Medical Genetics - V. M. Zaporozhan 2005

Multifactorial Diseases
Pharmacogenetics
Examples of pharmacogenetic reactions - Erythrocyte hemolysis associated with glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency in red blood cells

The Gene encoding G6PD is located on the X chromosome (Xq28). While approximately 400 G6PD variants are known, only a few of them trigger pathological reactions. For instance, the G6PDB allele controls variant B, which maintains normal enzyme activity, whereas the G6PDA allele encodes variant A, characterized by sharply reduced activity.

In terms of its biochemical and electrophoretic properties, the mutant variant A enzyme closely resembles the normal type, yet it is significantly less stable. The half-life of form A enzyme in erythrocytes is about 13 days, compared to 62 days for form B. Consequently, the reduced activity of G6PD form A stems from a much faster Denaturation of the enzyme within erythrocytes than is observed under normal conditions.

When the enzyme is defective, the maintenance of erythrocyte membrane stability is impaired, and the intake of certain medications can trigger a hemolytic crisis. There are about forty such drugs, including sulfonamides, furazolidone, nitrofuran, quinidine, and primaquine. Certain medications exhibit hemolytic properties without necessarily causing clinically overt hemolysis under "normal" conditions, such as in the absence of infection. These agents include ascorbic acid, acetylsalicylic acid, chloramphenicol, and methylene blue.

The first description of acute erythrocyte hemolysis in African Americans resulting from the administration of the antimalarial drug primaquine was reported by Dern et al. in 1937. In this case, enzyme activity did not exceed 15% of the normal level. Another form of G6PD deficiency was identified in populations of the Mediterranean basin and the Middle East. With this variant, enzyme activity drops to about 4% of normal, and hemolytic crises are triggered not only by numerous drugs but also by fava beans, a dietary staple in that region. Consequently, the condition became known as favism, derived from the Latin name for these beans. The onset is typically sudden, marked by chills and severe adynamia, with the erythrocyte count plunging to (1-2)x10¹² g/L, which may lead to collapse. The condition frequently affects children aged 2 to 4, and occasionally nursing infants whose mothers consumed fava beans while remaining completely healthy themselves. Erythrocyte hemolysis can also be triggered by the consumption of gooseberries and red currants.

Table 7.11. Examples of pharmacogenetic reactions associated with the genetic polymorphism of the CYP2 family (Yu. I. Bazhora, 2003)

Human populations exhibit remarkable polymorphism regarding G6PD genes. The prevalence of various enzyme deficiency types fluctuates across countries, ranging from 0 to 15%, and reaching up to 30% in certain populations (such as African Americans and Mediterranean populations), because individuals with G6PD deficiency possess a selective advantage due to increased resistance to malaria.