Moderate hyperhomocysteinemia in the Czech population:

the analysis of genetic factors in patients with atherosclerosis

In this study we have examined allelic variants in 4 genes of the methionine cycle and the metabolism of aminothioles of homocysteine, cysteine and glutathione during the six-hour load test with L-methionine in 591 control examinations and in 296 patients with an ischemic heart disease or of an ischemic disease of lower limbs. In the control population we found out the distribution of polymorphisms, incidence of heterozygote for selected pathogenic mutations in genes for cystathionine beta-synthase and the reference interval of B6, B125 vitamins, folates and aminothiols during the methionine test. Data from patients and control examinations are tested by the regression analysis with the aim to find out whether genetic variants of the methionine cycle have an influence on the origin of atherosclerosis. In the logistic regression model we proved the significance of known risk factors. The unique result is the demonstration of protective effect of MTRR I22M and CBS 844ins68 polymorphisms and on the contrary the complexly interconnected risk influence of polymorphisms in the gene for MTHFR in the origin and development of the ischemic heart disease. In the linear regression we found out a complex impact of polymorphisms on the metabolism of homocysteine and cysteine. Generally, a trend toward the increase of homocysteine in some genetic variants of a remethyle path and towards the reduction of homocysteine in CBS 844ins68 variants is evident. Preliminary interpretation of data shows that genotypes increasing homocysteine are associated with the increased risk of atherosclerosis and vice versa. Our data are in accord with the homocysteine theory of atherosclerosis and on the basis of genetic data they support the opinion that homocysteine can be one of the independent risk factors of atherosclerosis.

In the framework of the project we have carried out many minor satellite studies of a clinical kind (analysis of the methionine test complications or effectiveness of vitaminotherapy in the treatment of hyperhomocysteinemia), of a biochemical kind (detailed comparison of two analytical techniques in determination of aminothioles or change of markers of the NO metabolism, oxidative stress and hemocoagulation in acute hyperhomocysteinemia) and of a genetic kind (epidemiological study of the most frequent pathogenic I278T mutation, haplotyping of alleles in genes for CBS).