Medical Genetics - V. M. Zaporozhan 2005

Multifactorial Diseases
Genetics of Certain Common Multifactorial Diseases
Coronary Heart Disease

The Development of Molecular Genetics has made it possible to identify susceptibility genes for the most common Multifactorial Diseases. The prevalence of susceptibility Gene alleles and their contribution to disease development can vary among different ethnic groups.

The development of coronary artery disease is primarily associated with hypercholesterolemia. The genetic causes of hypercholesterolemia vary, with monogenic inherited forms having been identified. These include familial primary hypercholesterolemia caused by a mutation in the low-density lipoprotein receptor gene (LDRL, 19p 13.2) and the apolipoprotein B100 gene, as well as hypobetalipoproteinemia caused by a mutation in the ApoB-100 gene (2p24) (the R3500Q mutation—the substitution of glutamine for Arginine at position 3500). An important role in the development of polygenic hypercholesterolemia is played by apolipoprotein E genes (ApoE, 19q13.2), GENES OF THE receptor complex involved in the internalization of low-density Lipoproteins (OLR1, 2p 13-p 12), and genetically determined overproduction of very low-density lipoproteins in the Liver. Additional environmental factors—such as a high Dietary intake of saturated fats and obesity—are also required for the development of hypercholesterolemia.

A non-lipid factor associated with a high risk of coronary artery disease is an elevated Blood homocysteine level. Hyperhomocysteinemia is linked to a 50% decrease in The activity of the enzyme methylenetetrahydrofolate reductase (MTHFR, 1p36.3) due to the C677T mutation (cytosine-to-thymine substitution at position 677). Consequently, this causes a valine-to-Alanine substitution in the protein, making it more thermolabile. The prevalence of the C677T mutation among Europeans ranges from 5 to 15 %.

Impaired MTHFR function is also associated with neural tube closure defects. Mothers with the functionally deficient C677T allele variant have an increased risk (7.2-fold) of giving birth to children with anencephaly, Spina bifida, and encephalocele.