Cardiovascular Diseases Poster Session
Wong, B.Y.-L. (Dept. of Laboratory Medicine, The Toronto Hospital, Canada)
Boggis, C. (Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Canada)
Rubin, L.A. (Dept. of Medicine, University of Toronto, Canada)
Cole, D.E.C. (Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Canada)
Homocysteine is recognized as an independent predictor of arteriosclerotic disease, including stroke, myocardial infarction, and peripheral vascular disease. The C677T polymorphism of the MTHFR gene is one genetic factor contributing substantially to the variation in total plasma homocysteine (tHcy). Two other MTHFR polymorphisms -- A1298C and T1317C -- have been identified more recently, but information about the combined prevalence of the 3 sites is still scanty. DNA was isolated from healthy adult populations of Caucasian Canadians (n=197), Asian Canadians (n=51) and African-Americans (n=51). C677T was genotyped by HinfI cleavage of a 198bp PCR product beginning at bp644 and ending in an intronic sequence. A1298C was genotyped by mutation selective PCR (MS-PCR) and the PCR products were digested with BbsI for detection of the T1317C polymorphism. We found a lower frequency of the 677T polymorphism in African-Americans (13%, p < 0.001) and Asians (30%, p=0.01), as compared to Caucasians (34%). F or the A1298C polymorphism, there was no difference in 1298C frequency between Asians (20%) and Caucasians (30%), but the allele frequency in African-Americans (16%) was significantly lower (p=0.01) compared to Caucasians . Interestingly, the silent 1317C polymorphism was seen only once (out of 494 chromosomes) in Caucasians and Asians, but was frequent in African-Americans (37%). For the 677/1298 haplotype, linkage disequilibrium between sites was substantial in Caucasians (p < 0.001). Both 677T and 1298C polymorphisms cause amino acid substitutions in the MTHFR protein and may be independently associated with a significantly elevated tHcy phenotype. However, the variation in linkage disequilibrium we observe may be a significant confounding factor in interpretation of a single genotype. In particular, the assumption that genotyping either C677T or A1298C locus alone is sufficient to identify predisposition to hyperhomocystinemia may be violated to differing degrees, depending on the linkage disequ ilibrium in the population studied, and the degree to which tHcy is modified by other factors, such as folate status. Further studies of this complex interaction are warranted, if the full effect of MTHFR genotype on tHcy and associated risk for arteriosclerotic disease is to be understood.
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|Langman, L.J.; Wong, B.Y.-L.; Boggis, C.; Rubin, L.A.; Cole, D.E.C.; (1998). The prevalence and linkage disequilibrium of three methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms varies in different ethnic groups.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/cvdisease/langman0264/index.html|
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