**4.1 Genetics of homocysteinaemia**

There are various causes of homocysteinaemia. 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). In addition, HHcy can be caused by a diet rich in folate, but also by deficiencies of folate, vitamin B12 and, to a lesser extent, deficiencies of vitamin B6, which affects methionine metabolism, and also by impaired renal function.

MTHFR catalyzes the conversion reaction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is an intermediate in the conversion of Hcy to methionine. Mutations in MTHFR occur frequently in the population and are common inborn errors of folate metabolism that result in phenotypes ranging from asymptomatic to severe neurological deterioration and even early death in the classic form of MTHFR deficiency [49].

Homocystinuria is also an autosomal recessive error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts Hcy to methionine and is catalyzed by the enzyme methionine synthase.

Hcy in the blood is generally found 70–80% as a disulfide bound to plasma proteins, 20–30% as a homodimer with itself and about 1% as a free thiol, or a heterodimer with other thiols [50]. Levels of the Hcy are usually controlled by 2 biochemical processes: (1) roughly ~50% of the Hcy goes to transsulfuration pathway for producing the glutathione and the remaining and (2) ~50% can be remethylated back to methionine [51, 52]. Normally, the synthesis and elimination of Hcy stay pretty much in balance, but in diseased conditions, i.e., in HHcy, the overall plasma Hcy levels tend to increase due to the errors in the Hcy metabolism [53].

Causes of homocystinaemia include regular consumption of an excessively methionine-rich protein diet, or B12/folate deficiency, or 'loss-of-function type' mutations of the CBS gene as heterozygous or homozygous, and finally insufficient Hcy clearance from the kidney. Several other factors are influential among which are gender, age, smoking, alcohol consumption, certain medications, and medical conditions that can potentially modulate the methionine cycle can increase Hcy levels. Furthermore, there are additional genetic factors that are key in promoting HHcy status, such as genetic defects in enzyme proteins involved in '1-carbon metabolism' [54–56]. As this cycle is the only pathway that gives methyl group in both biosynthesis of cellular compounds such as creatine, epinephrine, carnitine, phospholipids, proteins, and polyamines and in epigenetic changes (like methylation of DNA, RNA, and histones) [57]. Nevertheless, HHcy mediated metabolic malfunctioning because of the higher circulating Hcy levels promote oxidant stress-induced vascular inflammation and vessel dysfunction leading to atherosclerosis, myocardial infarction, stroke, multiple sclerosis, cognitive impairment, epilepsy, dementia, Parkinson's disease, and ocular disorders [58, 59].

An interesting scientific discussion is being conducted in the context of the importance of the common MTHFR gene polymorphism and its significance in endothelial diseases. Heterozygous polymorphisms of the MTHFR gene reduce enzyme activity by 40% (CT variant, MTHFR c. [665C > T];[665C =]) and up to 70% in the homozygous form (TT variant, MTHFR c. [665C > T], [665C > T]). The CT variant is very common as it occurs in up to 20–40% of the Caucasian population and 1–4% of most other ethnic groups. The homozygous TT variant occurs in about 10% of the general population in Europe.

Retrospective studies conducted in the 1980s showed an increased prevalence of homocysteine concentrations in the 15–30 μmol/l range dependent on the MTHFR 677C > T polymorphism (new nomenclature, c.665 C > T) in the presence of concomitant folate deficiency in patients with atherosclerosis after myocardial infarction, stroke and coronary artery disease, and with a history of venous thromboembolism (VTE), i.e. deep vein thrombosis and/or pulmonary embolism. Quite different results were published from a prospective study published in 2002 in which these correlations were shown to be weak or even non-existent. In 2010, the American College of Cardiology and the American Heart Association unequivocally spoke out against homocysteine determination in cardiovascular risk assessment, considering hyperhomocysteinaemia to be a non-significant risk factor at the public health level [60].

*Genetic Markers of Endothelial Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.109272*

In contrast, during protein biosynthesis, Hcy can be misused by methionyl-tRNA synthase to produce homocysteine thiolactone (HTL), a cyclic thioester that reacts rapidly with proteins to form amide bonds with the amino groups of lysine residues [61]. The resulting N-homocysteinylated proteins with altered structure and biochemical properties contribute to the vascular pathology associated with HHcy [62]. In fact, studies on cell cultures confirmed that Hcy supplemented in the medium was converted to HTL, and the extent of this conversion was proportional to Hcy concentration.
