Nicotinic Acetylcholine Receptor Variants Are Related to Smoking Habits, but Not Directly to COPD

Genome-wide association studies identified single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine receptors (nAChRs) cluster as a risk factor for nicotine dependency and COPD. We investigated whether SNPs in the nAChR cluster are associated with smoking habits and lung function decline, and if these potential associations are independent of each other. The SNPs rs569207, rs1051730 and rs8034191 in the nAChR cluster were analyzed in the Vlagtwedde-Vlaardingen cohort (n = 1,390) that was followed for 25 years. We used GEE and LME models to analyze the associations of the SNPs with quitting or restarting smoking and with the annual FEV1 decline respectively. Individuals homozygote (CC) for rs569207 were more likely to quit smoking (OR (95%CI) = 1.58 (1.05–2.38)) compared to wild-type (TT) individuals. Individuals homozygote (TT) for rs1051730 were less likely to quit smoking (0.64 (0.42; 0.97)) compared to wild-type (CC) individuals. None of the SNPs was significantly associated with the annual FEV1 decline in smokers and ex-smokers. We show that SNPs in the nAChR region are associated with smoking habits such as quitting smoking, but have no significant effect on the annual FEV1 decline in smokers and ex-smokers, suggesting a potential role of these SNPs in COPD development via smoking habits rather than via direct effects on lung function

Multidrug resistance-associated protein-1 (MRP1) genetic variants, MRP1 protein levels and severity of COPD

<p>Abstract</p> <p>Background</p> <p>Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in <it>MRP1 </it>significantly associate with level of FEV₁in two independent population based cohorts. The aim of our study was to assess the associations of <it>MRP1 </it>SNPs with FEV₁level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients.</p> <p>Methods</p> <p>Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in <it>MRP1 </it>were genotyped in 110 COPD patients. The effects of <it>MRP1 </it>SNPs were analyzed using linear regression models.</p> <p>Results</p> <p>One SNP, rs212093 was significantly associated with a higher FEV₁level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV₁level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies.</p> <p>Conclusions</p> <p>This is the first study linking <it>MRP1 </it>SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of <it>MRP1 </it>SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies.</p

SNPs in the <i>nAChR</i> cluster and annual FEV₁ decline (ml/year) in smokers, ex-smokers and never smokers.

<p>B = regression coefficient from the linear mixed-effect model, adjusted for 1 = quitting smoking, 2 = restarting smoking, 3 = never smoker, gender, height and age at the first of two successive surveys and time between two successive surveys. “Smokers” refer to those paired observations in which the subject was a smoker at the first of two successive surveys and quitted smoking or continued smoking at the nearest follow-up survey. “Ex-smokers” refer to those paired observations in which the subject was an ex-smoker at the first of two successive surveys and continued being an ex-smoker or restarted smoking at the nearest follow-up survey. “Never smoker” refer to those paired observations in which the subject was a never smoker at the first of two successive surveys and continued being a never smoker at the nearest follow-up survey. a = heterozygotes vs. wild-type; b = homozygote variant vs. wild-type.</p

SNPs in the <i>nAChR</i> cluster with cigarettes smoked per day in current smokers, and packyears in ever smokers at the last survey.

<p>B = regression coefficient derived from linear regression model, adjusted for age and gender;</p>*<p>only current smokers at the last survey;</p>**<p>ever smokers are current smokers and ex-smokers together.</p><p>a = heterozygote vs. wild-type.</p><p>b = homozygote variant vs. wild-type.</p

Summary of the observed associations in the current study.

<p>SNPs = single nucleotide polymorphisms; COPD = Chronic Obstructive Pulmonary Disease; <i>nAChR</i> = <i>nicotinic acetylcholine receptor</i>; + = association; − = no association.</p

SNPs in the <i>nAChR</i> cluster and OR (95%CI) for quitting smoking in subjects who smoke (upper graph), and OR (95%CI) for restarting to smoke in ex-smokers (lower graph).

<p>Nr. of pairs = number of paired observations in which the subject stopped respectively restarted smoking/ total number of paired observations included in the analysis; Circles represent the odd ratio (OR) and vertical bars represent 95% confidence interval (CI); Wild type was set to one as the reference category; Different total number of paired observations for the SNP genotypes are due to missing data on genotype or smoking habits. The analyses are adjusted for gender and the time between 2 successive surveys. rs569207 TT = wild-type, TC = heterozygote, CC = homozygote variant rs1051730 CC = wild-type CT = heterozygote TT = homozygote variant rs8034191 GG = wild-type, GA = heterozygote, AA = homozygote variant.</p

<i>TLR4</i> SNPs and FEV₁ level at baseline and FEV₁ decline.

<p>FEV₁ level adjusted for age, gender, height, pack-year, current smoking; FEV₁ decline adjusted for FEV₁ baseline, age, gender, height, current smoking, treatment, the period when there is a change in treatment and its interaction with treatment and their interaction with time; a = heterozygotes vs. wild-type; b = homozygote variant vs. wild-type, p = p-value.</p

rs12377632 and inflammatory cells in induced sputum.

<p>Circles represent the regression coefficient (estimate) and vertical bars the 95% confidence interval (CI); Nr. = number of subjects; Wild type was set as the reference category (TT); At baseline analyses are adjusted for age, gender, height, packyears and smoking status; Over time analyses are adjusted for age, gender, height, smoking status, the corresponding initial baseline variable, treatment, the period when there is a change in treatment and its interaction with treatment and the interaction of all variables with time.</p

Clinical characteristics of COPD patients.

<p>Data are presented as mean (standard deviation) or</p>*<p>median (25^th–75^th percentile); FEV₁ = Forced Expiratory Volume in one second; FEV₁/IVC = FEV₁/Inspiratory Vital Capacity;</p>**<p>% pred. = percentage of predicted value.</p

rs10759931 and inflammatory cells in induced sputum.

<p>Circles represent the regression coefficient (estimate) and vertical bars the 95% confidence interval (CI); Nr. = number of subjects; Wild type was set as the reference category (GG); At baseline analyses are adjusted for age, gender, height, packyears and smoking status; Over time analyses are adjusted for age, gender, height, smoking status, the corresponding initial baseline variable, treatment, the period when there is a change in treatment and its interaction with treatment and the interaction of all variables with time.</p