title: Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia.
abstract: Chromosome 3p21-22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28-6.31) among four major AIDS-defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.
authors: Basic Research Laboratory, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, USA. pingan@nih.gov
authors: Ping
authors: P
authors: An
authors: Rongling
authors: R
authors: Li
authors: Ji Ming
authors: JM
authors: Wang
authors: Teizo
authors: T
authors: Yoshimura
authors: Munehisa
authors: M
authors: Takahashi
authors: Ram
authors: R
authors: Samudralal
authors: Stephen J
authors: SJ
authors: O'Brien
authors: John
authors: J
authors: Phair
authors: James J
authors: JJ
authors: Goedert
authors: Gregory D
authors: GD
authors: Kirk
authors: Jennifer L
authors: JL
authors: Troyer
authors: Efe
authors: E
authors: Sezgin
authors: Susan P
authors: SP
authors: Buchbinder
authors: Sharyne
authors: S
authors: Donfield
authors: George W
authors: GW
authors: Nelson
authors: Cheryl A
authors: CA
authors: Winkler
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D015331:Cohort Studies; D018450:Disease Progression; D005091:Exons; D056726:Genetic Association Studies; D057809:HEK293 Cells; D015497:HIV-1; D006801:Humans; D015810:Linkage Disequilibrium; D011020:Pneumonia, Pneumocystis / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054388:Receptors, CCR / Q000737:chemistry* / Q000235:genetics*; D054397:Receptors, CCR3 / Q000235:genetics; D054401:Receptors, CCR8 / Q000235:genetics; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000235:genetics; D011991:Receptors, Virus / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: C515350:CCR3 protein, human; C103330:CCR8 protein, human; C487531:CCRL2 protein, human; C106330:CXCR6 protein, human; D054388:Receptors, CCR; D054397:Receptors, CCR3; D054401:Receptors, CCR8; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus