During the 1980s, there was a time when we wondered if any drug-metabolizing-enzyme (DME) gene might have more than one or two mutant variants. Then, in the late 1980s came the first paper in which five variant alleles were cloned and characterized for the CYP2D6 pharmacogene (Nature, 4 Feb 1988; 331: 442-446).
In the 1990s, several publications began recommending nomenclature for clinical DME genes, some of which comprised dozens, and even more than 100 alleles. The first web site for the P450 alleles was cypalleles.ki.se, which included only P450 variants. Today, an all-inclusive repository for DME variants can be found at pharmvar.org; their archives index includes 13 “Useful Links” around the world. For example, check out the PharmGKB (pharmacogenomics knowledge base) useful link, https://www.pharmgkb.org/vips (“vips” = very important pharmacogene summaries). Therein this site includes 34 genes that have “substantial evidence supporting their importance in clinical pharmacogenomics” (Tier 1; G6PD is #21), 25 genes that have “limited evidence supporting their importance in clinical pharmacogenomics” (Tier 2), and nine (“cancer genome”) genes that are “important in tumor pharmacogenomics.”
The attached article describes “the winning pharmacogene, G6PD” (glucose-6-phosphate dehydrogenase) for having the largest number of identified variants: 1,341 alleles(!!). Interpreting the effect of sequence variation in G6PD can be used to predict which individuals are at risk for adverse drug reactions (ADRs). By analyzing data from publications and databases, authors provided interpretations for 186 additional G6PD variants of uncertain significance, bringing the total number of interpreted (“mechanistically understood”) variants to 400 (the remaining 941 variants are still not “mechanistically understood”).
Why would a gene exhibit so many variant alleles? Several reasons include: [a] the length of the gene (kb of coding region, plus 5’ and 3’ regulatory regions in the genome); [b] the poorly understood “high rate of mutability” in some regions of the genome; and [c] how thoroughly and how large a number of individuals has been characterized and sequenced.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic defect, worldwide, that presents as a missing or defective enzyme — affecting more than 500 million individuals. G6PD is important in red blood cells, because it is the sole source of NADPH (needed for detoxication of reactive oxygen species).
Individuals with G6PD deficiency have variants with decreased activity, which can lead to three main clinical manifestations: [a] neonatal jaundice, [b] chronic non-spherocytic hemolytic anemia (CNSHA), and [c] acute hemolytic anemia (AHA) — in response to stressors such as certain foods, antibiotics, antimalarial drugs, and infections that elevate reactive oxygen species. The underlying G6PD deficiency reveals great genetic diversity, with 1,341 (currently identified) variant alleles, mostly missense variants in the coding region.
Interpreting the function and clinical effects of G6PD variants is critical to prevent adverse drug reactions, which can be avoidable by prescribing alternative drugs, and to promote neonatal health by prompting increased monitoring. This is the reason why G6PD qualifies as a “pharmacogene.” 😊
Am J Hum Genet, 2 Feb 2023; 110: 228-239
Good point, Alvaro. In Croton, southern Italy, the Greek philosopher/mathematician Pythagoras (570-490 BC) is believed to be the first to describe the “dangers of eating fava beans,” because many individuals in that area who ate fava beans often experienced painful red blood cell hemolysis (i.e., developed hemolytic anemia). Now we know that this disease (favism) is associated with G6PD deficiency, and the incidence of G6PD deficiency in Sardinia and parts of southern Italy is as high as one in three.
One story (about how the G6PD polymorphism was discovered) concerns a World War II observation that certain soldiers — especially African-Americans — who were taking the antimalarial drug primaquine and flying in troop transport aircraft at more than 8000 feet altitude (lowered pO2)—were reported to develop painful acute hemolytic crises. This led to the (1956) discovery of low red blood cell G6PD activity and decreased GSH concentrations in affected individuals. Subsequently, it was found that this enzyme is extremely polymorphic, that almost one in ten African-Americans has the A-type of G6PD deficiency, that more than two dozen commonly prescribed drugs in addition to primaquine cause hemolytic anemia in G6PD-deficient patients, and that G6PD deficiency is inherited as an X-linked recessive trait and currently affects more than 500 million people worldwide.
This is an example of an enzyme polymorphism having an indirect effect on drug toxicity. G6PD is an enzyme in the hexose monophosphate shunt, one of the principal sources of NADPH generation (which restores oxidized glutathione, GS-SG, to its reduced form, GSH) in normal red cells and many other tissues. Many drugs and their metabolites can put a burden on GSH levels, and this can lead to a GSH deficiency in G6PD-deficient patients who have little GSH reserves to spare. GSH deficiency in the red cell leads to membrane fragility and hemolysis — hence, hemolytic anemia. The G6PD gene is located on the X chromosome, which is consistent with G6PD deficiency being transmitted as an X-linked recessive trait; this means that a “carrier” mother and a healthy father will have children displaying one of four possibilities: a healthy female, a carrier female, a healthy male, and an afflicted male. Interestingly, there is a more than 100-fold difference in the incidence of G6PD deficiency between Ashkenazic (0.4%) and Sephardic (53%) Jewish males (Ashkenazic Jews live mainly in further north, whereas Sephardic Jews live around the Mediterranean Sea).
Excellent point, Doron. The frequencies of low-activity alleles of G6PD in humans are highly correlated with the prevalence of malaria in Africa and Southeast Asia. These deficiency alleles are thought to provide decreased risk for infection by the Plasmodium parasite and are maintained at high frequency — despite the illnesses that they cause. The “high frequencies of low-activity G6PD alleles” in malaria-infested areas worldwide is an example of selective advantage in a human population (i.e., those resistant to malaria are more likely to have offspring in each subsequent generation). 😊😊
From: Doron Lancet
Sent: Saturday, May 6, 2023 12:04 AM
Highly interesting! Another explanation of the large number of genetic variants may be an “evolutionary benefit,” similar to the case of MHC genes. It would be interesting to fathom the analog of “at least some members in the population will likely survive a viral attack”.
Prof. Doron Lancet
Dept. Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
From: Puga, Alvaro Sent: Saturday, May 6, 2023 2:16 PM
Who was the Greek or Italian philosopher in ancient times who warned the citizens of some village not to eat fava beans? Wasn’t the G6PD polymorphism the reason for those genetic differences in response to toxicity of fava beans, which is often regarded as “the earliest example of pharmacogenetics”?