Genetic Polymorphism rs6922269 in the MTHFD1L Gene Is Associated with Survival and Baseline Active Vitamin B12 Levels in Post-Acute Coronary Syndromes Patients

Abstract

Background and AimsThe methylene-tetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L) gene is involved in mitochondrial tetrahydrofolate metabolism. Polymorphisms in MTHFD1L, including rs6922269, have been implicated in risk for coronary artery disease (CAD). We investigated the association between rs6922269 and known metabolic risk factors and survival in two independent cohorts of coronary heart disease patients.Methods and ResultsDNA and plasma from 1940 patients with acute coronary syndromes were collected a median of 32 days after index hospital admission (Coronary Disease Cohort Study, CDCS). Samples from a validation cohort of 842 patients post-myocardial infarction (PMI) were taken 24–96 hours after hospitalization. DNA samples were genotyped for rs6922269, using a TaqMan assay. Homocysteine and active vitamin B12 were measured by immunoassay in baseline CDCS plasma samples, but not PMI plasma. All cause mortality was documented over follow-up of 4.1 (CDCS) and 8.8 (PMI) years, respectively. rs6922269 genotype frequencies were AA n = 135, 7.0%; GA n = 785, 40.5% and GG n = 1020, 52.5% in the CDCS and similar in the PMI cohort. CDCS patients with AA genotype for rs6922269 had lower levels of co-variate adjusted baseline plasma active vitamin B12 (p = 0.017) and poorer survival than patients with GG or GA genotype (mortality: AA 19.6%, GA 12.0%, GG 11.6%; p = 0.007). In multivariate analysis, rs6922269 genotype predicted survival, independent of established covariate predictors (p = 0.03). However the association between genotype and survival was not validated in the PMI cohort.Conclusion MTHFD1L rs6922269 genotype is associated with active vitamin B12 levels at baseline and may be a marker of prognostic risk in patients with established coronary heart disease.

Influence of SH2B3, MTHFD1L, GGCX, and ITGB3 Gene Polymorphisms on theVariability on Warfarin Dosage Requirements and Susceptibility to CVD in the Jordanian Population

“…While the minor allele frequencies for rs11065987, rs17696736, and rs3184504 SNPs within the SH2B3 gene in our population are 38%, 38%, and 39%, respectively, which is inconsistent with the frequencies in the European population, with 34%, 42%, and 40–49%, respectively [ 37 , 38 , 39 ]. For the polymorphisms rs6922269 and rs803422 within the MTHFD1L gene, the minor allele frequency in our population for both is 26%, which is in agreement with the European population with 27% [ 24 ]. While the rs491552 SNP is high in our population, with 46%, the rs803455 is low, with only 9%.…”

“…The methylene-tetrahydrofolate dehydrogenase (NADP + -dependent) 1-like gene ( MTHFD1L ) is involved in the mitochondrial metabolism of tetrahydrofolate [ 24 ]. However, the polymorphism of this gene is closely related to the development of coronary heart disease (CHD), as found in a recent meta-analysis [ 25 ].…”

Plasma levels of soluble VEGF receptor isoforms, circulating pterins and VEGF system SNPs as prognostic biomarkers in patients with acute coronary syndromes

“…Ethnicity was self-declared and categorized as Maori/Pacific Islander, European, Other or Unknown. Standardized transthoracic echocardiography was performed at baseline and at each follow-up clinic using a GE Vivid 3 (GE Medical Systems) ultrasound system at Christchurch Hospital and Philips ATL HDI 5000 and ie33 (Philips Healthcare, Bothell, WA) ultrasound systems at the University of Auckland as described previously [ 21 , 23 ]. The study was approved by the New Zealand (NZ) Multi-Region Ethics Committee and all participating patients provided written, informed consent.…”

“…Extraction of genomic DNA for genotyping was performed as described previously [ 23 ]. DNA samples were genotyped for the rs2071559 (T-604C), rs2305948 (G1192A), rs1870377 (T1719A) polymorphisms in the VEGFR-2 receptor gene (encoding KDR) and rs748252 (C8764T) and rs9513070 (A189427G) in the VEGFR-1 receptor gene (encoding Flt-1).…”

Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma

“…The 6q25.1 locus that associates with MM-OS spans a region of LD intergenic to MTHFD1L and AKAP12 genes. While variation at 6q25.1 has previously been linked to coronary heart disease 20 21 (rs6922269) and late-onset Alzheimer disease 22 (rs11754661) the risk SNPs for these diseases are not correlated with rs12574648 (respective LD metrics– r 2 =0.002, D ′=0.08 and r 2 =0.046, D ′=0.65). MTHFD1L is involved in mitochondrial tetrahydrofolate (THF) synthesis 23 24 .…”