title: Mucin variable number tandem repeat polymorphisms and severity of cystic fibrosis lung disease: significant association with MUC5AC.
abstract: Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2×10(-4) after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.
authors: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Xueliang
authors: X
authors: Guo
authors: Rhonda G
authors: RG
authors: Pace
authors: Jaclyn R
authors: JR
authors: Stonebraker
authors: Clayton W
authors: CW
authors: Commander
authors: Anthony T
authors: AT
authors: Dang
authors: Mitchell L
authors: ML
authors: Drumm
authors: Ann
authors: A
authors: Harris
authors: Fei
authors: F
authors: Zou
authors: Dallas M
authors: DM
authors: Swallow
authors: Fred A
authors: FA
authors: Wright
authors: Wanda K
authors: WK
authors: O'Neal
authors: Michael R
authors: MR
authors: Knowles
mesh_terms: D000483:Alleles; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D018598:Minisatellite Repeats / Q000235:genetics*; D055271:Mucin 5AC / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C524678:MUC5AC protein, human; D055271:Mucin 5AC