CHRNA3/5, IREB2, and ADCY2 Are Associated with Severe Chronic Obstructive Pulmonary Disease in Poland

Abstract

We examined the association between single-nucleotide polymorphisms (SNPs) previously associated with chronic obstructive pulmonary disease (COPD) and/or lung function with COPD and COPD-related phenotypes in a novel cohort of patients with severe to very severe COPD. We examined 315 cases of COPD and 330 Caucasian control smokers from Poland. We included three SNPs previously associated with COPD: rs7671167 (FAM13A), rs13180 (IREB2), and rs8034191 (CHRNA 3/5), and four SNPs associated with lung function in a genome-wide association study of general population samples: rs2070600 (AGER), rs11134242 (ADCY2), rs4316710 (THSD4), and rs17096090 (INTS12). We tested for associations with severe COPD and COPD-related phenotypes, including lung function, smoking behavior, and body mass index. Subjects with COPD were older (average age 62 versus 58 years, P , 0.01), with more pack-years of smoking (45 versus 33 pack-years, P , 0.01). CHRNA3/5 (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.5-2.4; P ¼ 7.4 3 10 27 ), IREB2 (OR, 0.69; 95% CI, 0.5-0.9; P ¼ 3.4 3 10 23 ), and ADCY2 (OR, 1.35; 95% CI, 1.1-1.7; P ¼ 0.01) demonstrated significant associations with COPD. FAM13A (OR, 0.8; 95% CI, 0.7-1.0; P ¼ 0.11) approached statistical significance. FAM13A and ADCY2 also demonstrated a significant association with lung function. Thus, in severe to very severe COPD, we demonstrate a replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2).Keywords: chronic obstructive pulmonary disease; genetic association analysis; lung function; smoking; nicotine addiction Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, and its prevalence continues to grow (1). Although cigarette smoking is the most significant risk factor for COPD, cigarette smoking differentially affects lung function decline, and not all smokers will develop COPD (2). The individual response to cigarette smoke and other environmental factors is affected in part by genetic factors, and the development of COPD is the culmination of the environment acting in concert with a complex array of genetic traits (3).Although the development of COPD is mediated by multiple genetic factors, to date few susceptibility genes other than a 1 -antitrypsin (SERPINA1) have been convincingly identified.Early candidate gene studies yielded inconsistent results (4). These studies were limited by small sample sizes and a lack of uniformity in COPD phenotypes, including the degree of airflow obstruction and intensity of smoking exposure in subjects examined. However, several recent genome-wide association studies (GWAS) have identified genomic regions that demonstrate a highly significant and reproducible association with COPD in large studies including subjects with a range of impaired lung function and smoking history. These GWAS regions are located in FAM13A on chromosome 4q22 (5), on chromosome 4q31...

DNA methylation profiling in human lung tissue identifies genes associated with COPD

“…33 Variants in the THSD4 locus have been found to be associated with lung function 34 and, in particular, lung function in severe COPD. 35 This study revealed differentially methylated sites annotated to COPD GWAS candidate genes and genes with previously identified links to lung disease and treatment response, as well as others in physical proximity with known GWAS susceptibility loci. These sites have strong support in this study.…”

Gain‐of‐function ADCY5 mutations in familial dyskinesia with facial myokymia

“…25–27 In prior reports, neither the connection between ADCY and the disorder nor the nature of the cAMP changes were clearly defined. Our findings, that ADCY5 mutations in FDFM in different protein domains increase intracellular cAMP in mutant ADCY5 -transfected cells in response to isoproterenol, an agonist of the β-adrenergic system through its receptor, are to our knowledge the first demonstration directly linking mutations in an ADCY and a human disease.…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…Development of AC2-selective inhibitors may overcome the difficulties to elucidate the (patho)physiologic functions of AC2 (Pinto et al, 2008;Erdorf et al, 2011;Kinast et al, 2012;Conley et al, 2013). ADCY2 polymorphisms may be related to neuropsychiatric (Mühleisen et al, 2014;Suarez-Rama et al, 2015) and pulmonary diseases (Hardin et al, 2012;Panasevich et al, 2013). Pharmacological studies point to a role of AC2 in the pathogenesis of Lesch-Nyhan disease, a neuropsychiatric disorder with severe self-injurious behavior (Kinast et al, 2012).…”