RESUMO
BACKGROUND AND OBJECTIVE: Dysregulation of respiratory mucins, MUC5AC in particular, has been implicated in respiratory disease and MUC5AC expression is up-regulated in response to environmental challenges and inflammatory mediators. The aim of this study was to examine the effect of genetic variation on susceptibility to common respiratory conditions. METHODS: The association of MUC5AC and the closely linked genes MUC2 and MUC5B with respiratory outcomes was tested in the MRC National Survey of Health and Development, a longitudinal birth cohort of men and women born in 1946. Also examined were the functional variants of the genes encoding inflammatory mediators, IL13, IL1B, IL1RN, TNFA and ERBB1, for which there is a likely influence on MUC5AC expression and were explored potential gene-gene interactions with these inflammatory mediators. RESULTS: Statistically significant associations between the 3'ter MUC5AC simple nucleotide polymorphism (SNP) rs1132440 and various non-independent respiratory outcomes (bronchitis, wheeze, asthma, hay fever) were reported while the adjacent loci show slight (but largely non-statistically significant) differences, presumably reflective of linkage disequilibrium (allelic association) across the region. A novel association between bronchitis and a non-synonymous functional ERBB1â SNP, rs2227983 (aka epidermal growth factor receptor:R497K, R521K) is also reported and evidence presented of interaction between MUC5AC and ERBB1 and between MUC5AC and IL1RN with respect to bronchitis. The ERBB1 result suggests a clear mechanism for a biological interaction in which the allelic variants of epidermal growth factor receptor differentially affect mucin expression. CONCLUSIONS: The MUC5AC association and the interactions with inflammatory mediators suggest that genetically determined differences in MUC5AC expression alter susceptibility to respiratory disease.
Assuntos
Asma/genética , Bronquite/genética , Receptores ErbB/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Mucina-5AC/genética , Sons Respiratórios/genética , Rinite Alérgica Sazonal/genética , Adulto , Idoso , Asma/epidemiologia , Bronquite/epidemiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Rinite Alérgica Sazonal/epidemiologia , Inquéritos e Questionários , Reino Unido/epidemiologiaRESUMO
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.
Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Idoso , Estudos de Casos e Controles , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The highly heterogeneous epithelial mucins show considerable inter-individual variability attributable to allelic variations in their tandem repeat (TR) peptide domains. Most mucins are known to show variations in repeat number but variation in the sequence of the individual TRs is not as well characterised. Here, we have studied variation in the immunodominant PDTR motif in the TR domain of the membrane-associated "cancer" mucin MUC1 by using the Minisatellite Variant Repeat-Polymerase chain reaction (MVR-PCR) technique. We have fully or partially mapped two nucleotide changes that encode two amino-acid changes, PDTR to PESR, across the arrays of 149 alleles. A total of 103 different maps was obtained when these changes alone were considered and additional variations were also observed. Most maps showed blocks of PDTR repeats interspersed with PESR repeats, although these were possibly more irregular in the longer alleles that also tended to have more PESR repeats. This variability has potential functional consequences and possible implications for some individuals with respect to the efficacy of immune targetting and immune therapy.