title: Influence of common variants of TLR4 and TLR9 on clinical outcomes of Plasmodium falciparum malaria in Odisha, India.
abstract: BACKGROUND
  In malaria, the toll-like receptors (TLRs) have recently emerged as major player of innate immunity. However, implication of TLR variants on clinical manifestations of malaria is conflicting. The present study aims to provide relevant information of growing interest in understanding the role of TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms on clinical outcomes of malaria.
  
  
  METHODS
  We genotyped TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms by PCR-RFLP methods and subsequently analyzed in 200 uncomplicated patients and 200 severe patients. Further, the severe malaria categorized into sub-clinical groups such as cerebral malaria (CM), non-cerebral severe malaria (NCSM), single organ dysfunction (SOD) and multi-organ dysfunctions (MODS) are analyzed.
  
  
  RESULTS
  The TLR9-1237CC genotype was observed at significantly low frequency in MODS (p=0.0008), while in heterozygous state (TC) it was proportionately more frequent in SOD (p=0.087) as compared to mild malaria. The TLR9T-1486C heterozygote was more common in all categories of severe malaria. However, pair wise LD analysis revealed significant linkage between T-1237C and T-1486C, whereas haplotype analysis showed significantly low frequency of C-T haplotype in CM (p=0.005, pc=0.02) and high frequency of T-C haplotype in NCSM as compared to mild malaria.
  
  
  CONCLUSIONS
  Although TLR9-1237C could be a risk factor for severe malaria in heterozygous state, negative association of CC genotype with MODS warrants caution of segregating severe malaria into its sub-clinical groups while interpreting data. Further, clinical outcome in malaria was observed to be apparently modulated by LD between TLR9 promoter variants.
authors.affiliation: Department of Biotechnology, North Orissa University, Baripada, Odisha 757003, India.
authors.forename: Avishek
authors.initials: A
authors.lastname: Kar
authors.affiliation: Department of General Medicine, VSS Medical College and Hospital, Burla 768017, India.
authors.forename: Subhendu
authors.initials: S
authors.lastname: Panigrahi
authors.affiliation: Department of General Medicine, VSS Medical College and Hospital, Burla 768017, India.
authors.forename: Sagnika
authors.initials: S
authors.lastname: Tripathy
authors.affiliation: Department of General Medicine, VSS Medical College and Hospital, Burla 768017, India.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mohapatra
authors.affiliation: Laboratory of Microbial Biotechnology, North Orissa University, Baripada, Odisha 757003, India.
authors.forename: Kumananda
authors.initials: K
authors.lastname: Tayung
authors.affiliation: Department of Biotechnology, North Orissa University, Baripada, Odisha 757003, India. Electronic address: gunarmrc@gmail.com.
authors.forename: Gunanidhi
authors.initials: G
authors.lastname: Dhangadamajhi
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007194:India; D015810:Linkage Disequilibrium; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000235:genetics* / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D018512:Parasitemia / Q000235:genetics / Q000469:parasitology; D063868:Patient Outcome Assessment; D010963:Plasmodium falciparum / Q000145:classification / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D055815:Young Adult
chemical_list: D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9
keywords: Cerebral malaria; Organ dysfunctions; Plasmodium falciparum; Polymorphisms; TLR