title: Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India.
abstract: BACKGROUND
  IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). Variants at CXCR1 and CXCR2 have been associated with susceptibility to cutaneous and mucocutaneous leishmaniasis in Brazil. Here we investigate the role of CXCR1/CXCR2 in visceral leishmaniasis (VL) in India.
  
  
  METHODS
  Three single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3138060) that tag linkage disequilibrium blocks across CXCR1/CXCR2 were genotyped in primary family-based (313 cases; 176 nuclear families; 836 individuals) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between CXCR1/CXCR2 variants and VL. Quantitative RT/PCR was used to compare CXCR1/CXCR2 expression in mRNA from paired splenic aspirates taken before and after treatment from 19 VL patients.
  
  
  RESULTS
  Family-based analysis using FBAT showed association between VL and SNPs CXCR1_rs2234671 (Z-score = 2.935, P = 0.003) and CXCR1_rs3138060 (Z-score = 2.22, P = 0.026), but not with CXCR2_rs4674259. Logistic regression analysis of the case-control data under an additive model of inheritance showed association between VL and SNPs CXCR2_rs4674259 (OR = 1.15, 95%CI = 1.01-1.31, P = 0.027) and CXCR1_rs3138060 (OR = 1.25, 95%CI = 1.02-1.53, P = 0.028), but not with CXCR1_rs2234671. The 3-locus haplotype T_G_C across these SNPs was shown to be the risk haplotype in both family- (TRANSMIT; P = 0.014) and population- (OR = 1.16, P = 0.028) samples (combined P = 0.002). CXCR2, but not CXCR1, expression was down regulated in pre-treatment compared to post-treatment splenic aspirates (P = 0.021).
  
  
  CONCLUSIONS
  This well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India.
authors.affiliation: Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Michaela
authors.initials: M
authors.lastname: Fakiola
authors.forename: Joyce
authors.initials: J
authors.lastname: Oommen
authors.forename: Sarra E
authors.initials: SE
authors.lastname: Jamieson
authors.forename: Anshuman
authors.initials: A
authors.lastname: Mishra
authors.forename: Medhavi
authors.initials: M
authors.lastname: Sudarshan
authors.forename: Puja
authors.initials: P
authors.lastname: Tiwary
authors.forename: Deepa Selvi
authors.initials: DS
authors.lastname: Rani
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
authors.forename: Madhukar
authors.initials: M
authors.lastname: Rai
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B