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Tishkoff SA, Varkonyi R, Cahinhinan N, Abbes S, Argyropoulos G, Destro-Bisol G et al.. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science (New York, NY) 293: 455-462

Sapienza University of Rome, Roma, Latium, Italy
Science (Impact Factor: 31.48). 08/2001; 293(5529):455-62. DOI: 10.1126/science.1061573
Source: PubMed

ABSTRACT The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.

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    • "Globally, the CATT5 allele is more frequently identified among African-Americans and Africans compared with their Caucasian American or Western European counterparts [64]. The proposed MIF-TB susceptibility allele (−794 CATT5) is found commonly in Caucasians (~45%) and is more prevalent in African-Americans and in Africans (60–80%), indicating that MIF genotype may make a clinically meaningful contribution to TB disease risk [64, 65]. The results from a recent study in Uganda found that mycobacteremic subjects were more likely to be genotypic low expressers of MIF (−794 CATT5/5, 33% versus 18%, odds ratio (OR) 2.2, P = 0.009). "
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    ABSTRACT: Sub-Saharan Africa has continued leading in prevalence and incidence of major infectious disease killers such as HIV/AIDS, tuberculosis, and malaria. Epidemiological triad of infectious diseases includes susceptible host, pathogen, and environment. It is imperative that all aspects of vertices of the infectious disease triad are analysed to better understand why this is so. Studies done to address this intriguing reality though have mainly addressed pathogen and environmental components of the triad. Africa is the most genetically diverse region of the world as well as being the origin of modern humans. Malaria is relatively an ancient infection in this region as compared to TB and HIV/AIDS; from the evolutionary perspective, we would draw lessons that this ancestrally unique population now under three important infectious diseases both ancient and exotic will be skewed into increased genetic diversity; moreover, other evolutionary forces are also still at play. Host genetic diversity resulting from many years of malaria infection has been well documented in this population; we are yet to account for genetic diversity from the trio of these infections. Effect of host genetics on treatment outcome has been documented. Host genetics of sub-Saharan African population and its implication to infectious diseases are an important aspect that this review seeks to address.
    08/2014; 2014(108291). DOI:10.1155/2014/108291
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    • "G6PD is encoded by a 16.2 kb gene located on the X chromosome. Approximately 160 genetic variants causing clinical deficiency of G6PD have been characterized, and the geographical distribution of these alleles is closely related to populations’ history of exposure to endemic malaria [2]. "
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    ABSTRACT: Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. Methods A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. Results It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (< 1% versus Dogon 7.9%). The Betica-Selma 968C/376G (~11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. Conclusions The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.
    Malaria Journal 07/2014; 13(1):270. DOI:10.1186/1475-2875-13-270 · 3.49 Impact Factor
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    • "Malaria mortality is higher in children worldwide and malarial resistance genes serves as strongest know force for recent evolutionary selection in human genome, since first human started moving out of Africa [2]. Various population-specific natural genetic defense mechanisms have evolved in malaria-endemic regions [3], such as sickle cell trait, glucose-6-phosphate dehydrogenase deficiency, β-thalassaemia, duffy phenotypes; which are maintained in endemic populations by balancing selection [4,5]. The genetic basis of malaria resistance and susceptibility is complex in many ways as several genes have been found to be involved along with environmental and parasite genetic factors. "
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    ABSTRACT: There are increasing evidences on the role of non-coding RNA (ncRNA) as key regulator of cellular homeostasis. LOC284889 is an uncharacterized ncRNA gene on reverse strand to MIF mapped to 22q11.23. MIF, a lymphokine, regulates innate immune response by up-regulating the expression of TLR4, suppressing the p53 activity and has been shown to be involved in malaria pathogenesis. In this study, the possible effect of MIF variations on malaria susceptibility was investigated by re-sequencing the complete MIF gene along with 1 kb each of 5[prime] and 3[prime] region in 425 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 160 cases of severe malaria, 101 of mild malaria and 164 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with Plasmodium falciparum malarial outcome. It is the first study, which shows that the allele A (rs34383331T > A) in ncRNA is significantly associated with increased risk to P. falciparum malaria [severe: OR = 2.08, p = 0.002 and mild: OR = 2.09, P = 0.005]. In addition, it has been observed that the higher MIF-794CATT repeats (>5) increases malaria risk (OR = 1.61, P = 0.01). Further, diplotype (MIF-794CATT and rs34383331T > A) 5 T confers protection to severe malaria (OR = 0.55, P = 0.002) while 6A (OR = 3.07, P = 0.001) increases malaria risk. These findings support the involvement of ncRNA in malarial pathogenesis and further emphasize the complex genetic regulation of malaria outcome. In addition, the study shows that the higher MIF-794CATT repeats (>5) is a risk factor for severe malaria. The study would help in identifying people who are at higher risk to malaria and adapt strategies for prevention and treatment.
    Malaria Journal 09/2013; 12(1):345. DOI:10.1186/1475-2875-12-345 · 3.49 Impact Factor
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