和甘氨酸的相互转化以及亚甲基四氢叶酸脱氢酶1（MTHFD1）介导的一碳转移是一碳代谢中甲基基团的主要来源。最近，血浆甘氨酸和MTHFD1中的一种常见多态性与急性心肌梗死（AMI）风险相关。因此，探讨这两条途径是否与AMI相互作用具有重要意义。
方法与结果
对挪威西部B族维生素干预试验（WENBIT）中因稳定型心绞痛接受冠状动脉造影的2571名参与者进行了研究。在Cox回归模型中探讨了血浆丝氨酸和甘氨酸浓度与两种常见且具有功能的MTHFD1多态性（rs2236225和rs1076991）与AMI风险之间的关联。在中位随访4.7年期间，212名患者（8.2%）发生了AMI。在年龄和性别调整分析中，血浆甘氨酸（P<0.01）而非丝氨酸（P=0.52）与AMI总体相关。然而，观察到MTHFD1 rs2236225多态性与血浆丝氨酸和甘氨酸均存在相互作用（两者P均=0.03）。血浆丝氨酸和甘氨酸水平低与携带rs2236225次要A等位基因的患者发生AMI风险增加相关。同样，血浆甘氨酸水平低在rs1076991 CC基因型携带者中与AMI的风险关系更强，而在携带次要T等位基因的患者中关联较弱（P=0.02）。
结论
我们的结果表明，MTHFD1基因中的两种常见且具有功能的多态性调节血浆丝氨酸和甘氨酸与AMI的风险关联。这些发现强调了MTHFD1在调节与动脉粥样硬化并发症相关的丝氨酸和甘氨酸代谢中的可能作用。
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