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

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

Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice

Myeloid differentiation factor 88 (MyD88) and MyD88-adaptor like (Mal)/Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) play a critical role in transducing signals downstream of the Toll-like receptor (TLR) family. While genetic ablation of the TLR4/MyD88 signaling axis in mice leads to pulmonary cell death and oxidative stress culminating in emphysema, the involvement of Mal, as well as TLR2 which like TLR4 also signals via MyD88 and Mal, in the pathogenesis of emphysema has not been studied. By employing an in vivo genetic approach, we reveal here that unlike the spontaneous pulmonary emphysema which developed in Tlr42/2 mice by 6 months of age, the lungs of Tlr22/2 mice showed no physiological or morphological signs of emphysema. A more detailed comparative analysis of the lungs from these mice confirmed that elevated oxidative protein carbonylation levels and increased numbers of alveolar cell apoptosis were only detected in Tlr42/2 mice, along with up-regulation of NADPH oxidase 3 (Nox3) mRNA expression. With respect to Mal, the architecture of the lungs of Mal2/2 mice was normal. However, despite normal oxidative protein carbonylation levels in the lungs of emphysema-free Mal2/2 mice, these mice displayed increased levels of apoptosis comparable to those observed in emphysematous Tlr42/2 mice. In conclusion, our data provide in vivo evidence for the non-essential role for TLR2, unlike the related TLR4, in maintaining the normal architecture of the lung. In addition, we reveal that Mal differentially facilitates the anti-apoptotic, but not oxidant suppressive, activities of TLR4 in the lung, both of which appear to be essential for TLR4 to prevent the onset of emphysema

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

<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

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