title: CXCR1 and CXCR2 haplotypes synergistically modulate cystic fibrosis lung disease.
abstract: Cystic fibrosis (CF) lung disease severity is largely independent on the CF transmembrane conductance regulator (CFTR) genotype, indicating the contribution of genetic modifiers. The chemokine receptors CXCR1 and CXCR2 have been found to play essential roles in the pathogenesis of CF lung disease. Here, we determine whether genetic variation of CXCR1 and CXCR2 influences CF lung disease severity. Genomic DNA of CF patients in Germany (n = 442) was analysed for common variations in CXCR1 and CXCR2 using a single-nucleotide polymorphism (SNP) tagging approach. Associations of CXCR1 and CXCR2 SNPs and haplotypes with CF lung disease severity, CXCR1 and CXCR2 expression, and neutrophil effector functions were assessed. Four SNPs in CXCR1 and three in CXCR2 strongly correlated with age-adjusted lung function in CF patients. SNPs comprising haplotypes CXCR1_Ha and CXCR2_Ha were in high linkage disequilibrium and patients heterozygous for the CXCR1-2 haplotype cluster (CXCR1-2_Ha) had lower lung function compared with patients with homozygous wild-type alleles (forced expiratory volume in 1 s ≤ 70% predicted, OR 7.24; p = 2.30 × 10(-5)). CF patients carrying CXCR1-2_Ha showed decreased CXCR1 combined with increased CXCR2 mRNA and protein expression, and displayed disturbed antibacterial effector functions. CXCR1 and CXCR2 genotypes modulate lung function and antibacterial host defence in CF lung disease.
authors.affiliation: Children's hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Tübingen, Germany. michael.kormann@med.uni-tuebingen.de
authors.forename: Michael S D
authors.initials: MS
authors.lastname: Kormann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hector
authors.forename: Veronica
authors.initials: V
authors.lastname: Marcos
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Mays
authors.forename: Matthias
authors.initials: M
authors.lastname: Kappler
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Sonja
authors.initials: S
authors.lastname: Zeilinger
authors.forename: Melanie
authors.initials: M
authors.lastname: Carevic
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rieber
authors.forename: Olaf
authors.initials: O
authors.lastname: Eickmeier
authors.forename: Stefan
authors.initials: S
authors.lastname: Zielen
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.forename: Barbara
authors.initials: B
authors.lastname: Moepps
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003550:Cystic Fibrosis / Q000276:immunology* / Q000382:microbiology; D005260:Female; D014644:Genetic Variation; D005858:Germany; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D023062:Receptors, Interleukin-8A / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B