Altered levels of IFN-γ, IL-4, and IL-5 depend on the TLR4 rs4986790 genotype in COPD smokers but not those exposed to biomass-burning smoke.

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with tobacco smoking and biomass-burning smoke exposure. Toll-like receptor 4 (TLR4) single-nucleotide polymorphisms (SNPs) may contribute to its pathogenesis. The study aimed to assess the association of rs4986790 and rs4986791 in the TLR4 gene in a Mexican mestizo population with COPD secondary to tobacco smoking (COPD-TS) and biomass-burning smoke (COPD-BBS) and to evaluate whether the genotypes of risk affect cytokine serum levels. Materials and methods: We enrolled 2,092 participants and divided them into two comparisons according to their environmental exposure. SNPs were genotyped using TaqMan probes. Serum cytokine levels (IL-4, IL-5, IL-6, IL-10, and INF-γ) were quantified by ELISA. Results: The rs4986790 AA genotype in COPD-TS was associated with a higher COPD risk (OR = 3.53). Haplotype analysis confirmed this association, identifying a block containing the rs4986790 allele (A-C, OR = 3.11). COPD-TS exhibited elevated IL-6, IL-4, and IL-5 levels compared with smokers without COPD (SWOC), whereas COPD-BBS displayed higher IFN-γ, IL-6, and IL-10 levels. The AA carriers in the COPD-TS group had elevated IL-4, IL-5, and IFN-γ compared with carriers of AG or GG. Conclusion: The rs4986790 common allele and the A-C haplotype (rs4986790-rs4986791) were associated with a higher COPD risk in smokers; COPD patients carrying the AA genotype showed increased pro-inflammatory cytokines.

sRAGE levels are decreased in plasma and sputum of COPD secondary to biomass-burning smoke and tobacco smoking: Differences according to the rs3134940 AGER variant.

The receptor for advanced glycation end products (RAGE) and its gene (AGER) have been related to lung injury and inflammatory diseases, including chronic obstructive pulmonary disease (COPD). We aimed to evaluate the association of rs2071288, rs3134940, rs184003, and rs2070600 AGER single-nucleotide variants and the soluble-RAGE plasma and sputum levels with COPD secondary to biomass-burning smoke (BBS) and tobacco smoking. Four groups, including 2189 subjects, were analyzed: COPD secondary to BBS exposure (COPD-BBS, n = 342), BBS-exposed subjects without COPD (BBES, n = 774), tobacco smoking-induced COPD (COPD-TS, n = 434), and smokers without COPD (SWOC, n = 639). Allelic discrimination assays determined the AGER variants. The sRAGE was quantified in plasma (n = 240) and induced-sputum (n = 72) samples from a subgroup of patients using the ELISA technique. In addition, a meta-analysis was performed for the association of rs2070600 with COPD susceptibility. None of the studied genetic variants were found to be associated with COPD-BBS or COPD-TS. A marginal association was observed for the rs3134940 with COPD-BBS (p = 0.066). The results from the meta-analysis, including six case-control studies (n = 4149 subjects), showed a lack of association of rs2070600 with COPD susceptibility (p = 0.681), probably due to interethnic differences. The sRAGE plasma levels were lower in COPD-BBS compared to BBS and in COPD-TS compared to SWOC. The sRAGE levels were also lower in sputum samples from COPD-BBS than BBES. Subjects with rs3134940-TC genotypes exhibit lower sRAGE plasma levels than TT subjects, mainly from the COPD-BBS and SWOC groups. The AGER variants were not associated with COPD-BBS nor COPD-TS, but the sRAGE plasma and sputum levels are related to both COPD-BBS and COPD-TS and are influenced by the rs3134940 variant.

Variant rs4986790 of toll-like receptor 4 affects the signaling and induces cell dysfunction in patients with severe COVID-19.

OBJECTIVES: We investigated the expression of toll-like receptor (TLR)-4 on the cell surface of innate and adaptive cells from patients with COVID-19 carrying the rs4986790 GG genotype in the TLR4 gene and the functional profile of these cells. METHODS: We included 1169 hospitalized patients with COVID-19. The rs4986790 in TLR4 was identified by real-time polymerase chain reaction. Peripheral blood mononuclear cells were isolated and cultured to evaluate TLR-4 expression on immune cells. Supernatants recovered culture assays were stored, and we measured cytokines and cytotoxic molecules. RESULTS: We showed that the rs4986790 (GG) was significantly associated (P = 0.0310) with severe COVID-19. Cells of patients with COVID-19 carrying the GG genotype have increased the frequency of monocytes and activated naïve and non-switched B cells positive to TLR-4 when cells are stimulated with lipopolysaccharide and with spike protein of SARS-CoV-2. Also, cells from patients with GG COVID-19 cannot produce pro-inflammatory cytokines after lipopolysaccharide stimulus, but they are high producers of cytotoxic molecules at baseline. CONCLUSIONS: The rs4986790 GG genotype of the TLR4 is associated with the risk of COVID-19 and acute respiratory distress syndrome. Peripheral blood mononuclear cells of patients carrying the rs4986790 (TLR4) GG genotype had a limited delivery of pro-inflammatory cytokines compared to the AA and AG genotypes in which TLR-4 stimulation induces IL-10, IL-6, tumor necrosis factor-α, and Fas ligand production.

Impacto de las exacerbaciones en la enfermedad pulmonar obstructiva crónica / Impact of Exacerbations on Chronic Obstructive Pulmonary Disease

La enfermedad pulmonar obstructiva crónica (EPOC) es la tercera causa de muerte en todo el mundo. Sin embargo, ante la falta de herramientas diagnósticas precisas en el primer nivel de atención médica, como la espirometría, es difícil determinar la prevalen-cia real de la EPOC.Por otro lado, la falta de una definición clara y precisa de las exacerbaciones de la EPOC hace que se subestime su impacto en la salud pública; habitualmente, los pacien-tes con EPOC que cursan una exacerbación retrasan la búsqueda de atención médica inmediata porque se acostumbran al deterioro asociado a la enfermedad o lo confun-den con cambios por la edad avanzada. Esto puede provocar un aumento de la mor-bilidad y la mortalidad, asimismo, mayor utilización de los recursos sanitarios y mayor carga económica. Por lo tanto, es importante sensibilizar sobre la importancia del diagnóstico temprano y el tratamiento adecuado de las exacerbaciones de la EPOC, del mismo modo que el mayor conocimiento público de los síntomas, las causas y los factores de riesgo de la EPOC. Con ello, se podrán aplicar estrategias de prevención, diagnóstico y tratamiento más eficaces que mejoren la calidad de vida de los pacientes y disminuyan la carga de la enfermedad para la sociedad.Esta revisión ofrece un análisis crítico de la definición más reciente y esboza las impli-caciones del comportamiento de las exacerbaciones, su impacto en los distintos ám-bitos del sistema sanitario, así como en las diferentes esferas de la vida de los pacien-tes con EPOC. (AU)

Chronic Obstructive Pulmonary Disease (COPD) is a common disease and the third leading cause of death worldwide. However, due to the lack of accurate diagnostic tools at the first level of care, such as spirometry, the true prevalence of COPD is difficult to determine.In addition, the lack of a clear definition of COPD exacerbations means that its pub-lic health impact is underestimated. Patients with COPD often do not seek immediate medical attention because they become used to the deterioration associated with the disease. This can lead to increased patient morbidity and mortality, as well as increased utilization of healthcare resources and higher economic costs. Therefore, it is important to promote greater awareness of the importance of early di-agnosis and proper management of COPD exacerbations, as well as increased public awareness of COPD symptoms, etiologic agents, and risk factors.By better understanding COPD exacerbations, more effective prevention, diagnosis and treatment strategies can be implemented to improve the quality of life of patients and reduce the burden of the disease on society.This review aims to provide a critical analysis of the most recent definition and to out-line the implications of the behavior of COPD exacerbations and their impact on the dif-ferent settings of the health care system, as well as on the different spheres of patients' lives. (AU)

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.

Clinical and microbiological characteristics and inflammatory profile during an exacerbation of COPD due to biomass exposure. A comparison with COPD due to tobacco exposure.

BACKGROUND: Patients with biomass exposure-related COPD (BE-COPD) is a prevalent disease in developing countries and requires a detailed study of its clinical and inflammatory characteristics, specifying interventions that may differ from tobacco exposure-related COPD (TE-COPD). The objective was to describe clinical characteristics, biomarkers of inflammation, T-helper cells, and microbiological agents during a COPD exacerbation in BE-COPD in comparison with TE-COPD. METHODS: A prospective observational study in patients with moderate or severe exacerbation was recruited either in the emergency room or the COPD clinic. At enrollment, nasopharyngeal swabs and sputum were collected to identify viral and bacterial pathogens. Blood samples were also collected to measure inflammatory biomarkers and T-helper cells levels. Days of hospitalization and mechanical ventilation requirement was evaluated. RESULTS: Clinical characteristics, vaccination history, hospitalization, history of exacerbations, and microbiological pattern between BE-COPD and TE-COPD were similar. The Th2 profile was higher in BE-COPD than in TE-COPD (2.10 [range 1.30-3.30] vs. 1.40 [range 1.20-1.80], p = 0.001). The Th2/Th1 ratio was higher in BE-COPD than TE-COPD (1.22 [range 0.58-2.57 ] vs. 0.71 [range 0.40-1.15], p = 0.004). The need of mechanical ventilation (MV) was higher in TE-COPD than BE-COPD (13% vs. 31.1%, p = 0.01). Nonvaccination history and high CRP levels were significantly associated with hospitalization [OR 1.48 (CI 95% 1.30-4.61, p = 0.005) and OR 1.17 (CI 95% 1.10-1.24, p = 0.001), respectively]. CONCLUSIONS: Clinical characteristics, inflammatory markers, and microbiological isolates were similar in both groups but BE-COPD show a tendency to present higher inflammatory Th2 cells and low requirement MV compared with TE-COPD.

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.

Hypomethylation of AHRR (cg05575921) Is Related to Smoking Status in the Mexican Mestizo Population.

Tobacco smoking results in a multifactorial disease involving environmental and genetic factors; epigenome-wide association studies (EWAS) show changes in DNA methylation levels due to cigarette consumption, partially reversible upon tobacco smoking cessation. Therefore, methylation levels could predict smoking status. This study aimed to evaluate the DNA methylation level of cg05575921 (AHRR) and cg23771366 (PRSS23) and their correlation with lung function variables, cigarette consumption, and nicotine addiction in the Mexican smoking population. We included 114 non-smokers (NS) and 102 current tobacco smokers (TS); we then further subclassified them as heavy smokers (HS) (n = 53) and light smokers (LS) (n = 49). We used restriction enzymes (MspI/HpaII) and qPCR to determine the DNA methylation level. We observed significant hypomethylation of cg05575921 in smokers compared to NS (p = 0.003); further analysis found a difference between HS and NS (p = 0.02). We did not observe differences between other groups or a positive correlation between methylation levels and age, BMI, cigarette consumption, nicotine addiction, or lung function. In conclusion, the cg05575921 site of AHRR is significantly hypomethylated in Mexican smokers, especially in HS (≥20 cigarettes per day).

Genetic Factors Associated with COPD Depend on the Ancestral Caucasian/Amerindian Component in the Mexican Population.

Genetic variability influences the susceptibility to and severity of complex diseases; there is a lower risk of COPD in Hispanics than in non-Hispanic Caucasians. In this study, we included 830 Mexican-Mestizo subjects; 299 were patients with COPD secondary to tobacco smoking, and 531 were smokers without COPD. We employed a customized genotyping array of single nucleotide polymorphisms (SNPs). The population structure was evaluated by principal component analysis and allele association through a logistic regression model and haplotype identification. In this study, 118 individuals were identified with a high Caucasian component and 712 with a high Amerindian component. Independent of the ancestral contribution, two SNPs were associated with a reduced risk (p ≤ 0.01) of developing COPD in the CYP2A6 (rs4105144) and CYP2B6 (rs10426235) genes; however, a haplotype was associated with an increased risk of COPD (p = 0.007, OR = 2.47) in the CHRNA5-CHRNA3 loci among smokers with a high Caucasian component. In Mexican-Mestizo smokers, there are SNPs in genes that encode proteins responsible for the metabolism of nicotine associated with a lower risk of COPD; individuals with a high Caucasian component harboring a haplotype in the CHRNA5-CHRNA3 loci have a higher risk of suffering from COPD.

The SNP rs13147758 in the HHIP Gene Is Associated With COPD Susceptibility, Serum, and Sputum Protein Levels in Smokers.

BACKGROUND: Genetic association studies have identified single nucleotide polymorphisms (SNPs) related to chronic obstructive pulmonary disease (COPD) susceptibility. The aim of this study was to identify HHIP genetic variants associated with COPD, pulmonary function, and serum and sputum HHIP protein levels in Mexican mestizo smokers. MATERIALS AND METHODS: Association analysis was performed by carrying out a case-control study in Mexican mestizo smokers comprised of two groups: tobacco-smoking subjects with COPD (COPD-TS, n = 222) and smokers without COPD (SWOC, n = 333). We evaluated three SNPs (rs13147758, rs1828591, and rs13118928) in the HHIP gene. Allele discrimination was accomplished by qPCR using TaqMan probes, and determination of protein levels in the serum and sputum supernatants (SS) was performed using ELISA. RESULTS: Statistically significant differences were observed in the rs13147758 GG genotype (adjusted p = 0.014, OR = 1.95) and the rs13147758-rs1828591 GA haplotype (p = 6.6E-06, OR = 2.65) in the case-control comparison. HHIP protein levels were elevated in SS samples from the COPD-TS group compared to those from the SWOC group (p = 0.03). Based on genotype analysis, HHIP protein levels were lower in the serum samples of rs13147758 GG genotype carriers in the COPD-TS group than in the serum samples of rs13147758 GG genotype carriers from the SWOC group (p < 0.05), but there were no differences in the sputum samples. CONCLUSION: The rs13147758 GG genotype and the rs13147758-rs1828591 GA haplotype are associated with susceptibility to COPD. Furthermore, an association in protein levels was observed between the HHIP rs13147758 genotype and COPD in Mexican mestizo smokers.

Heterozygous Genotype rs17580 AT (PiS) in SERPINA1 is Associated with COPD Secondary to Biomass-Burning and Tobacco Smoking: A Case-Control and Populational Study.

Purpose: The protease inhibitor S (PiS) and Z (PiZ) variants have been stated as the only genetic cause of chronic obstructive pulmonary disease (COPD) in Caucasians. However, its frequency in admixed populations is low. We aimed to identify genetic susceptibility between PiS (rs17580) and PiZ (rs28929474) polymorphisms with COPD related to tobacco smoking and biomass-burning smoke as well as to determine its frequencies in Mestizo and Amerindian populations from Mexico. Patients and Methods: One thousand and eight hundred seventy-eight subjects were included in two comparisons of cases and controls, (1) smokers with and without COPD (COPD-S, n=399; SWOC, n=1106); (2) Biomass-burning smoke-exposed subjects with and without COPD (COPD-BS, n=98; BBES, n=275). In addition, 2354 Mexican subjects identified as Mestizos (n=1952) and Amerindian (n=402) were included. The population structure was evaluated using 59 informative ancestry markers. Results: The AT genotype of rs17580 is associated with COPD in both comparisons (COPD-S vs SWOC p<0.001, OR=2.16; COPD-BS vs BBES p<0.0001, OR=11.50). The population of the Mexico-North has a greater Caucasian contribution (54.7%) compared to the center (46.9%) and southeast (42.7%). Conclusion: The rs17580, AT genotype, is associated with COPD in Mexican-Mestizo smokers and exposed to biomass-burning smoke. The rs17580 AT is more frequent in the Mexican-Mestizo population of the North of the country, which has a high Caucasian component.

SYMPTOMATIC AND ASYMPTOMATIC SMOKERS WITHOUT AIRFLOW OBSTRUCTION: A NEW CLINICAL ENTITY?

Non-obstructed ever-smokers, with or without symptoms, have generated a great deal of information recently, but few reviews. Even individuals with normal spirometry can present changes in sputum with inflammatory biomarkers (cellular and molecular) and airways and parenchyma with remodeling; when symptomatic (cough, sputum, wheezing, and dyspnea) exacerbations are frequent affecting the individuals' quality of life, there is an increased use of health resources: more medication, emergency visits, and hospital admissions. Non-obstructed smokers may have exercise limitations, increased lung volumes, low diffusion capacity, air entrapment, peripheral airways obstruction, elevated airways resistance, and abnormal multiple breath nitrogen washout, as well as abnormalities in computed tomography studies, such as airway wall thickening, emphysema, or interstitial lung abnormalities. Quitting smoking comprises a first, inexpensive, and often abandoned intervention to arrest respiratory impairment. It is controversial whether or not this population should be treated with other medications. Further studies should be conducted to elucidate the consequences of follow-up and prognosis in this clinical entity.

Symptomatic and asymptomatic smokers without airflow obstruction: a new clinical entity?

Abstract Non-obstructed ever-smokers, with or without symptoms, have generated a great deal of information recently, but few reviews. Even individuals with normal spirometry can present changes in sputum with inflammatory biomarkers (cellular and molecular) and airways and parenchyma with remodeling; when symptomatic (cough, sputum, wheezing, and dyspnea) exacerbations are frequent affecting the individuals’ quality of life, there is an increased use of health resources: more medication, emergency visits, and hospital admissions. Non-obstructed smokers may have exercise limitations, increased lung volumes, low diffusion capacity, air entrapment, peripheral airways obstruction, elevated airways resistance, and abnormal multiple breath nitrogen washout, as well as abnormalities in computed tomography studies, such as airway wall thickening, emphysema, or interstitial lung abnormalities. Quitting smoking comprises a first, inexpensive, and often abandoned intervention to arrest respiratory impairment. It is controversial whether or not this population should be treated with other medications. Further studies should be conducted to elucidate the consequences of follow-up and prognosis in this clinical entity.

Genetic polymorphisms in CYP2A6 are associated with a risk of cigarette smoking and predispose to smoking at younger ages.

Nicotine is the main component of cigarettes that causes addiction, which is considered a complex disease, and genetic factors have been proposed to be involved in the development of addiction. The CYP2A6 gene encodes the main enzyme responsible for nicotine metabolism. Depending on the study population, different genetic variants of CYP2A6 associated with cigarette smoking have been described. Therefore, we evaluated the possible association between SNPs in CYP2A6 with cigarette smoking and nicotine addiction-related variables in Mexican mestizo smokers. We performed a genetic association study comparing light smokers (LS, n=349), heavy smokers (HS, n=351) and never-smokers (NS, n=394). SNPs rs1137115, rs4105144, rs1801272 and rs28399433 were genotyped in the CYP2A6 gene. We found that the A allele of rs1137115 (OR=1.41) in exon 1 of CYP2A6 and the T allele of rs4105144 (OR=1.32) in the 5' UTR of the gene are associated with the risk of cigarette smoking (p<0.05); rs1137115 affects the level of alternative splicing, resulting in a CYP2A6 isoform with low enzymatic activity, whereas rs4105144 is likely to be in a binding site for the transcription factor for glucocorticoids receptor (GR) and regulates the expression of CYP2A6. In addition, having a greater number of risk alleles (rs1137115 (A), rs4105144 (T) and rs28399433 (G)) is associated with a younger age at onset. The present study shows that in Mexican mestizos, the analyzed SNPs confer greater risk in terms of consumption and age of onset.

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.

Identification of genetic variants in the TNF promoter associated with COPD secondary to tobacco smoking and its severity.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that arises in response to noxious particles or gases. Associations of genetic polymorphisms in TNF have been reported in Asians and Caucasians, but not in Mestizo populations. A case-control study was conducted in two stages: in the first stage, patients with COPD (COPD group, n=165) and smokers without disease (SNC group, n=165) were included and the TNF promoter sequence was determined using direct sequencing. In the second stage, the identified polymorphisms were validated by real-time polymerase chain reaction (PCR) in COPD (n=260) and SNC (n=506). In the first stage, 11 different sets of "contig" alignments were determined, of which contig 10 was found to be associated with susceptibility (P=5.0E-04, OR [odds ratio] =3.64) and contig 1 with Global Initiative for COPD (GOLD) greater grade (P=1.0E-02, OR =3.82). The single nucleotide polymorphisms found in this region were individually identified; the GA genotypes of rs1800629 (P=0.038, OR =2.07), rs56036015 (P=0.0082, OR =3.18), and rs361525 (P=1.0E-02, OR =4.220) were higher in the COPD group vs the SNC group; after second-stage validation, rs1800629 (P=6.00E-03, OR =2.26) and rs56036015 (P=1.10E-03, OR =2.54) are maintained. There are genetic variants in the TNF promoter associated with increased risk of COPD secondary to smoking and with a higher GOLD grade in the Mexican Mestizo population.