CD209 and Not CD28 or STAT6 Polymorphism Mediates Clinical Malaria and Parasitemia among Children from Nigeria.

Olanrewaju B Morenikeji,Jessica L Metelski,Bolaji N Thomas,Catherine O Falade,Brooke N Seamans,Olusola Ojurongbe,Megan E Hawkes,Anna L Capria

doi:10.3390/microorganisms8020158

Olanrewaju B Morenikeji, Jessica L Metelski + Show 6 more

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https://doi.org/10.3390/microorganisms8020158

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Abstract

Malaria remains a significant disease, causing epic health problems and challenges all over the world, especially in sub-Saharan Africa. CD209 and CD28 genes act as co-stimulators and regulators of the immune system, while the STAT6 gene has been reported to mediate cytokine-induced responses. Single nucleotide polymorphisms of these genes might lead to differential disease susceptibility among populations at risk for malaria, due to alterations in the immune response. We aim to identify key drivers of the immune response to malaria infection among the three SNPs: CD209 (rs4804803), CD28 (rs35593994) and STAT6 (rs3024974). After approval and informed consent, we genotyped blood samples from a total of 531 children recruited from Nigeria using the Taqman SNP genotyping assay and performed comparative analysis of clinical covariates among malaria-infected children. Our results reveal the CD209 (rs4804803) polymorphism as a susceptibility factor for malaria infection, significantly increasing the risk of disease among children, but not CD28 (rs35593994) or STAT6 (rs3024974) polymorphisms. Specifically, individuals with the homozygous mutant allele (rs4804803G/G) for the CD209 gene have a significantly greater susceptibility to malaria, and presented with higher mean parasitemia. This observation may be due to a defective antigen presentation and priming, leading to an ineffective downstream adaptive immune response needed to combat infection, as well as the resultant higher parasitemia and disease manifestation. We conclude that the CD209 gene is a critical driver of the immune response during malaria infection, and can serve as a predictor of disease susceptibility or a biomarker for disease diagnosis.

Highlights

Malaria remains a parasitic disease with about 3.2 billion people at risk of infection [1,2], with an estimated annual death toll of ~400,000 people out of 219 million clinical cases of malaria [3]
We have previously demonstrated the importance of the CD14 promoter gene polymorphism [17] in malaria infection, showing that clinical malaria among Nigerian children is significantly regulated by this gene, in addition to its correlation with parasitemia, and a marker of disease severity
Considering the paucity of available data, what are the roles of CD209, CD28 and signal transducer and activator of transcription 6 (STAT6) gene polymorphisms, either individually or in combination, with malaria infection among children, and how are they associated with markers of disease severity? Do these polymorphisms serve as susceptibility factors for malaria infection, or do they play any critical role in regulating disease covariates such as anemia and parasitemia in West Africa? To answer these questions, we evaluated the genetic variability of CD209, CD28 and STAT6 single nucleotide polymorphisms among malaria-infected children

Summary

Introduction

Malaria remains a parasitic disease with about 3.2 billion people at risk of infection [1,2], with an estimated annual death toll of ~400,000 people out of 219 million clinical cases of malaria [3]. Many of these deaths occur among young children and pregnant women from sub-Saharan Africa [4,5]. Such mortality rates among these vulnerable groups necessitates timely intervention and improved control initiatives [6]. The immune response against P. falciparum, in context of the host’s genetic contribution to disease outcome, is a complex process, and requires stepwise dissection

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