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Biochemical, Molecular, and Genetic Mechanisms

Clinical Utility of Genotyping the 677C>T Variant of Methylenetetrahydrofolate Reductase in Humans Is Decreased in the Post-Folic Acid Fortification Era^1,2

³ Department of Laboratory Medicine and Pathology and ⁴ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455; ⁵ Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD 20824; ⁶ Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and ⁷ Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98101

Moderate hyperhomocysteinemia is associated with many diseases. Major factors affecting plasma total homocysteine (tHcy) concentrations include folate concentrations and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. Because U.S.-mandated fortification of grain products with folic acid has improved folate and tHcy status in Americans, we investigated the effect of the MTHFR 677C>T variant before and after fortification. We determined tHcy and folate concentrations in sera from 844 Caucasian and 587 African American participants in the Coronary Artery Risk Development in Young Adults study before and after fortification and we genotyped the MTHFR 677C>T variant. MTHFR 677TT homozygotes had higher (P < 0.01) tHcy concentrations both before and after fortification compared with MTHFR 677CC homozygotes. However, the difference between these 2 genotypes decreased from 2.5 µmol/L before fortification to <0.7 µmol/L postfortification (P < 0.01). In addition, the prevalence of moderate hyperhomocysteinemia (tHcy > 13 µmol/L) in 677TT homozygotes decreased from 33% before fortification to 12% postfortification (P < 0.01). Using a cutoff value of 13 µmol/L to define moderate hyperhomocysteinemia, the sensitivity of the MTHFR 677TT genotype to predict elevations in homocysteine was low (30%) both before and after folic acid fortification. Increasing the cutoff from 13 to 19 µmol/L increased the sensitivity of the assay before fortification to 62% but decreased the sensitivity to 17% postfortification. We conclude that after folic acid fortification in the US, measurement of tHcy rather than genotyping of MTHFR 677TT should be used as the primary assay for the diagnosis and monitoring of moderate hyperhomocysteinemia.

^* To whom correspondence should be addressed. E-mail: tsaix001{at}tc.umn.edu.

Manuscript received 17 July 2008. Initial review completed 18 August 2008. Revision accepted 3 November 2008.

Published online 3 December 2008.