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Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC

Guo, XL; Pace, RG; Stonebraker, JR; Commander, CW; Dang, AT; Drumm, ML; Harris, A; ... Knowles, MR; + view all (2011) Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC. PLOS ONE , 6 (10) , Article e25452. 10.1371/journal.pone.0025452. Green open access

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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 x 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.

Type: Article
Title: Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0025452
Publisher version: http://dx.doi.org/10.1371/journal.pone.0025452
Language: English
Additional information: © 2011 Guo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by grants from the United States Cystic Fibrosis Foundation: STONEB08G0 (J.R.S.), KNOWLE00A0 (M.R.K.), DRUMM00A0 (M.L.D.), R026-CR02 (W.K.O.); the National Institutes of Health: CTRC RR00046, CTSA UL1RR025747, HL068890 (M.R.K.) and HL094585 (A.H.); and the British Lung Foundation P96/14 (D.M.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: ALLELIC ASSOCIATION, GENE POLYMORPHISM, AIRWAYS MUCUS, IDENTIFICATION, POPULATION, EXPRESSION, 11P15.5, COMPLEX, ASTHMA, REGION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/1335031
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