G6PD deficiency as protection againstfalciparum malaria: An epidemiologic critique of population and experimental studies

Abstract

Several recent reviews in the medical literature maintain that only heterozygous GGPD deficient females are relatively protected against falciparum malaria. However, a number of population studies provide compelling evidence that both the hemizygous GGPD deficient male and homozygous GGPD deficient female are also relatively protected against falciparum parasitization. An epidemiologic critique of a sample of these field investigations points out the methodological problems that underlie some of the negative findings. In vitro studies also provide compelling evidence that erythrocytes from all GGPD deficient genotypes are relatively protected against falciparum infestation, and that this protection is enhanced by oxidant substances derived from a number of food crops such as fava beans.It is suggested that "quinine" taste sensitivity reflects taste sensitivity to bitter-tasting, naturally occurring antimalarial substances of plant origin, and that the GGPD polymorphism and the genetic loci coding for "quinine" taste sensitivity have co-evolved in human populations. It appears that adaptation at the GGPD locus in human populations reflects an intricate web of interactions between a large number of different GGPD deficient alleles which have reached polymorphic frequencies and a variety of food crops from which oxidant substances may be derived. o 1993 Wiley-Liss, Inc.The specific goal of this article is to review the evidence indicating that all glucose-6-phosphate dehydrogenase (GGPD) deficient genotypes are relatively protected against Plasmodium falciparum malaria. A discussion of this issue is timely and necessary because several influential reviews of GGPD and GGPD deficiency in the medical literature over the past few years have reiterated the position that only GGPD deficient heterozygotes are protected against falciparum parasitization, while G6PD deficient hemizygotes and homozygotes are not (Luzzatto and Mehta, 1989;Luzzatto and Battistuzzi, 1985;Usanga and Luzzatto, 1985). However, this position is based on a single study (Bienzle et al., 1972), while a number of other field investigations support the view that all G6PD deficient genotypes are relatively protected against falciparum parasitization (Allison and Clyde, 1961;Gilles et al., 1967;Butler, 1973;Kar et al., 1992). The inaccuracy of the "heterozygote" position seriously obscures our understanding of how selection operates at the 0 1993 Wiley-Liss, Inc.

Glucose-6-Phosphate Dehydrogenase Deficiency and Malaria: A Method to Detect Primaquine-Induced Hemolysis in vitro

“…G6PD expression level is regulated by hormonal and nutritional factors in only a few tissues. G6PD expression is regulated in liver and adipose tissue, and its activity depends on the rate of fatty acid biosynthesis (Greene, 1993). The G6PD gene region is one of the first regions of the human genome to be completely sequenced (Chen, et al, 1996).…”

“…Exon 13 is about 800 nucleotides long and contains the translation stop codon (Nagel & Roth, 1989, Greene, 1993. The protein-coding region is divided into 12 segments, ranging in size from 12 to 236 bp .…”

“…The protein-coding region is divided into 12 segments, ranging in size from 12 to 236 bp . Exon and intron numbers and the exon sizes and sequences are conserved in higher eukaryotes (Nagel & Roth, 1989, Greene, 1993. The first exon contains no coding sequence and intron 2 between exons 2 and 3 is extraordinarily long, extending for 9,857 bp.…”

“…The analogy between the mouse and rat cDNA sequences is greater than humans with 93% similarity. Most of the sequence dissimilarity is in the 3´-UTR region, which has 600 nucleotides on average and contains a single polyA site (Nagel & Roth, 1989, Greene, 1993. G6PD gene promoter is embedded in a CpG island that starts about 680 nucleotides upstream of the transcription initiation site, extending about 1,050 nucleotides downstream of the initiation site, and ends at the start of the first intron (Chen, et al, 1991).…”

“…The G6PD activity and mRNA quantity differ between tissues (Nagel & Roth, 1989, Greene, 1993. S1 nuclease and primer extension analyses of mouse G6PD mRNA indicate that when the transcriptional start site regulated with lipogenesis in liver and adipose tissue, in kidney G6PD is expressed constitutively (Ho, et al, 1988); this quantity potentially depends on oxidative stress, tissue specific differences and reductive biosynthesis reactions (Nagel & Roth, 1989, Greene, 1993. Some different mRNA forms of G6PD mRNA have been found, but their functions are completely unknown.…”