Abstract
Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological research, the sickle cell trait (HbAS) sickle cell polymorphism, ABO blood group, and other hemoglobinopathies remain the few major determinants in severe malaria to be replicated across different African populations and study designs. Within a case-control study in a region of high transmission in Tanzania (n = 983), we investigated the role of 40 new loci identified in recent genome-wide studies. In 32 loci passing quality control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes to be putatively associated with differential susceptibility to severe malaria. Established candidates explained 7.4% of variation in severe malaria risk (HbAS polymorphism, 6.3%; α-thalassemia, 0.3%; ABO group, 0.3%; and glucose-6-phosphate dehydrogenase deficiency, 0.5%) and the new polymorphisms, another 4.3%. The regions encompassing the loci identified are promising targets for the design of future treatment and control interventions.
Highlights
Heritability studies have estimated that approximately 25% of the risk for severe malaria progression is determined through human genetic factors [2]
This genomic region, including INPP4B, USP38, GAB1, GUSBP5, FREM3, and GYPB loci has been implicated as being under ancient selective pressure, with strong signals for the FREM3 locus, which is in almost perfect LD with GYPB and GYPA [8]
We investigated the role of 114 polymorphisms in 40 new candidate loci, including DDC and FREM3, identified from previous Genome-wide association studies (GWASs) [3,4,5,6]
Summary
Heritability studies have estimated that approximately 25% of the risk for severe malaria progression is determined through human genetic factors [2]. The 3 population GWAS analysis revealed a putative region centered on SMARCA5 in chromosome 4 [5], 250 kb upstream of the GYPE/A/B gene cluster encoding the MNS blood group system, known putative receptors for the P. falciparum parasite This genomic region, including INPP4B, USP38, GAB1, GUSBP5, FREM3, and GYPB loci has been implicated as being under ancient selective pressure, with strong signals for the FREM3 locus, which is in almost perfect LD with GYPB and GYPA [8]. Other candidates found in GWAS association or selection analysis have no apparent previous link to infectious disease (eg, OXNAD1, LOC727982, SDC1, ZSWIM2, and LPHN2) [6]
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