Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria

Mmbando, Bruno P.; Mgaya, Josephine; Cox, Sharon E.; Mtatiro, Siana N.; Soka, Deogratius; Rwezaula, Stella; Meda, Elineema; Msaki, Evarist; Snow, Robert W.; Jeffries, Neal; Geller, Nancy L.; Makani, Julie

doi:10.1371/journal.pone.0125929

Cited by 18 publications

(15 citation statements)

References 21 publications

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“…The differences observed between the protective effects of 3.7-kb alpha-thalassemia against severe bacterial infection contrasts with its deleterious effect against respiratory infections where it appears to favor an increase in the incidence rate. Although this latter result is unexpected, negative epistasis between sickle hemoglobin and 3.7-kb alpha-thalassemia or between sickle hemoglobin and fetal hemoglobin levels resulting in an increased risk of malaria infection have been reported in epidemiologic studies in Kenya (Mmbando et al, 2015).…”

Section: Discussionmentioning

confidence: 93%

Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia

et al. 2017

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Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient's infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the -196 to -174 indel, SNP rs4696480, and a (GT)n short tandem repeat. The infectious subphenotypes included (A) recurrent respiratory infections and (B) severe bacterial infection at least once during the patient's follow-up. The absence of the haplotype [Del]-T-[n ≥ 17] (Hap7) in homozygocity protected against subphenotype (B), in a statistically significant association, resisting correction for multiple testing. For the individual loci, the same association tendencies were observed as in the haplotype, including a deleterious association between the SNP rs4696480 T allele and subphenotype (A), whereas the A/A genotype was protective, and a deleterious effect of the A/T genotype with subphenotype (B), as well as including the protective effect of -196 to -174 insert (Ins) and deleterious effect of the deletion (Del) in homozygocity, against subphenotype (B). Moreover, a reduction in the incidence rate of severe bacterial infection was associated to a rise in the hemolytic score, fetal hemoglobin levels (prior to hydroxyurea treatment), and 3.7-kb alpha-thalassemia. Interestingly, differences between the effects of the two latter covariables favoring a reduction in the incidence rate of subphenotype (B) contrast with a resulting increase in relation to subphenotype (A). These results could have practical implications in health care strategies to lower the morbidity and mortality of SCA patients.

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Section: Discussionmentioning

confidence: 93%

Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia

et al. 2017

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“…The present results also fail to compare with conclusions from a study in Mali in which an age stratified analysis showed sickle trait-mediated malaria protection to be more evident in early childhood [ 39 ]. Possible explanations for the lower incidence of uncomplicated malaria among HBB wild types in the current study could relate to protection conferred by fetal hemoglobin and maternal antibodies during early childhood [ 40 – 42 ]. However the present study did not assess for the levels of fetal haemoglobin and maternal antibodies in infancy, thus other studies would be needed to confirm this relationship.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda

Lwanira

Kironde

Kaddumukasa

et al. 2017

Malar J

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BackgroundHost genetics play an important role in Plasmodium falciparum malaria susceptibility. However, information on host genetic factors and their relationships with malaria in the vaccine trial site of Iganga, Uganda is limited. The main objective of this study was to determine the prevalence of selected host genetic markers and their relationship to malaria incidence in the vaccine trial site of Iganga, Uganda. In a 1-year longitudinal cohort study, 423 children aged below 9 years were recruited and their malaria episodes were investigated. Host genetic polymorphisms were assessed by PCR–RFLP, haemoglobin electrophoresis and DNA sequencing. Using a multivariate negative binomial regression model, estimates of the impact of human genetic polymorphisms on malaria incidence were performed. In all statistical tests, a P value of <0.05 was considered as significant.ResultsThe prevalences of sickle cell haemoglobin trait, G6PD c.202 G>A (rs 1050828) and NOS2 −954 G>C (rs 1800482) variants were 26.6, 22.7 and 17.3%, respectively. Inducible nitric oxide synthase 2 (NOS2 −954 G>C; rs 1800482) heterozygosity was associated with lower incidence of malaria in all age groups {Adjusted incident rates ratio (aIRR) 0.59; 95% CI [0.386–0.887]; P = 0.012)}. About 4% of study subjects had co-existence of sickle cell Hb trait and G6PD deficiency. Sickle cell Hb heterozygotes (Hb AS) aged less than 1 year experienced significantly more malaria episodes annually than children with normal haemoglobin (Hb AA) {aIRR = 1.98; 95% CI [1.240–3.175]; P = 0.004}. There was no significant influence of the sickle cell trait on malaria incidence among older children of 1–9 years.ConclusionsMutation (NOS2 −954 G>C; rs 1800482) of nitric oxide synthase 2 gene promoter was associated with a lower incidence of acute malaria. The normal haemoglobin (wild genotype; HbAA) was associated with reduced malaria incidence rates during the first year of life. More understanding of the interplay between host genetics and malaria susceptibility is required.

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“…With regards to understanding mechanisms of protection from sickle haemoglobin (HbS), the programme reported on negative epistasis with fetal haemoglobin (HbF) (Mmbando et al , ). This work proposed that high HbF, which is the aim of hydroxycarbamide treatment for SCD, may result in loss of HbS‐related malaria protection, resulting in higher malaria‐related mortality in SCD.…”

Section: Researchmentioning

confidence: 99%

Sickle cell disease in Africa: an overview of the integrated approach to health, research, education and advocacy in Tanzania, 2004–2016

Tluway

Makani

2017

Br J Haematol

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Summary Sickle cell disease (SCD) is the single most important genetic cause of childhood mortality globally. Tanzania has one of the highest annual births of SCD individuals in the world, estimated to reach 11 000 births a year. Without intervention, 50–90% of children will die in childhood. However, cost-effective interventions have the potential to reduce childhood mortality by up to 70%. The effects of SCD are multi-dimensional, ranging from causing high morbidity and mortality, and reducing the quality of life, to imposing a high socio-economic burden on individuals, families and health systems. In the past 12 years, the SCD programme in Tanzania has developed, with local and global partnerships, a systematic framework for comprehensive research that is integrated into providing healthcare, training and advocacy in SCD. This report outlines the approach and achievements of collective initiatives for management and control of SCD in Tanzania.

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Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria

Cited by 18 publications

References 21 publications

Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia

Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia

Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda

Sickle cell disease in Africa: an overview of the integrated approach to health, research, education and advocacy in Tanzania, 2004–2016

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