Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia

Ping An; Rongling Li; Ji Ming Wang; Teizo Yoshimura; Munehisa Takahashi; Ram Samudralal; Stephen J. O'Brien; John Phair; James J. Goedert; Gregory D. Kirk; Jennifer L. Troyer; Efe Sezgin; Susan P. Buchbinder; Sharyne Donfield; George W. Nelson; Cheryl A. Winkler

doi:10.1371/journal.pgen.1002328

Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia

Ping An^*, Rongling Li, Ji Ming Wang, Teizo Yoshimura, Munehisa Takahashi, Ram Samudralal, Stephen J. O'Brien, John Phair, James J. Goedert, Gregory D. Kirk, Jennifer L. Troyer, Efe Sezgin, Susan P. Buchbinder, Sharyne Donfield, George W. Nelson, Cheryl A. Winkler

^*Corresponding author for this work

Medicine, Infectious Diseases Division

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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.

Original language	English (US)
Article number	e1002328
Journal	PLoS genetics
Volume	7
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1002328
State	Published - Oct 2011

Funding

ASJC Scopus subject areas

Genetics(clinical)
Genetics
Ecology, Evolution, Behavior and Systematics
Molecular Biology
Cancer Research

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An, P., Li, R., Wang, J. M., Yoshimura, T., Takahashi, M., Samudralal, R., O'Brien, S. J., Phair, J., Goedert, J. J., Kirk, G. D., Troyer, J. L., Sezgin, E., Buchbinder, S. P., Donfield, S., Nelson, G. W., & Winkler, C. A. (2011). Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia. PLoS genetics, 7(10), Article e1002328. https://doi.org/10.1371/journal.pgen.1002328

@article{084aa1b4e1b74211b53282940c96f8a9,

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-na{\"i}ve 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.",

author = "Ping An and Rongling Li and Wang, {Ji Ming} and Teizo Yoshimura and Munehisa Takahashi and Ram Samudralal and O'Brien, {Stephen J.} and John Phair and Goedert, {James J.} and Kirk, {Gregory D.} and Troyer, {Jennifer L.} and Efe Sezgin and Buchbinder, {Susan P.} and Sharyne Donfield and Nelson, {George W.} and Winkler, {Cheryl A.}",

year = "2011",

month = oct,

doi = "10.1371/journal.pgen.1002328",

language = "English (US)",

volume = "7",

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An, P, Li, R, Wang, JM, Yoshimura, T, Takahashi, M, Samudralal, R, O'Brien, SJ, Phair, J, Goedert, JJ, Kirk, GD, Troyer, JL, Sezgin, E, Buchbinder, SP, Donfield, S, Nelson, GW & Winkler, CA 2011, 'Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia', PLoS genetics, vol. 7, no. 10, e1002328. https://doi.org/10.1371/journal.pgen.1002328

TY - JOUR

T1 - Role of exonic variation in chemokine receptor genes on AIDS

T2 - CCRL2 F167Y association with pneumocystis pneumonia

AU - An, Ping

AU - Li, Rongling

AU - Wang, Ji Ming

AU - Yoshimura, Teizo

AU - Takahashi, Munehisa

AU - Samudralal, Ram

AU - O'Brien, Stephen J.

AU - Phair, John

AU - Goedert, James J.

AU - Kirk, Gregory D.

AU - Troyer, Jennifer L.

AU - Sezgin, Efe

AU - Buchbinder, Susan P.

AU - Donfield, Sharyne

AU - Nelson, George W.

AU - Winkler, Cheryl A.

PY - 2011/10

Y1 - 2011/10

N2 - 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.

AB - 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.

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ER -

Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia

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UN SDGs

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