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.

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.

MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression.

BACKGROUND: The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD. METHODS: Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline. RESULTS: Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern. CONCLUSION: In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

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.

Genetic variants in IL17A and serum levels of IL-17A are associated with COPD related to tobacco smoking and biomass burning.

IL-17A is an important pro-inflammatory cytokine involved in the inflammatory response in chronic obstructive pulmonary disease (COPD). To evaluate the role played by single nucleotide polymorphisms of IL17A and protein levels in susceptibility to COPD, 1,807 subjects were included in a case-control study; 436 had COPD related to tobacco smoking (COPD-S) and 190 had COPD related to biomass burning (COPD-BB). Six hundred fifty-seven smokers without COPD (SWOC) and 183 biomass burning-exposed subjects (BBES) served as the respective control groups. The CC genotype and C allele of rs8193036 were associated with COPD (COPD-S vs. SWOC: p < 0.05; OR = 3.01, and OR = 1.28, respectively), as well as a recessive model (p < 0.01; OR = 2.91). Significant differences in serum levels were identified between COPD-S vs. SWOC, COPD-S vs. COPD-BB, and SWOC vs. BBES (p < 0.01). By comparing genotypes in the COPD-BB group TT vs. CC and TC vs. CC (p < 0.05), we found lower levels for the CC genotype. Logistic regression analysis by co-variables was performed, keeping the associations between COPD-S vs. SWOC with both polymorphisms evaluated (p < 0.05), as well as in COPD-BB vs. BBES but with a reduced risk of exacerbation (p < 0.05). In conclusion, polymorphisms in IL17A are associated with COPD. Serum levels of IL-17A were higher in smokers with and without COPD.

IL10 rs1800872 Is Associated with Non-Steroidal Anti-Inflammatory Drugs Exacerbated Respiratory Disease in Mexican-Mestizo Patients.

Non-steroidal anti-inflammatory drugs (NSAID) exacerbated respiratory disease (N-ERD) is a disease integrated by asthma, nasal polyps, and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAID). Genetic association studies have explored single nucleotide polymorphisms (SNPs) in genes involved in theoretical pathophysiological mechanisms, but most of these lack replication of findings in second populations. Our objective was to evaluate the association of SNPs in candidate genomic regions described in Asian and European subjects with N-ERD in Mexican-mestizo patients. We designed a replicative study in two stages. We included 381 SNPs selected by fine mapping of associated genes in a microarray, which were tested in three groups: N-ERD (N), asthma (A), and control group (CG); by means of GoldenGate array, positive results by genetic models were validated in the second stage in another population through qPCR with the same methodology. In the allelic model, we identified 11 SNPs in N vs. CG comparison, and five in N vs. A and A vs. CG, respectively. By genetics models, all SNPs in PPARG, rs13239058 in TBXAS1, and rs1554286 and rs1800872 in IL10 were associated in both models. In the second stage, only rs1800872CC showed an association in the dominant model comparing N vs. GC, p = 0.004, OR = 0.44. In conclusion, rs1800872 in IL10 was the only associated with N-ERD in Mexican-mestizo patients.

Genetic variants as risk factors for cigarette smoking at an early age and relapse to smoking cessation treatment: A pilot study.

OBJECTIVES: Tobacco smoking is a complex and multifactorial disease involving both environmental and genetic factors. In the Mexican mestizo population, single-nucleotide polymorphisms (SNPs) associated with cigarette smoking and a greater degree of nicotine addiction have been identified; however, no possible roles have been explored in regard to the age of onset of smoking or in the success of quitting. METHODS: In this study, 151 Mexican mestizo, who smoke cigarettes, were included. They were grouped according to the age at which they started smoking: those who started smoking before 18 years of age (early smokers, ES) and those who started smoking ≥18 years of age (late smokers, LS). In addition, relapse in smoking was evaluated at the first month after the end of treatment. Genetic association was evaluated characterizing 10 SNPs in 4 genes (CHRNA5, CHRNA3, NRXN1, and HTR2A). RESULTS: According to the dominant model of genetic inheritance, rs6313 (CT+TT) of the HTR2A gene was associated (p = 0.0201) with cigarette consumption at early ages (OR = 2.68, CI = 1.18-6.07). When the risk of relapse was analyzed one month after the end of treatment, regardless of the age of onset, the T allele (rs6313) of HTR2A appeared to be a risk factor for relapse (OR = 2.92, 95% CI = 1.06-8.11); the T allele was found more frequently in those who relapsed (50.0%) compared with people who maintained abstinence (25.4%) (p = 0.0332). CONCLUSIONS: Our findings suggest that in Mexican mestizos who smoke cigarettes, the presence of the T allele in rs6313 of the HTR2A gene increases the risk for the early onset of cigarette smoking as well as the risk for relapsing one month after completing smoking cessation treatment.

Allergic sensitization increases the amount of extracellular ATP hydrolyzed by guinea pig leukocytes.

Increased levels of ATP have been found in the bronchoalveolar lavage of patients with asthma, and subjects with this disease, but not healthy subjects, develop bronchospasm after nebulization with ATP. Because the main mechanism for controlling the noxious effects of extracellular ATP is its enzymatic hydrolysis, we hypothesized that allergic sensitization is accompanied by a decreased functioning of such hydrolysis. In the present study, peripheral blood leukocytes from sensitized and non-sensitized guinea pigs were used for determining the extracellular metabolism (as assessed by inorganic phosphate production) of ATP, ADP, AMP, or adenosine, and for detecting possible changes in the expression (qPCR and Western blot) of major ectonucleotidases (NTPDase1, NTPDase3, and NPP1) and purinoceptors (P2X1, P2X7, P2Y4, and P2Y6). Contrary to our hypothesis, we found that leukocytes from allergic animals produced higher amounts of inorganic phosphate after stimulation with ATP and ADP, as compared with leukocytes from non-sensitized animals. Although at first glance, this result suggested that sensitization caused higher efficiency of ectonucleotidases, their mRNA and protein expressions were unaffected. On the other hand, after sensitization, we found a significant increase in the protein expression of P2X7 and P2Y4, two purinoceptors known to be responsible for ATP release after activation. We concluded that allergic sensitization increased the amount of ATP hydrolyzed by ectonucleotidases, the latter probably not due to the enhanced efficiency of its enzymatic breakdown, but rather due to an increased release of endogenous ATP or other nucleotides, partly mediated by enhanced expression or P2X7 and P2Y4 receptors.

Effect of SNPs in HSP Family Genes, Variation in the mRNA and Intracellular Hsp Levels in COPD Secondary to Tobacco Smoking and Biomass-Burning Smoke.

Heat shock proteins (HSP) genes are a superfamily responsible for encoding highly conserved proteins that are important for antigen presentation, immune response regulation, and cellular housekeeping processes. These proteins can be increased by cellular stress related to pollution, for example, smoke from biomass burning and/or tobacco smoking. Single nucleotide polymorphisms (SNPs) in these genes could affect the levels of their proteins, as well as the susceptibility to developing lung diseases, such as chronic obstructive pulmonary disease (COPD), related to the exposure to environmental factors. Methods: The subjects included were organized into two comparison groups: 1,103 smokers (COPD patients, COPD-S = 360; smokers without COPD, SWOC = 743) and 442 never-smokers who were chronically exposed to biomass smoke (COPD patients, COPD-BS = 244; exposed without COPD, BBES = 198). Eight SNPs in three HSP genes were selected and genotyped: four in HSPA1A, two in HSPA1B, and two in HSPA1L. Sputum expectoration was induced to obtain pulmonary cells and relative quantification of mRNA expression. Subsequently, the intracellular protein levels of total Hsp27, phosphorylated Hsp27 (Hsp27p), Hsp60, and Hsp70 were measured in a sample of 148 individuals selected based on genotypes. Results: In the smokers' group, by a dominant model analysis, we found associations between rs1008438 (CA+AA; p = 0.006, OR = 1.52), rs6457452 (CT+TT; p = 0.000015, OR = 1.99), and rs2763979 (CT+TT; p = 0.007, OR = 1.60) and the risk to COPD. Among those exposed to biomass-burning smoke, only rs1008438 (CA+AA; p < 0.01, OR = 2.84) was associated. Additionally, rs1008438 was associated with disease severity in the COPD-S group (AA; p = 0.02, OR = 2.09). An increase in the relative expression level of HSPA1A was found (12-fold change) in the COPD-BS over the BBES group. Differences in Hsp27 and Hsp60 proteins levels were found (p < 0.05) in the comparison of COPD-S vs. SWOC. Among biomass-burning smoke-exposed subjects, differences in the levels of all proteins (p < 0.05) were detected. Conclusion: SNPs in HSP genes are associated with the risk of COPD and severe forms of the disease. Differences in the intracellular Hsp levels are altered depending on the exposition source.

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

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.

TNF promoter polymorphisms are associated with genetic susceptibility in COPD secondary to tobacco smoking and biomass burning.

Background: Smoking and smoke from biomass burning (BB) are the main environmental risk factors for COPD. Clinical differences have been described between COPD related to smoking and related to wood smoke, but no studies have shown genetic differences between patients exposed to these two risk factors. Methods: To investigate a possible association of tumor necrosis factor (TNF) promoter polymorphisms, we conducted a case-control study. A total of 1,322 subjects were included in four groups: patients with a diagnosis of COPD secondary to smoking (COPD-S, n=384), patients with COPD secondary to biomass burning (COPD-BB, n=168), smokers without COPD (SWOC, n=674), and biomass burning-exposed subjects (BBES n=96). Additionally, a group of 950 Mexican mestizos (MMs) was included as a population control. Three single nucleotide polymorphisms (SNPs) were selected in the TNF gene (rs1800629, rs361525, and rs1800750) and one SNP in the lymphotoxin alpha gene (rs909253). Results: Statistically significant differences were found with genotype GA of the rs1800629: COPD-S vs SWOC, (p<0.001, odds ratio [OR] =2.55, 95% CI=1.53-4.27); COPD-S vs COPD-BB (p,0.01). When performing the comparison of the less severe (G1: I + II) and the more severe (G2: III + IV) levels, differences were identified in G1 (p<0.05, OR=1.94, 95% CI=1.04-3.63) and G2 (p<0.001, OR=3.68, 95% CI=1.94-3.07) compared with SWOC. Regarding genotype GA of rs361525, it has been associated when comparing COPD-BB vs BBES (p=0.0079, OR=5.99, 95% CI=1.38-53.98). Conclusion: The heterozygous genotype GA of polymorphisms rs1800629 and rs361525 in the TNF promoter are associated with the risk of COPD.

Data on polymorphisms in CYP2A6 associated to risk and predispose to smoking related variables.

This article contains data on the single nucleotide polymorphisms (SNPs) rs1137115, rs1801272 and rs28399433 rs4105144 in CYP2A6 associated to smoking related variables in Mexican Mestizo smokers (Pérez-Rubio et al., 2017) [1]. These SNPs were selected due to previous associations with other populations. Mexican Mestizo smokers were classified according their smoking pattern. A genetic association test was performed.

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.

Polymorphisms in HTR2A and DRD4 Predispose to Smoking and Smoking Quantity.

BACKGROUND: Genes encoding the receptors involved in the dopaminergic and serotonergic pathways are potential candidates in the mechanisms of nicotine addiction. AIMS: To identify genetic variants in the promoter regions and exons of the DRD4 and HTR2A genes associated with tobacco smoking and the degree of nicotine addiction in Mexican mestizos. METHODS: The study included 438 non-smokers (NS) and 1,157 current smokers, ranked based on their consumption of cigarettes per day (cpd): 574 heavy smokers (HS, >20 cpd) and 583 light smokers (LS, 1-10 cpd). Genotyping was performed for 4 and 8 single nucleotide polymorphisms (SNPs) in the DRD4 and HTR2A genes, respectively. RESULTS: The C allele of rs1800955 in DRD4 was found to be associated with cigarette smoking in the HS vs. NS and LS vs. NS comparisons (p = 2.34E-03 and p = 1.13E-03, respectively); the association was maintained in the homozygous CC genotype (p = 5.00E-04 and p = 2.00E-04, respectively). The T allele of rs6313 in HTR2A was significantly associated with cigarette smoking and a greater degree of nicotine addiction (p = 4.77E-03, OR = 1.55); the association was maintained in the homozygous genotype (TT) (p = 4.90E-03, OR = 1.96). The A allele of rs6313 was associated with cigarette smoking in the HS vs. NS comparison (p = 1.53E-02, OR = 1.36); the risk was nearly doubled in the homozygous AA genotype (p = 1.30E-03, OR = 1.83) compared with the heterozygous GA genotype (OR = 1.38). CONCLUSIONS: Among Mexican mestizos, the C allele of rs1800955 in the DRD4 gene and the A allele of rs6311 in the HTR2A gene are associated with cigarette smoking, whereas the T allele of rs6313 in HTR2A is associated with cigarette smoking and the degree of nicotine addiction.