TY - JOUR
T1 - Genetic and epigenetic changes in host ABCB1 influences malaria susceptibility to Plasmodium falciparum
AU - Gupta, Himanshu
AU - Chaudhari, Sima
AU - Rai, Ayushi
AU - Bhat, Smitha
AU - Sahu, Pratima K.
AU - Hande, Manjunath H.
AU - D'Souza, Sydney C.
AU - Shashikiran, Umakanth
AU - Satyamoorthy, Kapaettu
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Multiple mechanisms such as genetic and epigenetic variations within a key gene may play a role in malarial susceptibility and response to anti-malarial drugs in the population. ABCB1is one of the well-studied membrane transporter genes that code for the P-glycoprotein (an efflux protein) and whose effect on malaria disease predisposition and susceptibility to drugs remains to be understood. We studied the association of single nucleotide variations in human ABCB1 that influences its function in subjects with uncomplicated and complicated malaria caused by Plasmodium falciparum (Pf). Global DNA methylation and ABCB1 DNA promoter methylation levels were performed along with transcriptional response and protein expression in subjects with malaria and healthy controls. The rs2032582 locus was significantly associated with complicated and combined malaria groups when compared to controls (p < 0.05). Significant DNA methylation difference was noticed between case and control (p < 0.05). In addition, global DNA methylation levels of the host DNA were inversely proportional to parasitemia in individuals with Pf infection. Our study also revealed the correlation between ABCB1 DNA promoter methylation with rs1128503 and rs2032582 polymorphisms in malaria and was related to increased expression of ABCB1 protein levels in complicated malaria group (p < 0.05) when compared to uncomplicated malaria and control groups. The study provides evidence for multiple mechanisms that may regulate the role of host ABCB1 function to mediate aetiology of malaria susceptibility, prognosis and drug response. These may have clinical implications and therapeutic application for various malarial conditions.
AB - Multiple mechanisms such as genetic and epigenetic variations within a key gene may play a role in malarial susceptibility and response to anti-malarial drugs in the population. ABCB1is one of the well-studied membrane transporter genes that code for the P-glycoprotein (an efflux protein) and whose effect on malaria disease predisposition and susceptibility to drugs remains to be understood. We studied the association of single nucleotide variations in human ABCB1 that influences its function in subjects with uncomplicated and complicated malaria caused by Plasmodium falciparum (Pf). Global DNA methylation and ABCB1 DNA promoter methylation levels were performed along with transcriptional response and protein expression in subjects with malaria and healthy controls. The rs2032582 locus was significantly associated with complicated and combined malaria groups when compared to controls (p < 0.05). Significant DNA methylation difference was noticed between case and control (p < 0.05). In addition, global DNA methylation levels of the host DNA were inversely proportional to parasitemia in individuals with Pf infection. Our study also revealed the correlation between ABCB1 DNA promoter methylation with rs1128503 and rs2032582 polymorphisms in malaria and was related to increased expression of ABCB1 protein levels in complicated malaria group (p < 0.05) when compared to uncomplicated malaria and control groups. The study provides evidence for multiple mechanisms that may regulate the role of host ABCB1 function to mediate aetiology of malaria susceptibility, prognosis and drug response. These may have clinical implications and therapeutic application for various malarial conditions.
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U2 - 10.1371/journal.pone.0175702
DO - 10.1371/journal.pone.0175702
M3 - Article
C2 - 28422980
AN - SCOPUS:85018511257
SN - 1932-6203
VL - 12
JO - PLoS One
JF - PLoS One
IS - 4
M1 - e0175702
ER -
