Co-inheritance of glucose-6-phosphate dehydrogenase deficiency mutations and hemoglobin E in a Kachin population in a malaria-endemic region of Southeast Asia

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobin E (HbE, β26 Glu-Lys) are two common red cell disorders in Southeast Asia. G6PD deficiency produces hemolytic anemia, which can be triggered by certain drugs or infections. HbE is asymptomatic or is manifested as microcytic, minimally hemolytic anemia. The association between G6PD deficiency and HbE is little understood. This study aimed to investigate G6PD deficiency and HbE in a Kachin ethnic group in the China-Myanmar border area. G6PD enzyme activity was measured using a quantitative G6PD assay, G6PD variants genotyped by the SNaPshot assay, and an HbE gene mutation identified by an amplification refractory mutation system and subsequently confirmed by using a reverse dot blot hybridization assay from 100 unrelated individuals in the study area. G6PD enzyme activity ranged from 0.4 to 24.7 U/g Hb, and six males had severe G6PD deficiency (<0.12–1.2 U/g Hb), while six males and 12 females had mild G6PD deficiency (>1.2–4.5 U/g Hb). Among the 24 G6PD-deficient subjects, 22 (92%) had the Mahidol 487G>A mutation (12 male hemizygotes, one female homozygote, and nine female heterozygotes), while the G6PD genotypes in two female subjects were unknown. HbE was identified in 39 subjects (20 males and 19 females), including 15 HbEE (seven males and eight females) and 24 HbAE (13 males and 11 females). Twenty-three subjects co-inherited both G6PD deficiency and HbE (22 with HbAE and one with HbEE). Whereas mean Hb levels were not significantly different between the HbA and HbE groups, G6PD-deficient males had significantly lower Hb levels than G6PD-normal males (P < 0.05, t-test). However, it is noteworthy that two G6PD-deficient hemizygous males with HbAE were severely anemic with Hb levels below 50 g/L. This study revealed high prevalence of co-inheritance of G6PD deficiency with HbAE in the Kachin ethnicity, and a potential interaction of the G6PD Mahidol 487G>A and HbAE in males leading to severe anemia. The presence of 6% males with severe G6PD deficiency raised a major concern in the use of primaquine for radical cure of vivax malaria.

Hemoglobin E, malaria and natural selection

“…Additionally, one study observed high prevalence of HbE in highly malarious regions compared to the regions with a low incidence of malaria [94]. Recently, one study reported high prevalence of co-inheritance of HbAE and G6PD deficiency [95], which is another variant that provides protection against malaria and has gone through positive selection [96]. In addition, Deng et al pointed out that the time frame of HbE origination (between 1240 and 4440 years ago) [8] coincides with the origination of the most common G6PD variant in Southeast Asia, which had been affected by positive selection over the past 1500 years [97].…”

An Overview of the Most Common Enzyme Defect, Glucose-6-Phosphate-Dehydrogenase Deficiency

“…Heterozygous females who are G6PD deficient are genetic mosaics as an effect of X-chromosome inactivation; the abnormal cells of a heterozygous female can be as deficient for G6PD as similar to a G6PD-deficient male: consequently, such females can be vulnerable to the equivalent pathophysiological phenotype. While heterozygous females typically have less severe clinical presentations than G6PD-deficient males, yet some may develop severe acute hemolytic anemia [7,8] .…”

“…About 140 mutations have been so far been reported, majority are single-base substitutions causing amino acid replacements. In rare cases, a second mutation may be present in cis point mutations range all over the entire coding region [7] .…”

“…A surprisingly high amount of indirect bilirubin is noticed in the coinheritance of G6PD deficiency with Gilbert's syndrome. In neonates and G6PDdeficient adults, the bilirubin amount is influenced by the presence of the TA (7) allele in the uridine diphosphate glucuronosyl transferase gene and this gene is G6PD-dose dependent [25] .…”

Hemoglobin E protects against acute Plasmodium vivax infections in a Kachin population at the China–Myanmar border

“…The prevalence of HbE varies among populations; at the junction of Thailand, Laos and Cambodia, 50–60% of the human population are HbE carriers (7). In some ethnic groups residing along the China-Myanmar border, HbE prevalence is also high and almost reaches 40% (8, 9). Whereas there is particularly strong evidence to support that the HbS variant and α-thalassemias offer protection against severe malaria, evidence about HbE’s protection against malaria is less convincing (1, 10).…”