**Abstract**

The rate of endothelial dysfunction is influenced by genetic variation and thus inherited in families. Genetic disorders, such as familial hypercholesterolemia and homocystinuria, are at risk for premature atherosclerosis, and exhibit early endothelial dysfunction. The known spectrum of mutations in LDL receptor, APOB and PCSK9 gene represent the monogenic dominant hypercholesterolemia. An autosomal recessive form of hypercholesterolaemia in the caused by homozygous mutations in the LDL-R adaptor protein. The polygenic hypercholesterolaemia for patients with a clinical diagnosis of FH is based on the cumulative effect of LDL-C-raising alleles with a cumulative effect, in a complex interaction with the environment that leads to an increase in LDL-C, producing an FH-like phenotype and presenting this type of hypercholesterolaemia as a typical complex disease. The various causes of homocysteinaemia like genetic causes include mutations and enzyme deficiencies such as the most frequently mentioned 5, 10-methylenetetrahydrofolate reductase (MTHFR), but also methionine synthase (MS) and cystathionine β-synthase (CβS) but also by deficiencies of folate, vitamin B12 and, to a lesser extent, deficiencies of vitamin B6, which affects methionine metabolism, and leads also to endothelial disfunction in different mechanismms. Mutations in genes coding enzymes in homocysteine metabolism and also in nitric oxide (NO) synthesis, the main vasodilatator is also presented in this chapter. The crucial importance of microRNAs in endothelial physiology following EC-specific inactivation of the enzyme Dicer which is involved in altered expression of key regulators of endothelial function, including endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor receptor 2 (VEGF), interleukin-8, Tie-1 and Tie-2. The new discoveries based on genome-wide screening (GWAS) complement the knowledge of the topic.

**Keywords:** asymmetric dimethylarginine, endothelial nitric oxide, low density lipoprotein, hypercholesterolaemia, homocysteinaemia, epigenetic regulation, gene polymorphism, association studies
