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Malaria GWAS Uncovers Protective Locus

NEW YORK (GenomeWeb) – The severity of malaria infections caused by Plasmodium falciparum in African children appears to be partly influenced by a locus falling near genes coding for glycophorin proteins involved in red blood cell invasion.

Members of the Malaria Genomic Epidemiology Network performed a genome-wide association study involving more than 11,000 children from several African countries, searching genetic variants conferring resistance or susceptibility to severe malaria. The search led to a haplotype falling in a chromosome 4 locus that's undergone balancing selection early in the human lineage.

In addition to verifying this association in another 14,000 African individuals, the team estimated that individuals with a protective version of the haplotype are roughly 33 percent less likely to suffer from severe malaria than their counterparts without it. The group reported their findings online today in Nature.

"This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite's invasion machinery," co-corresponding author Dominic Kwiatkowski, with the Wellcome Trust Sanger Institute and the Wellcome Trust Centre for Human Genetics, said in a statement.

"We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act," Kwiatkowski added.

Past studies have highlighted the role that both the sickle cell hemoglobin trait and the presence of blood from the O group can play in protecting against malaria, the researchers explained. Such patterns are supported by prior GWAS papers, which pointed to malaria-associated signals in the hemoglobin beta gene HBB and ABO blood group gene, for example, as well as signals in the ion transport gene ATP2B4.

For the current study, the team set out to expand on those findings, first assessing genetic patterns in 5,633 children with severe malaria from The Gambia, Kenya, and Malawi and more than 5,900 unaffected children from the same populations.

Using variants that were directly genotyped with the Illumina Omni2.5M arrays and millions more variants imputed using clues from the 1000 Genomes Project, the researchers searched for potentially protective variants at play in individuals from one or more of the locations tested.

After accounting for known malaria risky loci and other potential confounders such as parasite diversity, they narrowed in on a suspicious new chromosome 4 site falling between the FREM3 gene and the GYPE, GYPB, and GYPA genes, which code for glycophorin proteins expressed in the red blood cell membrane.

At least two P. falciparum proteins bind host blood cells via interactions with the glycophorin proteins Glycophorin A and Glycophorin B, the team noted, consistent with a potential role for the glycophorin locus in helping to dodge severe malaria infection.

Moreover, the site in question has been shown as a site of balancing selection in the past, with an overlapping human and chimpanzee haplotype in this region.

The researchers verified the malaria-related association at chromosome 4 site using Sequenom iPLEX MassArray genotyping on individuals from the discovery set and on almost 14,000 more malaria cases and controls from The Gambia, Ghana, Malawi, Tanzania, Burkina Faso, and Cameroon.

The protective, derived version of the allele at this locus was more common in East Africa, the study's authors noted, and showed the most pronounced ties to malaria in the Kenyan population. There, individuals carrying one copy of the derived allele appeared to be around 40 percent less likely to develop severe malaria.

By scouring other regions in the genome that have reportedly undergone balancing selection events, meanwhile, the researchers identified half a dozen other variants with less pronounced ties to malaria that fell near genes belonging to ancient balanced polymorphism haplotypes.