Protection from severe malaria associated with novel genetic polymorphisms

February 04 –Malaria, caused by Plasmodium falciparum parasites, is a major cause of mortality and morbidity in endemic countries of Sub-Saharan Africa with a disproportional burden of 90% of the estimated 212 million annual cases and 92% of 429,000 annual deaths, mostly in children under five years of age. The majority of cases of Plasmodium falciparum infection are asymptomatic or cause only mild to moderate clinical symptoms, however, a subset of affected individuals present with severe manifestations such as severe malarial anaemia and cerebral malaria.

Significant selection pressure (evolutionary pressure) has been exerted on the genomes of human populations exposed to Plasmodium falciparum infection, resulting in the acquisition of mechanisms of resistance against severe malarial disease. Many host genetic factors have been associated with reduced risk of developing severe malaria. Such genetic factors, i.e. genetic variants, include erythrocyte-associated polymorphisms, particularly HbS (sickle cell trait), alpha-thalassaemia, ABO blood group, and G6PD deficiency. Novel polymorphisms in or around USP38, FREM3, glycophorins gypA/B/E, and ATP2B4 have more recently been identified which account for additional variation but, in sum, are less protective than heterozygous carriage of HbS, and do not account for all of the observed phenotypic variation.

In a newly published study, identification of novel inherited risk factors has relied upon high-resolution genome-wide association studies (GWAS). The study in the Journal PLOS Genetics presents the findings of a GWAS of severe malaria performed in a Tanzanian population (n = 914, 15.2 million SNPs). Beyond the expected association with the sickle cell HbS variant, protective associations within two interleukin receptors (IL-23R and IL-12RBR2) and the kelch-like protein KLHL3 (all p < 10⁻⁶), as well as near significant effects for Major Histocompatibility Complex (MHC) haplotypes were identified. Complementary analyses, based on detecting extended haplotype homozygosity, identified SYNJ2BP, GCLC and MHC as potential loci under recent positive selection. Through GWAS in an independent Tanzanian cohort (parent-child trios n = 247), the allele frequencies of common polymorphisms underlying associations and selection, as well as the presence of multiple structural variants that could be in linkage with these SNPs were confirmed. Imputation of structural variants in a region encompassing the glycophorin genes on chromosome 4, led to the characterisation of more than 50 rare variants, and individually no strong evidence of associations with severe malaria in the primary dataset (p > 0.3) were found. The approach demonstrates the potential of a joint genotyping-sequencing strategy to identify as-yet unknown susceptibility loci in an African population with well-characterised malaria phenotypes. The regions encompassing these loci are potential targets for the design of much needed interventions for preventing or treating malarial disease.