Type I Interferon Receptor Variants in Gene Regulatory Regions are Associated with Susceptibility to Cerebral Malaria in Malawi

Abstract

Cerebral malaria (CM) remains an important cause of morbidity and mortality. Risk for developing CM partially depends on host genetic factors, including variants encoded in the type I interferon (IFN) receptor 1 (IFNAR1). Type I IFNs bind to IFNAR1 resulting in increased expression of IFN responsive genes, which modulate innate and adaptive immune responses. To comprehensively study IFNAR1 genetic variant associations in Malawians with CM or uncomplicated malaria, we used a tag single nucleotide polymorphism approach, based on the HapMap Yoruba in Ibadan, Nigeria, population database. We identified three novel (rs914142, rs12626750, and rs1041867) and one previously published (Chr21:34696785 [C > G]) IFNAR1 variants to be associated with CM. Some of these variants are in gene regulatory regions. Chr21:34696785 (C > G) is in a region encoding histone modifications and transcription factor-binding sites, which suggests gene regulatory activity. Rs12626750 is predicted to bind embryonic lethal abnormal vision system-like RNA-binding protein 1, a RNA-binding protein which can increase the type I IFN response. Furthermore, we examined these variants in an expression quantitative trait loci database and found that a protective variant, rs914142, is associated with lower expression of IFNAR1, whereas the CM-associated variant rs12626750 was associated with increased IFNAR1 expression, suggesting that activation of the type I IFN pathway may contribute to pathogenesis of CM. Future functional studies of IFNAR1 variants are now needed to clarify the role of this pathway in severe malarial diseases.

Pathophysiology and neurologic sequelae of cerebral malaria

“…This is supported by the observations that, despite homozygote mortality, the HbS allele has a high prevalence in areas endemic with malaria as well as the observation that independent genetic mutations have developed in different ethnic and geographical populations [9]. Other host genetic factors contributing to CM susceptibility include inflammatory factors and regulatory regions, such as Type 1 Interferon receptor variants in Malawi [10], IL17 in Nigeria and IL4 and IL22 in populations in Mali [11,12]. In addition, earlier reports showed a role for intercellular adhesion molecular -1 (ICAM-1) Kilifi variants in CM [13].…”

Type I Interferons and Malaria: A Double-Edge Sword Against a Complex Parasitic Disease

“…In contrast, IFN-I responses have also been associated with immune suppression and severe diseases in human malaria infections. Association between IFNAR1 variants and CM in children from Africa was observed; variants with lower IFNAR1 expression were associated with protection, whereas variants with increased IFNAR1 expression were associated with CM ( Aucan et al., 2003 ; Khor et al., 2007 ; Ball et al., 2013 ; Feintuch et al., 2018 ). This is consistent with the observations that blocking IFNAR signaling can protect infected mice from severe disease symptoms.…”

Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

“…The contribution of individual IFN subtypes remains unclear, though divergent phenotypes in Irf3 −/− and Irf7 −/− mice suggest this could be an interesting question to explore. Importantly, genetic variants in IFNAR1 have been associated with either greater or lower risk of severe malaria disease (205,(214)(215)(216)(217). The impact of each genetic variant on IFNAR1 expression and function still need to be determined, but these findings suggest that type I IFNs are important regulators of malaria disease in humans.…”