Genome-wide association study indicates two novel resistance loci for severe malaria

Abstract

Malaria causes approximately one million fatalities per year, mostly among African children. Although highlighted by the strong protective effect of the sickle-cell trait, the full impact of human genetics on resistance to the disease remains largely unexplored. Genome-wide association (GWA) studies are designed to unravel relevant genetic variants comprehensively; however, in malaria, as in other infectious diseases, these studies have been only partly successful. Here we identify two previously unknown loci associated with severe falciparum malaria in patients and controls from Ghana, West Africa. We applied the GWA approach to the diverse clinical syndromes of severe falciparum malaria, thereby targeting human genetic variants influencing any step in the complex pathogenesis of the disease. One of the loci was identified on chromosome 1q32 within the ATP2B4 gene, which encodes the main calcium pump of erythrocytes, the host cells of the pathogenic stage of malaria parasites. The second was indicated by an intergenic single nucleotide polymorphism on chromosome 16q22.2, possibly linked to a neighbouring gene encoding the tight-junction protein MARVELD3. The protein is expressed on endothelial cells and might therefore have a role in microvascular damage caused by endothelial adherence of parasitized erythrocytes. We also confirmed previous reports on protective effects of the sickle-cell trait and blood group O. Our findings underline the potential of the GWA approach to provide candidates for the development of control measures against infectious diseases in humans.

Development and characterization of a novel fluorescent indicator protein PMCA4-GCaMP2 in cardiomyocytes

“…Our findings were later confirmed by Okunade and colleagues who generated a similar PMCA4 knockout mouse model [52]. In addition a very recent GWAS study showed the PMCA4 gene to be associated with resistance to infection by malaria plasmodium in humans [53]. Therefore, our discovery that ATA is a specific inhibitor for PMCA4 could have further potential applications in the fields of contraception and anti-malaria treatment.…”

“…At higher concentrations (up to 100 μM) ATA has been reported to have several effects on different cell types. For example, ATA has been described as an anti-viral [40][41][42][43][44][45] and anti-apoptotic agent [51][52][53]. It also inhibits several types of nucleases (DNAse I, RNAse A, SI nuclease, exonuclease) [46][47][48].…”

Optimisation and Validation of a High Throughput Screening Compatible Assay to Identify Inhibitors of the Plasma Membrane Calcium ATPase Pump - a Novel Therapeutic Target for Contraception and Malaria

“…These findings were confirmed by Okunade et al who generated a similar PMCA4 knockout mouse model [24]. In addition, a GWAS has shown the PMCA4 gene to be associated with resistance to infection by malaria plasmodium in humans [25]. These findings have collectively implicated PMCAs in a variety of diseases and have led us to optimise and validate a generic PMCA screening compatible assay to be performed for drug discovery purposes.…”

Decreased calcium pump expression in human erythrocytes is connected to a minor haplotype in the ATP2B4 gene

“…Several recent studies found potential associations between SNPs in the ATP2B4 gene, and diseases or disease-related conditions, including reduced bone mass [21], increased incidence of schizophrenia [22], cardiac hypertrophy [23], red blood cell traits [24], and the incidence of malaria infection [25]. In GWAS studies the SNP rs7551442 in the ATP2B4 gene was specifically linked to red blood cell MCHC (mean corpuscular hemoglobin concentration, Ref.…”

“…In GWAS studies the SNP rs7551442 in the ATP2B4 gene was specifically linked to red blood cell MCHC (mean corpuscular hemoglobin concentration, Ref. [24]), while SNPs rs2365860, rs10900589, rs2365858 and rs4951074 were linked to malaria infection sensitivity [25]. These conditions may be linked phenotypes, e.g.…”