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Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.

ABSTRACT: Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (?20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10(-5)) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value <10(-5) in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10(-6), OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10(-12)). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.

SUBMITTER: Dijkstra AE

PROVIDER: S-EPMC4498483 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.

Dijkstra Akkelies E AE Boezen H Marike HM van den Berge Maarten M Vonk Judith M JM Hiemstra Pieter S PS Barr R Graham RG Burkart Kirsten M KM Manichaikul Ani A Pottinger Tess D TD Silverman Edward K EK Cho Michael H MH Crapo James D JD Beaty Terri H TH Bakke Per P Gulsvik Amund A Lomas David A DA Bossé Yohan Y Nickle David C DC Paré Peter D PD de Koning Harry J HJ Lammers Jan-Willem JW Zanen Pieter P Smolonska Joanna J Wijmenga Ciska C Brandsma Corry-Anke CA Groen Harry J M HJ Postma Dirkje S DS

The European respiratory journal 20140918 1

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and met ...[more]

PMID: 25234806

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Project description:BackgroundWe organized this study in order to investigate differences in serum inflammatory profiles and circulating serum pneumoproteins between smokers with and without chronic obstructive pulmonary disease (COPD).MethodsPatients aged 35-70 years with COPD and a smoking history ≥10 pack-years (cases, n=38) and 38 participants with the same smoking history without COPD (controls) were included in a comparative study conducted as part of a population-based cross-sectional study with 2,388 individuals in northwestern Russia. Cases and controls were matched for age and smoking history. Airflow obstruction (AO) was defined using forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <0.70 and/or FEV1/FVC < lower limit of the normal cut-off values. Patients at risk for COPD were reassessed using a standardized diagnostic work-up protocol. Several parameters, among which four inflammatory biomarkers [the high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) levels] and two pneumoproteins [surfactant protein D (SP-D) and Clara cell secretory protein 16 (CC16)], were measured in the peripheral blood. Systemic inflammation was defined as at least 2 or more elevated biomarker levels.ResultsOut of all smokers, 57.9% with normal spirometry and 36.8% with COPD did not have systemic inflammation, whereas 44.7% of the patients with COPD and 5.3% of the patients without AO demonstrated at least two elevated biomarker levels. No difference in age, gender, and smoking history, environmental and occupational exposure was found between the non-inflamed and the inflamed smokers. Of all risk factors studied, only COPD was associated with systemic inflammation [odds ratio (OR) 11.42, 95% confidence interval (CI): 2.13-58.84].ConclusionsOur study describes the systemic inflammatory network pattern associated with COPD and how it differs from the pattern in smokers with normal lung function. Systemic inflammation is not present in all smokers with COPD; in contrast, some non-obstructed smokers are characterized by systemic inflammation. From this perspective, smoking itself could be seen as a disease and studied accordingly.Trial registrationNCT02307799.

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Dataset Information

Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.

Publications

Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.

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