The G6PD gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations and haplotypes will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
A- haplotype
The A- haplotype is a combination of 2 Single Nucleotide Polymorphisms (SNPs) which both confer missense mutations in the protein sequence [Articles:2836867, 3393536, 2572288]. To confuse the issue, what was previously defined as the A- G6PD enzyme form by biochemical properties is encoded by three possible different haplotypes (a set of linked SNP alleles that are inherited together) [Articles:12064901, 2572288]. Each is made up of two variants; the A variant coupled with a second SNP to give the A- haplotype [Articles:12064901, 2572288]. Here, in order to try to avoid confusion, we have distinguished the three different haplotypes according to the second variant nucleotide position:
A- 202A/ 376G: is a G>A nucleotide change at position 202 (rs1050828) resulting in the missense mutation Val to Met at amino acid 68, combined with the A variant.
A- 680T/ 376G: is a G>T nucleotide change at position 680 (rs137852328) resulting in the missense mutation Arg to Leu at amino acid 227, combined with the A variant.
A- 968C/ 376G: is a T>C nucleotide change at position 968 (rs76723693) resulting in the missense mutation Leu to Pro at amino acid 323, combined with the A variant.
Haplotype A-202A/ 376G is found at frequencies up to 0.24 in African populations, and has also been described as Distrito Federal, Matera, Betica, Castilla, Alabama, Tepic, Ferrara, Laghouat and Kabyle, found in populations from around the world [Articles:12064901, 3393536, 7906668, 2572288, 10747271, 18494377, 2321910]. The A-968C/ 376G haplotype has also been named Betica, Guantanamo and Selma [Articles:12064901, 2572288].
The Santamaria haplotype (542T/ 376G) is an A>T nucleotide change at position 542 (rs5030872) resulting in a missense mutation Asp to Val at amino acid 181, combined with the A variant [Articles:1879833, 6433630]. Though associated with G6PD deficiency, the Asp to Val does not result in a change of charge and so the electrophoretic properties of the Santamaria protein are not the same as those defined for the G6PD A- enzyme [Articles:1879833, 6433630], therefore this is not included here under the A- haplotype description (as discussed in [Article:1879833]). The Sierra Leone haplotype (311A/ 376G) is another example where the A variant is found combined with a second variant, resulting in G6PD deficiency [Article:18452027].
The G6PD A- enzyme has a Class III phenotype according to the WHO classification, conferring moderate enzyme deficiency of between 10-60% activity, and has been associated with hemolytic anemia [Articles:2633878, 12064901, 10747271]. Due to differences in both enzyme kinetics and genetic sequence, it is predicted that the G6PD A- haplotype derived from the A variant, which originally derived from the B wildtype [Articles:2836867, 5448, 1924316]. The A- enzyme is more likely to be found in a tetramer form than the A or B enzyme, which may explain a faster rate of enzyme inactivation [Article:5448]. The synergistic interaction of the two mutations spatially close together in the 3D structure of the A- enzyme has been shown to result in defective folding of the subunits, which decreases stability and thus results in lower levels of active enzyme within rbcs [Article:1073064]. The B, A and A- G6PD enzymes also have differences in the Km for glucose-6-phosphate (G6P) at pH7.2 (intracellular erythrocyte conditions) [Article:5448].
Numerous associations with G6PD A- and drug response have been described, although the underlying genotype may remain unknown (see Table 1). Some studies do not mention genotyping and only refer to the A- enzyme phenotype, as determined by electrophoretic or biochemical properties. In these cases, we have used the terms A- G6PD deficient individuals or A- enzyme. In studies which genotype for both variants of the A- haplotype, we indicate the location of the second variation if all three were not screened for. Other studies do not genotype at both loci, screening for only the 202A variant, yet use the description A- due to the strong linkage disequilibrium which exists between this and the 376G variant in African populations [Article:1924316].
The metabolism of daunorubicin into the less potent form daunorubinol was greatly diminished in rbcs from A- or Mediterranean G6PD deficient individuals [Article:8648264]. Methylene blue treatment of toxin-induced methemoglobinemia resulted in hemolysis in a patient carrying the A- G6PD deficiency [Article:5091568]. Large amounts of vitamin C was reported to induce hemolysis in an A- male individual [Article:1138591]. A woman diagnosed with Type 2 diabetes developed acute hemolysis after prescription of glibenclamide and metformin, and was subsequently genotyped homozygous for the A-202A/ 376G haplotype [Article:15126005]. Glibenclamide treatment was therefore ended, and hemoglobin levels rose on metformin treatment alone [Article:15126005]. Combined chlorproguanil-dapsone-artesunate (CDA) treatment is unsafe in carriers of the A- haplotype, resulting in severe reductions in hemoglobin level, and increased risk of requiring a blood transfusion [Article:19690618].
Studies revealing strong linkage disequilibrium between the SNPs 202A and 376G, and haplotype analysis with other polymorphic sites, provide evidence that the G6PD A- variant occurred more recently in evolution, originating from the A variant and expanding in African populations due to selection [Articles:2836867, 18494377, 5448, 1924316, 16020776].
The pharmacogenetic studies described below only genotype for the 202A variant but report individuals as carriers of the G6PD A- enzyme (also see Table 1). This is due to the evidence which supports the assumption that in African populations those with the 202A variant also carry the A variant (376G), and thus are defined as having the A- haplotype. A study of Artemisinin-based Combination Therapy (ACT) combined with primaquine, revealed carriers of the G6PD A- haplotype are more likely to have a significant reduction in hemoglobin and are at higher risk of developing moderate anemia compared to those with the wildtype genotype, though a significant reduction in hemoglobin was found in all individuals taking the combination therapy compared to placebo control [Article:20194698]. Chlorproguanil-dapsone (CD) combination therapy is more efficacious than sulfadoxine-pyrimethamine (SP) treatment, resulting in fewer new malaria infections, however G6PD deficient individuals are at higher risk of a drop in hemoglobin levels when taking the CD combination than SP [Article:15183620]. Combined chlorproguanil-dapsone-artesunate (CDA) treatment is unsafe in A- G6PD deficient individuals, resulting in severe decreases in hemoglobin levels and an increased risk of a blood transfusion compared to wildtype [Article:19112496]. A- G6PD deficient individuals are also more likely to require a blood transfusion when treated with anti-malarial sulphadoxine-pyrimethamine coadministered with amodiaquine [Article:19112496].
Though A- G6PD deficiency does not confer full protection from P. falciparum malaria infection, several studies have shown a protective effect of A- G6PD from severe malaria in hemizgous males [Articles:17355169, 7617034]. Contradictory results exist for females carrying A- G6PD, with some studies finding protection from severe and mild malaria in heterozygous females and lower levels of P. falciparum parasitaemia [Articles:7617034, 4108978], yet other studies find no protection from severe malaria [Article:17355169]. No significant association with protection from severe malaria was found in carriers of the A-202A/ 376G haplotype, however when pooled together with data from carriers of A-968C/376G and the Santamaria haplotype, a significant association with reduced risk of severe P. falciparum malaria in both males and females was observed [Article:19223928]. Therefore methodology and the extent of alleles examined likely contribute to these mixed reports [Articles:19223928, 19789650]. Increased carbonylation of numerous host membrane proteins involved in oxidative stress and transport of parasite proteins is seen in malaria infected A- deficient erythrocytes compared to rbcs from G6PD B individuals, and may underlie the mechanism which is thought to confer protection [Article:21376116].
Table 1: Associations between the A- Haplotype and drug response
| Variants Genotyped | Drug or Treatment | Associated Response | Reference* |
|---|
| 202A/ 376G (rs1050828 and rs1050829) | Glibenclamide | Acute hemolysis | [Article:15126005] (case study) |
| 202A (rs1050828) | Sulfadoxine-pyrimethamine and artemisinin plus primaquine | Increased risk of developing moderate anemia | [Article:20194698] (n=562 total population genotyped, 8.4% heterozygous, 3.9% homo/hemizygous). # |
| 202A (rs1050828) | Chlorproguanil-dapsone | Increased risk of a drop in hemoglobin levels, compared to sulfadoxine-pyrimethamine treatment. | [Article:15183620] (n=1480 total study group treated with CD, n=370 treated with SP. n=237 treated with CD had a >20g/L fall in hemoglobin and of these 35% were carriers of this variant, defined as G6PD deficient), compared to 24% treated with SP. |
| 202A (rs1050828) | Chlorproguanil-dapsone-artesunate | Severe decreases in hemoglobin levels and increased risk of blood transfusion | [Article:19112496] 13% were carriers of this variant and defined as A- G6PD deficient, in n=343 total genotyped. |
| 202A (rs1050828) | Sulphadoxine-pyrimethamine coadministered with amodiaquine | Increased risk of requiring a blood transfusion | [Article:19112496] 11% were carriers of this variant and defined as A- G6PD deficient in n=359 total genotyped. |
| 202A (rs1050828), 376G (rs1050829), 680T (rs137852328), 968C (rs76723693), 542G (rs5030872) | Chlorproguanil-dapsone-artesunate | Severe reduction in hemoglobin levels and an increased risk of requiring a blood transfusion | [Article:19690618] n=800 genotyped. G6PD deficient individuals were defined as A- hemizygous males (17% of n=388), and homozygous A-/A- females (4% of n=412). |
| Not specified | Rasburicase | Hemolytic anemia | [Article:20196170] (case study) |
| Not specified | Daunorubicin | Reduced drug metabolism | [Article:8648264] |
|
| Not specified | Methylene Blue | Hemolysis in an individual with methemoglobinemia | [Article:5091568] (case study) |
| Not specified | Vitamin C (high dose of 80g intravenously, 2 days) | Hemolysis | [Article:1138591] (case study) |
Table key:
*: For each reference, details of whether the study was a single case study, or total study numbers and percentage of individuals carrying the indicated G6PD allele, are given in the reference column.
#: Please note in this study heterozygous 202A individuals were considered G6PD A, and hemizygous/ homozygous 202A individuals were classified as G6PD A-.
