Categorical complexities of Plasmodium falciparum malaria in individuals is associated with genetic variations in ADORA2A and GRK5 genes

Himanshu Gupta, Aditya Jain, Abdul Vahab Saadi, Thanvanthri G. Vasudevan, Manjunath H. Hande, Sydney C. D'Souza, Susanta K. Ghosh, Shashikiran Umakanth, Kapaettu Satyamoorthy

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)188-199
Number of pages12
JournalInfection, Genetics and Evolution
Volume34
DOIs
Publication statusPublished - 01-08-2015

Fingerprint

Falciparum Malaria
malaria
Plasmodium falciparum
G-Protein-Coupled Receptors
Malaria
genetic variation
protein
gene
Single Nucleotide Polymorphism
Genes
genes
Haplotypes
Multifactor Dimensionality Reduction
Molecular Docking Simulation
Alleles
loci
Parasitic Diseases
Purinergic P1 Receptors
haplotypes
allele

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Microbiology (medical)
  • Infectious Diseases

Cite this

@article{c807783f1a6942688880aa9266d96d6e,
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.",
author = "Himanshu Gupta and Aditya Jain and Saadi, {Abdul Vahab} and Vasudevan, {Thanvanthri G.} and Hande, {Manjunath H.} and D'Souza, {Sydney C.} and Ghosh, {Susanta K.} and Shashikiran Umakanth and Kapaettu Satyamoorthy",
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Categorical complexities of Plasmodium falciparum malaria in individuals is associated with genetic variations in ADORA2A and GRK5 genes. / Gupta, Himanshu; Jain, Aditya; Saadi, Abdul Vahab; Vasudevan, Thanvanthri G.; Hande, Manjunath H.; D'Souza, Sydney C.; Ghosh, Susanta K.; Umakanth, Shashikiran; Satyamoorthy, Kapaettu.

In: Infection, Genetics and Evolution, Vol. 34, 01.08.2015, p. 188-199.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Categorical complexities of Plasmodium falciparum malaria in individuals is associated with genetic variations in ADORA2A and GRK5 genes

AU - Gupta, Himanshu

AU - Jain, Aditya

AU - Saadi, Abdul Vahab

AU - Vasudevan, Thanvanthri G.

AU - Hande, Manjunath H.

AU - D'Souza, Sydney C.

AU - Ghosh, Susanta K.

AU - Umakanth, Shashikiran

AU - Satyamoorthy, Kapaettu

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

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