Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Abstract

BackgroundChronic 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.MethodsGWA 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).ResultsA 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.ConclusionsOur 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.

A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis

“…After quality control, 717 heavy smokers with CMH (cases) and 1795 heavy smokers without CMH (controls) all with ≥20 pack-years were included for the analysis as previously published 16. Six SNPs were tested using multivariate logistic regression analysis under an additive model, with adjustment for ex-smokers or current smokers and the two population sites (Groningen and Utrecht).…”

Integrative genomics of chronic obstructive pulmonary disease

“…Dijkstra and colleagues performed a GWAS meta-analysis in a total of 2,704 subjects with chronic bronchitis with or without airflow obstruction (which they termed chronic mucus hypersecretion) and 7,624 controls, finding an association with an intronic SNP in the SATB homeobox 1 (SATB1) transcription factor. [42] The SNP was shown to effect SATB1 expression levels in lung tissue. In addition, SATB1 expression was increased in airway biopsies of subjects with mucus hypersecretion.…”

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

“…Moreover, also some replication cohorts were underpowered and CMH is rather a rough estimate. However, we found suggestive evidence for a genetic contribution to CMH in the full population without stratification for COPD, thus suggesting that power would be more of a problem than the definition of CMH [14]. When we analyzed whether our previously reported gene SATB1 was associated with CMH in individuals with and without COPD, we also found that the significance was considerably reduced, p-values of rs6577641 being 2.52 10 −2 and 5.69 10 −2 respectively.…”

“…Information on CMH and smoking behavior was collected by questionnaires as published previously [14]. Spirometry was performed according to the European Respiratory Society guidelines, including forced expiratory volume in 1 sec (FEV 1 ) and forced vital capacity (FVC), without using a bronchodilator [16].…”

“…One study suggested that CTLA4 is associated with chronic bronchitis in individuals with COPD without a direct association with COPD itself [13]. A second study showed that a SNP (rs6577641) in the SATB1 gene was strongly associated with CMH in a heavy smoking population [14]. …”