The 677C→T variant of MTHFR is the major genetic modifier of biomarkers of folate status in a young, healthy Irish population.
| Title: | The 677C→T variant of MTHFR is the major genetic modifier of biomarkers of folate status in a young, healthy Irish population. |
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| Authors: | Shane B; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA.; Pangilinan F; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD.; Mills JL; Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.; Fan R; Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center (GUMC), Washington, DC.; Gong T; Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center (GUMC), Washington, DC.; Cropp CD; Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD.; Kim Y; Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD.; Ueland PM; Department of Clinical Science, University of Bergen and Haukeland University Hospital, Bergen, Norway.; Bailey-Wilson JE; Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD.; Wilson AF; Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD.; Brody LC; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD.; Molloy AM; Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland. |
| Source: | The American journal of clinical nutrition [Am J Clin Nutr] 2018 Dec 01; Vol. 108 (6), pp. 1334-1341. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: United States NLM ID: 0376027 Publication Model: Print Cited Medium: Internet ISSN: 1938-3207 (Electronic) Linking ISSN: 00029165 NLM ISO Abbreviation: Am J Clin Nutr Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2023- : [New York, NY] : Elsevier; Original Publication: Bethesda, MD : American Society of Clinical Nutrition |
| MeSH Terms: | Biomarkers/*blood ; Folic Acid/*blood ; Methylenetetrahydrofolate Reductase (NADPH2)/*genetics ; Nutritional Status/*genetics ; Polymorphism, Single Nucleotide/*genetics; Erythrocytes/chemistry ; Homocysteine/blood ; Adolescent ; Adult ; Female ; Genome-Wide Association Study ; Genotype ; Humans ; Ireland ; Linkage Disequilibrium ; Male ; Young Adult |
| Abstract: | Background: Genetic polymorphisms can explain some of the population- and individual-based variations in nutritional status biomarkers.; Objective: We sought to screen the entire human genome for common genetic polymorphisms that influence folate-status biomarkers in healthy individuals.; Design: We carried out candidate gene analyses and genome-wide association scans in 2232 young, healthy Irish subjects to evaluate which common genetic polymorphisms influence red blood cell folate, serum folate, and plasma total homocysteine.; Results: The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) variant was the major genetic modifier of all 3 folate-related biomarkers in this Irish population and reached genome-wide significance for red blood cell folate (P = 1.37 × 10-17), serum folate (P = 2.82 × 10-11), and plasma total homocysteine (P = 1.26 × 10-19) concentrations. A second polymorphism in the MTHFR gene (rs3753584, P = 1.09 × 10-11) was the only additional MTHFR variant to exhibit any significant independent effect on red blood cell folate. Other MTHFR variants, including the 1298A→C variant (rs1801131), appeared to reach genome-wide significance, but these variants shared linkage disequilibrium with MTHFR 677C→T and were not significant when analyzed in MTHFR 677CC homozygotes. No additional non-MTHFR modifiers of red blood cell or plasma folate were detected. Two additional genome-wide significant modifiers of plasma homocysteine were found in the region of the dipeptidase 1 (DPEP1) gene on chromosome 16 and the Twist neighbor B (TWISTNB) gene on chromosome 7.; Conclusions: The MTHFR 677C→T variant is the predominant genetic modifier of folate status biomarkers in this healthy Irish population. It is not necessary to determine MTHFR 677C→T genotype to evaluate folate status because its effect is reflected in concentrations of standard folate biomarkers. The MTHFR 1298A→C variant had no independent effect on folate status biomarkers. To our knowledge, this is the first genome-wide association study report on red blood cell folate and the first report of an association between homocysteine and TWISTNB. |
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| Grant Information: | N01 HD033348 United States HD NICHD NIH HHS |
| Substance Nomenclature: | 0 (Biomarkers); 0LVT1QZ0BA (Homocysteine); 935E97BOY8 (Folic Acid); EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2)) |
| Entry Date(s): | Date Created: 20181020 Date Completed: 20190905 Latest Revision: 20250529 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC6290363 |
| DOI: | 10.1093/ajcn/nqy209 |
| PMID: | 30339177 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.