ABSTRACT
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.
Subject(s)
Cytochrome P-450 CYP2A6/genetics , Genetic Association Studies , Polymorphism, Genetic , Smoking/genetics , Adult , Age Factors , Aged , Alleles , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Male , Mexico , Middle Aged , Polymorphism, Single Nucleotide , Tobacco Use Disorder/geneticsABSTRACT
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.
Subject(s)
ADAM Proteins/genetics , Cytochrome P-450 Enzyme System/genetics , Ethnicity/genetics , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Surfactant-Associated Protein D/genetics , Receptors, Interleukin-6/genetics , Aged , Alleles , Case-Control Studies , Female , Haplotypes , Humans , Male , Mexico , Middle Aged , Polymorphism, Single Nucleotide , Prospective Studies , Pulmonary Disease, Chronic Obstructive/physiopathology , Severity of Illness Index , Smoking/geneticsABSTRACT
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.
Subject(s)
Biomass , Environmental Exposure/adverse effects , Forced Expiratory Volume , Pulmonary Disease, Chronic Obstructive/physiopathology , Smoke/adverse effects , Aged , Cohort Studies , Female , Humans , Male , Smoking/physiopathologyABSTRACT
Objetivos: Determinar la variabilidad de la prueba de caminata de 6 minutos después de eliminar el efecto de aprendizaje, en pacientes con severa enfermedad pulmonar obstructiva crónica.Pacientes y métodos: Se realizó un estudio en 11 pacientes masculinos de la cohorte de la Clínica de Enfermedad Pulmonar Obstructiva Crónica del Instituto Nacional de Enfermedades Respiratorias con promedio de edad de 63 ñ 11 años y FEV1 42 ñ 22 por ciento del predicho. Se aplicó la prueba a los pacientes durante cinco días diferentes por un mismo observador.Resultados: La distancia promedio que caminaron los pacientes fue de 460 ñ 86m; 442 ñ 72m; 451 ñ 78m; 428 ñ 80m y 440 ñ 60m (1er, 2º 3er, 4º y 5º día respectivamente), (ANOVA 1.79, p=0.15), con un coeficiente de variación de 5 por ciento. Hubo una correlación significativa entre la distancia caminada y el FEV1 (r=0.6, p<0.05) en el primer día.Conclusiones: Nuestros resultados demuestran que la prueba es reproducible después de que se elimina el efecto de aprendizaje y que existe una buena correlación con las pruebas funcionales. La simplicidad y repetibilidad de la caminata de 6 minutos hacen de la prueba un instrumento útil para estimar la tolerancia al ejercicio en pacientes con enfermedad pulmonar obstructiva crónica.
