Susceptibility to chronic mucus hypersecretion, a genome wide association study

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 = 4.25x10-6, 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 (4.3x10 -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

Susceptibility to chronic mucus hypersecretion, a genome wide association study

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 metaanalysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (&gt;= 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 = 4.25610(-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 (4.3610 29) 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.</p

Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses

Rationale: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. Objectives: To investigate the genetic component of AWT. Methods: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. Measurements and Main Results: Three significant loci on chromosomes 2q (rs734556; P = 6.2 × 10-7) and 10q (rs10794108, P = 8.6 × 10-8; rs7078439, P = 2.3 × 10-7) were associated with AWTand confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10-8, 7.4 × 10-8, and 7.5 × 10-8, respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10-7) and rs4796712 in NT5C3B (P = 3.1 × 10-6). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10-41). Conclusions: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation

Overview of populations.

<p>Populations and corresponding period of data collection, type of population, genotyping platform and soft-ware used for imputation.</p><p>NA = not applicable.</p

Meta-analysis of top SNPs associated with CMH across replication cohorts and across identification and replication cohorts, corrected for smoking and sex.

<p>P-value is fixed p-value if p-value for heterogeneity (Q) >0.005, and random p-value if p-value for heterogeneity (Q) <0.005; OR is Odds Ratio; OR is fixed OR if p-value for heterogeneity (Q) >0.005, and random OR if p-value for heterogeneity (Q) <0.005; Q is p-value for heterogeneity;</p><p>N = number of cohorts;</p><p>*means that the corresponding SNP is an intron in this gene.</p

<i>SATB1</i>, <i>MUC5AC</i> and <i>FOXJ1</i> mRNA expression levels during mucociliary human airway epithelial cell differentiation (n = 2 donors).

<p>Expression of <i>SATB1</i>, the identified gene in our study, <i>MUC5AC</i> a marker of mucus, and <i>FOXJ1</i>, representing ciliated cells in epithelial cell culture on air liquid interface.</p

Meta-analysis of top SNPs associated with CMH in replication cohorts, in identification and replication cohorts and corresponding direction of effect in all cohorts and associated feature and gene(s).

<p>MAF = minor allele frequency in NELSON;</p><p>*Direction of effect per cohort: each sign reflects one cohort, direction of effect is presented by: + = (OR>1.05), − = (OR<0.95), 0 = (0.95Table 2; OR is odds ratio; Q is p-value for heterogeneity;</p>#<p>means corresponding SNP is located in an intron in this gene.</p