Polygenic influence on plasma homocysteine: Association of two prevalent mutations, the 844ins68 of cystathionine β-synthase and A2756G of methionine synthase, with lowered plasma homocysteine levels

Michael Y Tsai, Michelle Bignell, Feng Yang, Barry G. Welge, Kevin J. Graham, Naomi Q. Hanson

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

A moderately elevated plasma total homocysteine (tHcy), whether measured during fasting or post-methionine load (PML), is increasingly being recognized as a risk factor for coronary artery diseases (CAD). However, etiologies for moderately elevated plasma tHcy, particularly with regard to the role of genetic influence on plasma tHcy levels, are still not well understood. In the current investigation, we studied 1025 individuals with respect to the effect of the 68-bp insertion (844ins68 variant) of the cystathionine β-synthase (CBS) gene, the A2756G transition of the B12- dependent methionine synthase (MS) gene and the C677T transition of the methylenetetrahydrofolate reductase (MTHFR) gene on fasting and 4 h PML tHcy. Of these individuals, 153 (14.9%) were heterozygous for the 68-bp insertion, 329 (32.1%) were heterozygous for the G2756 allele and 122 (11.9%) were homozygous for the C677T transition. Individuals heterozygous for the insertion had significantly lower PML increase in tHcy concentrations, while individuals homozygous for the A2756G transition had significantly lower fasting tHcy levels. A 2-way ANOVA showed that there was no interaction between the 844ins68 and the A2756G transition for either fasting tHcy or PML increase in tHcy, confirming the fact that the effect of these two genotypes on plasma tHcy levels are additive. The effects are opposite but additive with the C677T genotype of the MTHFR gene. In conclusion, we document evidence of polygenic regulation of plasma tHcy. Overall, > 50% of all individuals in this study carried polymorphic traits, which predisposed them to either higher or lower plasma tHcy concentrations, thus providing new evidence of the importance of genetic influences as determinants of tHcy levels. (C) 2000 Elsevier Science Ireland Ltd.

Original languageEnglish (US)
Pages (from-to)131-137
Number of pages7
JournalAtherosclerosis
Volume149
Issue number1
DOIs
StatePublished - Mar 2000

Bibliographical note

Funding Information:
This study was supported in part by a grant from the American Heart Association, Minnesota Affiliate. We thank Cynthia Davey of the Biostatistics Consulting Laboratory of the University of Minnesota for her assistance in statistical data analysis.

Keywords

  • Cystathionine β-synthase
  • Genetic variants
  • Hyperhomocysteinemia
  • Methionine synthase
  • Methylenetetrahydrofolate reductase

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