Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study
نویسندگان
چکیده
BACKGROUND Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. METHODS GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). RESULTS A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10(-9)) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. CONCLUSIONS Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.
منابع مشابه
Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.
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-ye...
متن کاملRelation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes.
The relation of ventilatory impairment and chronic mucus hypersecretion to death from all causes and death from obstructive lung disease (chronic bronchitis, emphysema and asthma) was studied in 13,756 men and women randomly selected from the general population of the City of Copenhagen. During the 10 year follow up 2288 subjects died. In 164 subjects obstructive lung disease was considered to ...
متن کاملChronic cough and sputum production are associated with worse clinical outcomes in stable asthma.
BACKGROUND Chronic cough and sputum production (chronic mucus hypersecretion) is a poorly described clinical feature of asthma. Our objective was to identify clinical, immunological and computed tomography (CT) measures of airway wall dimensions associated with these symptoms in smokers and never smokers with asthma. METHODS Cross-sectional data was analysed from 120 smokers and never smokers...
متن کاملNeutrophil extracellular traps promote lipopolysaccharide-induced airway inflammation and mucus hypersecretion in mice
Bacterial lipopolysaccharide (LPS) contributes to airway inflammation and mucus hypersecretion in chronic airway inflammatory diseases, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Neutrophil extracellular traps (NETs) are extracellular meshworks composed of DNA fibers and antimicrobial proteins. Although NET formation has been detected in COPD and CF patients,...
متن کاملManagement of airway mucus hypersecretion in chronic airway inflammatory disease: Chinese expert consensus (English edition)
Airway mucus hypersecretion is one of the most important characteristics of chronic airway inflammatory diseases. Evaluating and managing airway mucus hypersecretion is of great importance for patients with chronic airway inflammatory diseases. This consensus statement describes the pathogenesis, clinical features, and the management of airway mucus hypersecretion in patients with chronic airwa...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 9 شماره
صفحات -
تاریخ انتشار 2014