title: Categorical complexities of Plasmodium falciparum malaria in individuals is associated with genetic variations in ADORA2A and GRK5 genes.
abstract: In the erythrocytes, malaria parasite entry and infection is mediated through complex membrane sorting and signaling processes. We investigated the effects of single-locus and multilocus interactions to test the hypothesis that the members of the GPCR family genes, adenosine A2a receptor (ADORA2A) and G-protein coupled receptor kinase5 (GRK5), may contribute to the pathogenesis of malaria caused by Plasmodium falciparum (Pf) independently or through complex interactions. In a case-control study of adults, individuals affected by Pf malaria (complicated n=168; uncomplicated n=282) and healthy controls (n=450) were tested for their association to four known SNPs in GRK5 (rs2230345, rs2275036, rs4752307 and rs11198918) and two in ADORA2A (rs9624472 and rs5751876) genes with malaria susceptibility, using techniques of polymerase chain reaction-restriction fragment length polymorphisms and direct DNA sequencing. Single-locus analysis showed significant association of 2 SNPs; rs5751876 (OR=3.2(2.0-5.2); p=0.0006) of ADORA2A and rs2230345 (OR=0.3(0.2-0.5); p=0.0006) of GRK5 with malaria. The mean of the serum creatinine levels were significantly higher in patients with variant GG (p=0.006) of rs9624472 in ADORA2A gene compared to AA and AG genotypes in complicated Pf malaria cases, with the G allele also showing increased risk for malaria (OR=1.3(1.1-1.6); p=0.017). Analyses of predicted haplotypes of the two ADORA2A and the four GRK5 SNPs have identified the haplotypes that conferred risk as well as resistance to malaria with statistical significance. Molecular docking analysis of evolutionary rs2230345 SNP indicated a stable activity of GRK5 for the mutant allele compared to the wild type. Further, generalized multifactor dimensionality reduction to test the contribution of individual effects of the six polymorphisms and higher-order interactions to risk of symptoms/clinical complications of malaria suggested a best six-locus model showing statistical significance. The study provides evidence for the role of ADORA2A and GRK5 that might influence the etiology of malaria infection.
authors.affiliation: Department of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Gupta
authors.affiliation: Department of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
authors.forename: Aditya
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
authors.forename: Abdul Vahab
authors.initials: AV
authors.lastname: Saadi
authors.affiliation: Department of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
authors.forename: Thanvanthri G
authors.initials: TG
authors.lastname: Vasudevan
authors.affiliation: Department of Medicine, Kasturba Medical College, Manipal, Manipal University, Karnataka, India.
authors.forename: Manjunath H
authors.initials: MH
authors.lastname: Hande
authors.affiliation: Department of Medicine, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.
authors.forename: Sydney C
authors.initials: SC
authors.lastname: D'Souza
authors.affiliation: National Institute of Malaria Research (Field Unit), Bangalore, India.
authors.forename: Susanta K
authors.initials: SK
authors.lastname: Ghosh
authors.affiliation: Department of Medicine, Dr. TMA Pai Hospital, Udupi, Melaka Manipal Medical College, Manipal University, Manipal, India.
authors.forename: Shashikiran
authors.initials: S
authors.lastname: Umakanth
authors.affiliation: Department of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India. Electronic address: ksatyamoorthy@manipal.edu.
authors.forename: Kapaettu
authors.initials: K
authors.lastname: Satyamoorthy
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000737:chemistry / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D016778:Malaria, Falciparum / Q000235:genetics* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D043705:Receptor, Adenosine A2A / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D043705:Receptor, Adenosine A2A; D054774:G-Protein-Coupled Receptor Kinase 5
keywords: ADORA2A; Association; GRK5; Gene interaction; Malaria; SNPs