A STAT6 Intronic Single-Nucleotide Polymorphism is Associated with Clinical Malaria in Ghanaian Children

Abstract

Malaria pathogenesis may be influenced by IgE responses and cytokine cross-regulation. Several mutations in the IL-4/STAT6 signaling pathway can alter cytokine cross-regulation and IgE responses during a Plasmodium falciparum malarial infection. This study investigated the relationship between a STAT6 intronic single-nucleotide polymorphism (rs3024974), total IgE, cytokines, and malaria severity in 238 Ghanaian children aged between 0.5 and 13 years. Total IgE and cytokine levels were measured by ELISA, while genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (RFLP). Compared with healthy controls, heterozygosity protected against clinical malaria: uncomplicated malaria (odds ratios [OR] = 0.13, P < 0.001), severe malarial anemia (OR = 0.18, P < 0.001), and cerebral malaria (OR = 0.39, P = 0.022). Levels of total IgE significantly differed among malaria phenotypes (P = 0.044) and rs3024974 genotypes (P = 0.037). Neither cytokine levels nor IL-6/IL-10 ratios were associated with malaria phenotypes or rs3024974 genotypes. This study suggests a role for rs3024974 in malaria pathogenesis and offers further insights into an IL-4/STAT6 pathway mutation in malaria pathogenesis.

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

“…The odds ratio showed no indication of an increased risk of malaria infection with the STAT6 (rs3024974) gene polymorphism. This observation, however, contradicts previous studies associating this polymorphism with malaria pathogenesis among Congolese children [41], as well as cerebral malaria among children from Ghana [42]. As shown from our findings, the STAT6 (rs3024974) polymorphism did not have any effect on disease susceptibility.…”

“…Protective immunity can be acquired naturally after consecutive malaria infections when dendritic cells, serving as antigen-presenting cells, prime and activate the T cells necessary for downstream adaptive response, for which CD209 and CD28 molecules are significant participants [47][48][49]. Likewise, the STAT6 gene is known to regulate the expression of regulatory T cells [50], while potentially modulating the immune response to malaria [41,42]. Therefore, elucidating the mechanism mediating susceptibility to or resistance against malaria would be significant in combatting disease pathogenesis.…”

“…Furthermore, published reports have shown that IL-10 production in response to a pathogenic stimulus is modulated by signal transducer and activator of transcription 6 (STAT6), enhancing IL-12 production in dendritic cells and driving a Th1 immune response in STAT6-/mice [40,41]. The role of STAT6 in the immune response to malaria infection is currently limited to a handful of studies, with no definitive conclusion [41,42]. A study examining regulatory gene variants in Congo showed a disparate response with STAT6 and FOXP3 among malaria-infected children [41], with the STAT6 promoter variant rs3024944 being associated with uncomplicated malaria, and the FOXP3 SNP rs11091253 being associated with parasitemia.…”

CYP2C19 and STAT6 Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis

“…Several studies have shown that PPIs block STAT6 binding to and transcriptional activation of CCL26 (12,13), which is an important chemokine that mediates chemotaxis of eosinophils to the esophagus in EoE (44,45). Variants of STAT6 are known to be associated with diseases that are driven by allergic inflammation including allergy (34), asthma (35,36), eczema (37), serum IgE (38,39), or viral infections (40) and food allergies (46), and a recent genome wide association study conducted by Rothenberg et al (32) identified a variant of STAT6 (rs167769) that is strongly associated with EoE. Upon activation of ST2 expressing cells by IL‐33, production of IL‐13 is increased (47) leading to activation of STAT6 via IL‐4R (48).…”

“…We selected eight STAT6 variants for analysis of associations with outcome of PPI therapy for EoE based on literature reports of associations with EoE (32,33), allergy (34), asthma (35,36), eczema (37), serum immunoglobulin E (IgE) (38,39), or viral infections (40) (Table S2, Supplemental Digital Content 4, http://links.lww.com/MPG/B708). Genotype counts, SNP frequencies, and Hardy-Weinberg equilibrium P values for the STAT6 variants are given in Table S2 (Supplemental Digital Content 4, http://links.lww.com/MPG/B708).…”