title: Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease.
abstract: Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function in which defective superoxide production results in deficient microbicidal activity. CGD patients suffer from recurrent, life-threatening infections, and nearly half develop chronic gastrointestinal (GI) complications (colitis, gastric outlet obstruction, or perirectal abscess) and/or autoimmune/rheumatologic disorders (AIDs). To identify genetic modifiers of disease severity, we studied a cohort of 129 CGD patients, in whom seven candidate genes (myeloperoxidase [MPO], mannose binding lectin [MBL], Fcgamma receptors IIa, IIIa, IIIb, TNF-alpha, and IL-1 receptor antagonist), each containing a physiologically relevant polymorphism predicted to influence the host inflammatory response, were selected for analysis. Genotypes of MPO (P = 0.003) and FcgammaRIIIb (P = 0.007) were strongly associated with an increased risk for GI complications, while an FcgammaRIIa (P = 0.05) genotype was suggestive for an association. Patients with all three associated genotypes had the highest risk for GI complications (P < 0.0001). The risk of AIDs was strongly associated with variant alleles of MBL (P = 0.01) and weakly associated with an FcgammaRIIa genotype (P = 0.04). Patients with variant forms of both MBL and FcgammaRIIa had the highest risk of developing an AID (P = 0.003).
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Foster
authors.forename: T
authors.initials: T
authors.lastname: Lehrnbecher
authors.forename: F
authors.initials: F
authors.lastname: Mol
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: D J
authors.initials: DJ
authors.lastname: Venzon
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: D
authors.initials: D
authors.lastname: Noack
authors.forename: J
authors.initials: J
authors.lastname: Rae
authors.forename: J A
authors.initials: JA
authors.lastname: Winkelstein
authors.forename: J T
authors.initials: JT
authors.lastname: Curnutte
authors.forename: S J
authors.initials: SJ
authors.lastname: Chanock
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D037222:Collectins; D016207:Cytokines / Q000235:genetics; D005260:Female; D005838:Genotype; D006105:Granulomatous Disease, Chronic / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007109:Immunity / Q000276:immunology*; D008297:Male; D009195:Peroxidase / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D002352:Carrier Proteins; D037222:Collectins; D016207:Cytokines; D017452:Receptors, IgG; D009195:Peroxidase