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Genetic and epigenetic changes in host ABCB1 influences malaria susceptibility to Plasmodium falciparum.

Abstract 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. ABCB1 is 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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 28422980
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170419
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Genetic and epigenetic changes in host ABCB1 influences malaria susceptibility to
      Plasmodium falciparum.
PG  - e0175702
LID - 10.1371/journal.pone.0175702 [doi]
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. ABCB1 is 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 &lt; 0.05). Significant DNA methylation 
      difference was noticed between case and control (p &lt; 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 &lt; 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.
FAU - Gupta, Himanshu
AU  - Gupta H
AD  - Department of Biotechnology, School of Life Sciences, Manipal University,
      Manipal, Karnataka, India.
FAU - Chaudhari, Sima
AU  - Chaudhari S
AUID- ORCID: http://orcid.org/0000-0001-7830-0407
AD  - Department of Biotechnology, School of Life Sciences, Manipal University,
      Manipal, Karnataka, India.
FAU - Rai, Ayushi
AU  - Rai A
AD  - Department of Biotechnology, School of Life Sciences, Manipal University,
      Manipal, Karnataka, India.
FAU - Bhat, Smitha
AU  - Bhat S
AD  - Department of Biotechnology, School of Life Sciences, Manipal University,
      Manipal, Karnataka, India.
FAU - Sahu, Pratima K
AU  - Sahu PK
AUID- ORCID: http://orcid.org/0000-0002-5572-7253
AD  - Department of Biochemistry &amp; Molecular Biology, VIMSAR, Burla, Sambalpur, Odisha,
      India.
FAU - Hande, Manjunath H
AU  - Hande MH
AUID- ORCID: http://orcid.org/0000-0001-9040-5252
AD  - Department of Medicine, Kasturba Medical College, Manipal, Manipal University,
      Karnataka, India.
FAU - D'Souza, Sydney C
AU  - D'Souza SC
AD  - Department of Medicine, Kasturba Medical College, Mangalore, Manipal University, 
      Karnataka, India.
FAU - Shashikiran, Umakanth
AU  - Shashikiran U
AUID- ORCID: http://orcid.org/0000-0001-5210-7457
AD  - Department of Medicine, Dr TMA Pai Hospital, Udupi, Karnataka, India.
FAU - Satyamoorthy, Kapaettu
AU  - Satyamoorthy K
AD  - Department of Biotechnology, School of Life Sciences, Manipal University,
      Manipal, Karnataka, India.
LA  - eng
PT  - Journal Article
DEP - 20170419
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2016/11/23 [received]
PHST- 2017/03/30 [accepted]
AID - 10.1371/journal.pone.0175702 [doi]
AID - PONE-D-16-46155 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 19;12(4):e0175702. doi: 10.1371/journal.pone.0175702.
      eCollection 2017.

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