Medical Genetics - V. M. Zaporozhan 2005

Multifactorial Diseases
Genetics of Certain Common Multifactorial Diseases
Essential Hypertension

Essential Hypertension is a polygenic disorder whose development is driven by multiple genetic loci alongside dietary factors (high salt intake), lifestyle influences (overeating, alcohol consumption, low physical activity), and psycho-emotional or social stresses. One of the primary regulators of Blood pressure and Water-salt balance is the renin-angiotensin-aldosterone system. It comprises several core components—angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensin receptors, and steroid Biosynthesis Enzymes—whose genetic variants may contribute to the Pathogenesis of hypertension.

Among all system components, angiotensin currently attracts the greatest research interest. It is cleaved from inactive angiotensinogen through the action of renin and angiotensin-converting enzyme. Upon binding to specific receptors, it induces vasoconstriction, stimulates aldosterone production, and promotes sodium and water retention. Over 15 polymorphisms have been described for the angiotensinogen Gene (AGT, 1q42-q43). Of these, the single nucleotide polymorphism resulting in either Methionine or Threonine substitution at position 235 of the protein (M235T) is of paramount importance. Three genotypes can exist within a population: TT (both allele genes code for threonine), MM (both allele genes code for methionine), and MT (one allele gene codes for methionine, the other for threonine). In homozygotes for the T allele, the level of this peptide is nearly 20% higher than in homozygotes for the M allele. Studies conducted in the late 1990s demonstrated a 20–40% increased risk of arterial hypertension in Caucasian carriers of the T allele. However, the exact association between the M235T polymorphism and arterial hypertension remains inconclusive, as this correlation has not been replicated by all researchers.

Renin serves as a key enzyme in the generation of angiotensin I and was initially considered a prime candidate gene in the search for genetic determinants of arterial hypertension; however, no definitive link between hypertension and specific renin genetic variants has been established to date.

Angiotensin-converting enzyme catalyzes The conversion of angiotensin I into angiotensin II, as well as bradykinin into kinin. The ACE gene (17q23) is characterized by an insertion/deletion (I/D) polymorphism: the I form represents the presence of a 287 bp Alu repeat in intron 16, while the D form represents the absence of this insertion. In individuals homozygous for the D allele, enzyme activity is twice as high compared to II homozygotes, accompanied by an increased risk of cardiovascular complications. The D allele has been associated with arterial hypertension, Left Ventricular Hypertrophy, myocardial infarction, and the progression of diabetic nephropathy. The frequency of DD homozygotes among Europeans is approximately 30%.

Polymorphism of the angiotensin II receptor gene is associated with arterial hypertension, vascular wall remodeling characterized by increased arterial stiffness, and an elevated risk of myocardial infarction.

Correlations with arterial hypertension have also been identified for genetic variants of aldosterone synthase and GENES OF THE nitric oxide system.

Genes of the Renin-Angiotensin System significantly influence the progression of renal pathologies. Genetic risk factors predisposing to an unfavorable course of nephropathies and The Development of Chronic Kidney Disease include the D allele of the angiotensin-converting enzyme and the T allele of angiotensinogen.