SNPs Sets in Codifying Genes for Xenobiotics-Processing Enzymes Are Associated with COPD Secondary to Biomass-Burning Smoke.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; the main risk factors associated with the suffering are tobacco smoking (TS) and chronic exposure to biomass-burning smoke (BBS). Different biological pathways have been associated with COPD, especially xenobiotic or drug metabolism enzymes. This research aims to identify single nucleotide polymorphisms (SNPs) profiles associated with COPD from two expositional sources: tobacco smoking and BBS. One thousand-five hundred Mexican mestizo subjects were included in the study and divided into those exposed to biomass-burning smoke and smokers. Genome-wide exome genotyping was carried out using Infinium Exome-24 kit arrays v. 1.2. Data quality control was conducted using PLINK 1.07. For clinical and demographic data analysis, Rstudio was used. Eight SNPs were found associated with COPD secondary to TS and seven SNPs were conserved when data were analyzed by genotype. When haplotype analyses were carried out, five blocks were predicted. In COPD secondary to BBS, 24 SNPs in MGST3 and CYP family genes were associated. Seven blocks of haplotypes were associated with COPD-BBS. SNPs in the ARNT2 and CYP46A1 genes are associated with COPD secondary to TS, while in the BBS comparison, SNPs in CYP2C8, CYP2C9, MGST3, and MGST1 genes were associated with increased COPD risk.

Microbiota composition in the lower respiratory tract is associated with severity in patients with acute respiratory distress by influenza.

Several factors are associated with the severity of the respiratory disease caused by the influenza virus. Although viral factors are one of the most studied, in recent years the role of the microbiota and co-infections in severe and fatal outcomes has been recognized. However, most of the work has focused on the microbiota of the upper respiratory tract (URT), hindering potential insights from the lower respiratory tract (LRT) that may help to understand the role of the microbiota in Influenza disease. In this work, we characterized the microbiota of the LRT of patients with Influenza A using 16S rRNA sequencing. We tested if patients with different outcomes (deceased/recovered) and use of antibiotics differ in their microbial community composition. We found important differences in the diversity and composition of the microbiota between deceased and recovered patients. In particular, we detected a high abundance of opportunistic pathogens such as Granulicatella, in patients either deceased or with antibiotic treatment. Also, we found antibiotic treatment correlated with lower diversity of microbial communities and with lower probability of survival in Influenza A patients. Altogether, the loss of microbial diversity could generate a disequilibrium in the community, potentially compromising the immune response increasing viral infectivity, promoting the growth of potentially pathogenic bacteria that, together with altered biochemical parameters, can be leading to severe forms of the disease. Overall, the present study gives one of the first characterizations of the diversity and composition of microbial communities in the LRT of Influenza patients and its relationship with clinical variables and disease severity.

Prevalence, attitude, knowledge, and risk perception towards COVID-19 in COPD patients associated to biomass exposure.

Chronic obstructive pulmonary disease (COPD) patients due to biomass exposure (BE-COPD) could be more affected than COPD due to tobacco smoke (TE-COPD) by the coronavirus disease 2019 (COVID-19) pandemic. The aim of this work was to determine the prevalence of COVID-19 in BE-COPD and TE-COPD and if housing conditions, poor attitude, knowledge, and risk perception towards COVID-19, particularly in BE-COPD women, could represent a risk factor for contagion.An 11% prevalence of COVID-19 was found with no significant difference between COPD groups. The BE-COPD group showed poorer socioeconomic status. No significant differences were found to be associated with SARS-CoV-2 infection regarding housing conditions, poor knowledge, attitude, and risk perception towards COVID-19. Living in urban areas and perceiving risk in COVID-19 were significantly associated with increased adherence to sanitary measures and concern of contagion. Around 40% of all patients showed poor risk perception and adherence to sanitary measures towards COVID-19.

Benralizumab for the Prevention of COPD Exacerbations.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Affective Comorbidity Associated with Symptoms, Lung Function, and Differences Between Patients with COPD for Biomass and Tobacco Smoke Exposure.

Anxiety and depression are common entities in patients diagnosed with Chronic Obstructive Pulmonary Disease (COPD). This study aimed to determine the prevalence of affective comorbidity (depression and anxiety) associated with lung function, functional capacity, dyspnea, and quality of life; as well as the differences between groups of patients diagnosed with COPD associated with biomass (COPD-BE) and patients with COPD secondary to tobacco (COPD-TS). Comparative cross-sectional observational study. Multiple hierarchical regression models, analysis of variance, and covariance were carried out. A total of 291 COPD patients were evaluated, symptoms of depression were found to be higher in patients with COPD-BE than in patients with COPD-TS (5.3 ± 4.2 versus 4.2 ± 4, 1, p = 0.016), as well as anxiety complications (4.1 ± 3.8 versus 3.8 ± 3.3, p = 0.095), although with anxiety it was not statistically significant, being adjusted for age and FEV1. Patients with COPD-BE had higher prevalence of depression, compared to COPD-TS (41.2% versus 27.7%, p = 0.028). In the multivariate regression models, the variables of dyspnea and quality of life were associated with depression and anxiety, explaining 25% and 24% of the variability, respectively. Depression is higher in COPD-BE patients compared to COPD-TE patients, it is necessary to consider affective comorbidity in routine evaluation and provide a comprehensive intervention to prevent the effects on other clinical conditions of the disease.

Protective Role of Genetic Variants in HSP90 Genes-Complex in COPD Secondary to Biomass-Burning Smoke Exposure and Non-Severe COPD Forms in Tobacco Smoking Subjects.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory disease characterized by airflow obstruction, commonly present in smokers and subjects exposed to noxious particles product of biomass-burning smoke (BBS). Several association studies have identified single-nucleotide polymorphisms (SNP) in coding genes related to the heat shock proteins family-genes that codify the heat shock proteins (Hsp). Hsp accomplishes critical roles in regulating immune response, antigen-processing, eliminating protein aggregates and co-activating receptors. The presence of SNPs in these genes can lead to alterations in immune responses. We aimed to evaluate the association of SNPs in the HSP90 gene complex and COPD. METHODS: We enrolled 1549 participants, divided into two comparison groups; 919 tobacco-smoking subjects (cases COPD-TS n = 294 and, controls SWOC n = 625) and 630 chronic exposed to BBS (cases COPD-BBS n = 186 and controls BBES n = 444). We genotyped 2 SNPs: the rs13296 in HSP90AB1 and rs2070908 in HSP90B1. RESULTS: Through the dominant model (GC + CC), the rs2070908 is associated with decreased risk (p < 0.01, OR = 0.6) to suffer COPD among chronic exposed BBS subjects. We found an association between rs13296 GG genotype and lower risk (p = 0.01, OR = 0.22) to suffer severe COPD-TS forms in the severity analysis. CONCLUSIONS: single-nucleotide variants in the HSP90AB1 and HSP90B1 genes are associated with decreased COPD risk in subjects exposed to BBS and the most severe forms of COPD in tobacco-smoking subjects.

Physical Activity Levels and Associated Factors in a Latin American COPD Population of Patients. The LASSYC Study.

Reduced physical activity (PA) is an independent risk factor for lung function decline, hospitalization and mortality in chronic obstructive pulmonary disease (COPD) and affects a large proportion of patients from Europe and the United States. However, little is known of the level of PA of COPD patients in Latin America. The aim of this study was to provide information of the level of PA and its determinants in COPD patients in Latin America. This is an observational, cross-sectional study on patients with COPD in seven Latin American countries. PA level was evaluated with the short version of the International Physical Activity Questionnaire (IPAQ) and the association between PA and other variables was investigated. Complete information of PA level was obtained in 734 COPD patients consecutively recruited from specialized outpatient clinics; 448 (61%) were men, with a mean age of 69.6 years (standard deviation [SD] = 8.7) and a mean FEV1 (% predicted) = 49.1% (17.5%). In 37.9% the level of PA was low, and the average sitting time was 36.1 h per week. Patients with low levels of PA were older, with higher levels of dyspnea and higher CAT scores. Additionally, we found that patients with low level of PA presented more symptoms during the day. Low levels of PA have been observed in a large proportion of COPD patients of Latin America, which is higher in women and older patients and it is related with worse functional and clinical characteristics.

Smoke exposure from chronic biomass burning induces distinct accumulative systemic inflammatory cytokine alterations compared to tobacco smoking in healthy women.

Long-term exposure to biomass-burning smoke (BS) is associated with chronic obstructive pulmonary disease (COPD), asthma, and other chronic inflammatory lung diseases. BS results from such processes as the burning of wood for indoor cooking and heating, with women and children having the highest exposure rate. This study aimed to analyze the accumulative alterations in cytokine levels associated with BS (from wood) compared to tobacco smoke (TS) in healthy adult women. The levels of 27 cytokines were analyzed in the serum of 100 women, including 40 tobacco smokers/non-exposed to BS (TS+/BS-), 30 never-smokers/exposed to BS (TS-/BS+) and 30 never-smokers/non-exposed to BS (TS-/BS-) as controls, using 27-Plex immunoassay. The chronic BS exposure index was rated at ≥100 h-years, and the tobacco-smoking index was ≥10 pack-years. Compared to TS-/BS-, TS+/BS- had higher levels of IL-2, IL-9, MCP-1, MIP-1ß, and VEGF, while TS-/BS+ showed higher levels of IL-1ra, IL-6, IL-8, Eotaxin, IP-10, RANTES, and VEGF, presenting a distinct inflammatory profile that may favor an eosinophil-derived inflammatory response to BS exposure. Compared to TS+/BS-, TS-/BS+ expressed higher levels of IP-10 and IL-8, but lower levels of IL-2 and MIP-1ß. Gene-disease database analysis showed that altered cytokines in both TS+/BS- and TS-/BS+ are associated with asthma, COPD, lung fibrosis, and lung cancer. In conclusion, chronic BS exposure induces distinct systemic inflammatory cytokine alterations compared to tobacco smokers in healthy women. These findings provide new insights into how long-term exposure to BS affects the inflammatory response-and potentially the health-of adult women.

Efficacy and Safety of Nitazoxanide in Addition to Standard of Care for the Treatment of Severe Acute Respiratory Illness.

BACKGROUND: Effective therapeutics for respiratory viruses are needed. Early data suggest that nitazoxanide (NTZ) may be beneficial for treating acute respiratory viral illness. METHODS: From March 2014 through March 2017, a double-blind, placebo-controlled trial was conducted in 260 participants ≥1 year old hospitalized with influenza-like illness at 6 hospitals in Mexico. Participants were randomized 1:1 to NTZ (age ≥12 years, 600 mg twice daily; age 4-11 years and 1-3 years, 200 or 100 mg twice daily, respectively) or placebo for 5 days in addition to standard of care. The primary endpoint was time from first dose to hospital discharge. Influenza reverse-transcription polymerase chain reaction and Respifinder 22 multiplex test were used for virus detection. RESULTS: Of 260 participants enrolled, 257 were randomized and took at least 1 dose of study treatment (intention-to-treat population): 130 in the NTZ group and 127 in the placebo group. The Kaplan-Meier estimate of the median duration of hospitalization was 6.5 (interquartile range [IQR], 4.0-9.0) days in the NTZ group vs 7.0 (IQR, 4.0-9.0) days in the placebo group (P = .56). Duration of hospitalization between the 2 treatments was similar in children (P = .29) and adults (P = .62), influenza A and B (P = .32), and other respiratory viruses. Seven (5.4%) and 6 (4.7%) participants in the NTZ and placebo groups, respectively, reported serious adverse events. CONCLUSIONS: Treatment with NTZ did not reduce the duration of hospital stay in severe influenza-like illness. Further analyses based on age and evaluations by virus did not reveal any subgroups that appeared to benefit from NTZ. CLINICAL TRIALS REGISTRATION: NCT02057757.

miR-34a in serum is involved in mild-to-moderate COPD in women exposed to biomass smoke.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities. The main causes of COPD are Gene-environment interactions associated with tobacco smoking (COPD-TS) and biomass smoke (COPD-BS). It is well know that microRNAs (miRNAs) participate in the control of post-transcriptional regulation and are involved in COPD-TS; nevertheless, those miRNAS are participating in the COPD-BS are unidentified. Thus, we studied which miRNAs are involved in COPD-BS (GOLD stages I-II). METHODS: In the screening phase, the profile of the miRNAs was analyzed in serum samples (n = 3) by means of a PCR array. Subsequently, the miRNAs were validated with RT-qPCR (n = 25) in the corresponding study groups. Additionally, the serum concentration of Notch1 was measured comparing COPD-BS vs COPD-TS. RESULTS: miR-34a was down-regulated in COPD- BS vs COPD-TS. In the other study groups, three miRNAs were differentially expressed: miR-374a was down-regulated in COPD-BS vs C, miR-191-5p was up-regulated in COPD-BS vs H-BS, and miR-21-5p was down-regulated in COPD-TS compared to the C group. Moreover, the serum concentration of Notch1, one of the targets of miR-34a, was increased in COPD-BS compared to women with COPD-TS. CONCLUSIONS: This is the first study in patients with COPD due to biomass that demonstrates miRNA expression differences between patients. The observations support the concept that COPD by biomass has a different phenotype than COPD due to tobacco smoking, which could have important implications for the treatment of these diseases.

Haplotype in SERPINA1 (AAT) Is Associated with Reduced Risk for COPD in a Mexican Mestizo Population.

Protease inhibitor S (PiS) and protease inhibitor Z (PiZ) variants in the SERPINA1 gene are the main genetics factors associated with COPD; however, investigations about other polymorphisms are scanty. The aim of this study was to evaluate two missense single nucleotide polymorphisms (SNPs) (rs709932 and rs1303) in the SERPINA1 gene in Mexican mestizo patients with chronic obstructive pulmonary disease (COPD) related to tobacco smoking and biomass-burning exposure. 1700 subjects were genotyped and divided into four groups: COPD related to tobacco smoking (COPD-S, n = 297), COPD related to biomass-burning exposure (COPD-BB, n = 178), smokers without COPD (SWOC, n = 674), and biomass-burning exposed subjects (BBES, n = 551) by real-time PCR. Moreover, the patients' groups were divided according to their exacerbations' frequency. We carried out a haplotype analysis. We did not find differences in allele and genotype frequencies between groups in unadjusted and adjusted analyses, neither with these SNPs and lung function decline. Exacerbations' frequency is not associated with these SNPs. However, we found a haplotype with major alleles (CT) associated with reduced risk for COPD (p < 0.05). Our analysis reveals that SNPs different from PiS and PiZ (rs709932 and rs1303) in the SERPINA1 gene are not associated with COPD and lung function decline in a Mexican mestizo population. However, a haplotype shaped by both major alleles (CT haplotype) is associated with reduced risk for COPD.

SMALLa AIRWAY DISEASE IN COPD ASSOCIATED TO BIOMASS EXPOSURE.

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous entity that may result from different causative agents and risk factors and may follow diverse clinical courses, including COPD secondary to biomass smoke exposure. At present, this phenotype is becoming more important for two reasons: first, because at least almost half of the world's population is exposed to biomass smoke, and second, because the possibility of it being diagnosed is increasing. Biomass smoke exposure COPD affects primarily women and is related with insults to the airways occurred during early life. Although constituents of biomass smoke and tobacco smoke are similar, the physiopathological changes they induce differ depending not only on the chemical composition (related with the type of fuel used) but also on the particle size and the inhalation pattern. Evidence has shown that biomass smoke exposure affects the airway, predominantly the small airways causing anthracofibrosis and peribronchiolar fibrosis changes that will clinically translate into chronic bronchitis symptoms, with a high impact on the quality of life. In this review, we focus especially on the main epidemiological and clinical differences between COPD secondary to biomass exposure and COPD caused by tobacco exposure.

Influence of proinflammatory cytokine gene polymorphisms on the risk of COPD and the levels of plasma protein.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a complex and multifactorial disease involving systemic inflammation. Although certain genetic components have been implicated in the development and progression of this disease, few studies have examined the participation of polymorphisms in proinflammatory genes and the extent to which polymorphisms are related to plasma levels of cytokines involved in the inflammatory process. METHODS: Of the 1125 smokers participating in the study, 438 had COPD, and 687 did not. We determined the genotype of 5 SNPs distributed in the genes: IL6, CXL8, CSF2, CCL1 and IL1B. The plasma protein expression of these genes was also evaluated and categorized according to genotype and the severity of COPD (GOLD grade). RESULTS: An analysis using the codominant model showed an association between rs1818879 in IL6 and susceptibility to COPD (GA OR = 1.1, AA OR = 1.77; p < 0.01), as well as an association between rs25882 in CSF2 and a greater severity of the disease (TC OR = 1.84, CC OR = 3.62; p < 0.01). No association was found between the presence of certain alleles in the SNPs and the plasma levels of the corresponding proteins. CONCLUSIONS: There are genetic polymorphisms related to susceptibility to COPD (rs1818879/A in IL6), as well as to the risk of greater severity of the disease (rs25882/T in CSF2). The presence of the alleles of interest did not significantly affect plasma levels of the codified proteins.

Deregulated MicroRNAs in Cancer-Associated Fibroblasts from Front Tumor Tissues of Lung Adenocarcinoma as Potential Predictors of Tumor Promotion.

Cancer-associated fibroblasts (CAFs) are the main component of the tumor stroma and promote tumor progression through several mechanisms. Recent evidence indicates that small noncoding RNAs, microRNAs (miRNAs), play key roles in CAF tumor-promoting properties; however, the role of miRNAs in lung cancer-associated fibroblasts remains poorly defined. We characterized the differential miRNA expression profile of fibroblasts isolated from matched tumor front (F-CAFs), inner tumor (In-CAFs), and normal adjacent (NFs) tissues from four lung adenocarcinoma patients (ADs) using microarray analysis. Proliferation and invasion assays of A549 human lung cancer cells in the presence of conditioned medium from F-CAFs, In-CAFs or NFs were performed to assess tumorigenic properties. Ten identified candidate miRNAs in F-CAFs, In-CAFs and NFs from 12 ADs were then validated by RT-PCR. Both F-CAFs and In-CAFs enhanced the proliferation and invasion of A549 cells compared with NFs; moreover, F-CAFs showed a significantly stronger effect than In-CAFs. RT-PCR validation demonstrated three downregulated miRNAs in F-CAFs compared with NFs (miR-145-3p, miR-299-3p, and miR-505-3p), two in F-CAFs compared with In-CAFs (miR-410-3p and miR-485-5p), but no differentially expressed miRNAs between In-CAFs and NFs. Further target-gene prediction and pathway enrichment analysis indicated that deregulated miRNAs in F-CAFs showed significant associations with "pathways in cancer" (miR-145-3p, miR-299-3p and miR-410-3p), "Wnt signaling pathway" (miR-410-3p and miR-505-3p), and "TGF-beta signaling pathway" (miR-410-3p). Importantly, a tumor-promoting growth factor targeted by those miRNAs, VEGFA, was upregulated in F-CAFs compared with NFs, as judged by RT-PCR. In conclusion, deregulated miRNAs in F-CAFs are potentially associated with CAF tumor-promoting properties.

Clinical characteristics of asthmatic patients with influenza-like illness and risk of severe exacerbations in Mexico.

BACKGROUND: Patients with chronic inflammatory lung diseases, such as asthma, are at higher risk for influenza-like illness (ILI) complications. Viral infections are known to trigger asthma exacerbations, but a thorough description of the clinical characteristics of ILI-associated asthma exacerbations and the role of viruses as a risk factor for severe exacerbation (SE) in ILI has not been published yet. OBJECTIVE: To investigate risk factors for SE in patients with ILI and asthma. METHODS: Patients with ILI symptoms were recruited from 6 hospitals of Mexico (LaRed sites) during 2010 to 2014. Those with a previous asthma diagnosis and ILI symptoms and who were 5 years or older were included. Patients were assigned as cases or controls based on symptoms reported. SE was defined when participants presented with wheezing or dyspnea and required hospitalization. RESULTS: A total of 486 patients with ILI and a diagnosis of asthma were included. There were no differences in the proportion, number, or type of viral illness among those with and without SE. Those with SE were less likely to report ILI symptoms. Muscle pain and nasal drip were predictors for patients not progressing to SE. A delay in seeking medical care was associated with SE (odds ratio, 2.93; 95% CI, 1.46-5.88). CONCLUSION: The presence of a particular virus did not predict SE. ILI symptoms in asthma patients are not associated with severe exacerbation. Patients with asthma should be encouraged to seek early medical care when ILI symptoms are first noticed to prevent serious complications.

Genetic Risk Determinants for Cigarette Smoking Dependence in Mexican Mestizo Families.

INTRODUCTION: Tobacco smoking is a leading cause of mortality in developed and developing countries. Despite antitobacco and smoke-free policies, the prevalence of active smokers in Mexican urban populations has remained stable. Mexican smokers differ from Caucasian and other ethnic groups, probably due to sociocultural and genetic background characteristics. This study explored the effect of known genetic variants on smoking behavior in Mexico City residents. METHODS: Three hundred sixty-four Mexican Mestizo Mexico City residents from 87 families with at least one smoker were assessed for association of 12 gene variants of six candidate genes (CHRNA4, CHRNB2, DRD2, ANKK1, SLC6A3, and CYP2A6) with cigarette consumption, age of initiation and smoking duration. The Family Based Association Test, an extension of the Transmission Disequilibrium Test, was used to perform family-based association analysis. RESULTS: The Family Based Association Test showed statistically significant association between the rs2072658 polymorphism of the CHRNB2 gene and smoking-related phenotypes such as: smoking status (SS), age of onset (AO), years of smoking, and psychological dependence (PD) evaluated by the Glover-Nilsson Smoking Behavior Questionnaire. After Bonferroni correction, only the association with AO remained significant (P = .003). Statistically significant association was also observed for the CYP2A6 rs28399433 T allele with SS (P = .003) and PD (P = .003). CONCLUSIONS: Our results indicate effects of the rs2072658 CHRNB2 and rs28399433 CYP2A6 gene variants on AO, SS and PD in Mexican Mestizo smokers. A mild effect of other analyzed gene variants, which may contribute to a putative polygenic predisposition for smoking, is suggested. IMPLICATIONS: The understanding of genetic and environmental determinants in the Mexican population is important for other Latin American populations as well, living in their own countries or moving to other ones, particular due to the current migration characteristics and particular genetic background like the Mexican Mestizo and other Central American populations with similar characteristics and migrating to neighbor developed countries, introducing their own smoking behavior and contributing importantly to the genetic pool of the receptor country.

Genetic Variants in IL6R and ADAM19 are Associated with COPD Severity in a Mexican Mestizo Population.

Chronic obstructive pulmonary disease (COPD) is a complex and multifactorial disease with a strong genetic component. Our objective is to identify the genetic variants associated with COPD risk and its severity in Mexican Mestizo population. We evaluated 1285 single-nucleotide polymorphisms (SNPs) of candidate genes in 299 smokers with COPD (COPD-S) and 531 smokers without COPD (SWOC) using an Illumina GoldenGate genotyping microarray. In addition, 251 ancestry informative markers were included. Allele A of rs2545771 in CYP2F2P is associated with a lower risk of COPD (p = 4.02E-10, odds ratio [OR] = 0.104, confidence interval [CI] 95% 0.05-0.18). When the COPD group was stratified by severity according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD; levels III + IV vs. I + II), 3 SNPs (rs4329505 and rs4845626 in interleukin 6 receptor [IL6R] and rs1422794 in a disintegrin and metalloproteinase domain 19 [ADAM19]) were associated with a lower risk of suffering the most severe stages of the disease. rs2819096 in the surfactant protein D (SFTPD) gene was associated with a higher risk of COPD GOLD III + IV (p = 7.79E-03, OR = 1.80, CI 95% 1.16-2.79). Finally, the haplotype in IL6R was associated with a lower risk of suffering from more severe COPD, whereas the haplotype in ADAM19 was associated with a higher risk (p = 7.40E-03, OR = 2.83, CI 95% 1.20-6.86) of suffering from the severe stages of the disease. Our data suggest that there are alleles and haplotypes in the IL6R, ADAM19, and SFTPD genes associated with different severity stages of COPD; in CYP2F2P, rs25455771 is associated with a lower risk of COPD.

Circulating levels of miR-150 are associated with poorer outcomes of A/H1N1 infection.

BACKGROUND: Overproduction of pro-inflammatory cytokines and chemokines is frequently associated with severe clinical manifestations in patients infected with influenza A/H1N1 virus. Micro-RNAs (miRNAs) are highly conserved small non-coding RNA molecules that post-transcriptionally regulate gene expression and are potential biomarkers and therapeutic targets in different inflammatory conditions. METHODS: We studied the circulating and miRNA profiles in critically ill A/H1N1 patients, A/H1N1 patients with milder disease, asymptomatic housemates and healthy controls. Cytokine, chemokine and growth factors that were potential targets of differentially expressed miRNAs were assessed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and interactome analysis of these miRNAs were also performed. RESULTS: Critically ill patients exhibited a significant over-expression of circulating miR-150 (p<0.005) when compared to patients with milder disease. miR-29c, miR-145 and miR-22 were differentially expressed in patients with severe A/H1N1 disease whereas miR-210, miR-126 and miR-222 were downregulated in individuals exposed to the A/H1N1 virus. Significant correlations (p<0.05) between circulating levels of miR-150 with IL-1ra, IL-2, IL-6, CXCL8, IFN-γ, CXCL10 and G-CSF were detected, particularly in critically ill patients. CONCLUSION: The up-regulation of miR-150 is associated with poorer outcomes of A/H1N1 infection. The differential expression of miRNAs related with immune processes in severe A/H1N1 disease supports the potential role of these miRNAs as biomarkers of disease progression.

FEV1 decline in patients with chronic obstructive pulmonary disease associated with biomass exposure.

RATIONALE: Biomass exposure is an important risk factor for chronic obstructive pulmonary disease (COPD). However, the time-course behavior of FEV1 in subjects exposed to biomass is unknown. OBJECTIVES: We undertook this study to determine the FEV1 rate decline in subjects exposed to biomass. METHODS: Pulmonary function was assessed every year in a Mexican cohort of patients with COPD associated with biomass or tobacco during a 15-year follow-up period. MEASUREMENTS AND MAIN RESULTS: The mean rate of decline was significantly lower for the biomass exposure COPD group (BE-COPD) than for the tobacco smoke COPD group (TS-COPD) (23 vs. 42 ml, respectively; P < 0.01). Of the TS-COPD group, 11% were rapid decliners, whereas only one rapid decliner was found in the BE-COPD group; 69 and 21% of smokers versus 17 and 83% of the BE-COPD group were slow decliners and sustainers, respectively. A higher FEV1 both as % predicted and milliliters was a predictive factor for decline for BE-COPD and TS-COPD, whereas reversibility to bronchodilator was a predictive factor for both groups when adjusted by FEV1% predicted and only for the TS-COPD group when adjusted by milliliters. CONCLUSIONS: In the biomass exposure COPD group the rate of FEV1 decline is slower and shows a more homogeneous rate of decline over time in comparison with smokers. The rapid rate of FEV1 decline is a rare feature of biomass-induced airflow limitation.

Nicotine Addiction Development: From Epidemiology to Genetic Factors.

BACKGROUND: Nicotine addiction is a complex and multifactorial disease affecting the central nervous system and consists of a set of characteristic symptoms and signs. OBJECTIVE: The objective of this study was to provide an overview on smoking and the complexity of dependency, with special emphasis on the involvement of genetic factors, including neurexin and nicotinic cholinergic receptor genes. METHODS: The following two aspects are discussed in the present article: (i) epidemiology in Mexico; and (ii) a review of the published literature on genetic association studies using the National Center for Biotechnology Information (NCBI) database of the USA as a search tool. The search key words were: nicotine, smoking, dependence, genetic, tobacco, neurobiology and GWAS. The publication period of the reviewed articles was January 2005 to July 2015. RESULTS: There are numerous studies that provide evidence of the involvement of a genetic component that contributes to the risk of developing nicotine addiction, but the multifactorial nature of addiction requires coordinated research from multiple disciplines. CONCLUSION: Research is needed on the factors associated with genetic risk for nicotine addiction and their interaction with environmental factors.