Role of genetic susceptibility in nicotine addiction and chronic obstructive pulmonary disease

Abstract Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries. Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. The extent of cigarette smoking (pack-years and smoking duration) accounts for only 15% of the variation in lung function, indicating that differences in susceptibility to COPD must exist. We provide an overview of the complexity of nicotine addiction and COPD, with special attention to the involvement of genetic factors. The following aspects are discussed in the present article: (1) epidemiology in Mexico and (2) a review of the published literature on genetic association studies using the National Center for Biotechnology Information database of the United States as a search tool. COPD is unique among complex genetic diseases where an environmental risk factor is known and the level of exposure can be documented with some precision. The high morbidity and mortality associated with COPD and its chronic and progressive nature has prompted the use of molecular genetic studies to identify susceptibility factors for the disease. Biomedical research has a remarkable set of tools to aid in the discovery of genes and polymorphisms. We present a review of the most relevant genetic associations in nicotine addiction and COPD.

Análisis de frecuencias alélicas y genotípicas de las variantes CYP2A6*12 y rs16969968 de CHRNA5 y su asociación con el hábito de fumar y el índice de masa corporal (IMC) en sujetos jóvenes del noreste de México / Association between genotype and allele frequencies of CYP2A6*12 and rs16969968 in CHRNA5 variants with smoking and body mass index in young subjects from Northeast Mexico

Background: Several studies have reported that variants rs16969968 G>A of the CHRNA5 gene and CYP2A6*12 of the CYP2A6 gene are associated with smoking and smoking refusal, respectively. In addition, some studies report that a higher cigarette consumption is associated with low body mass index (BMI). Aim: To analyze the allele and genotypic frequencies of these variants and their impact on smoking and BMI. Material and Methods: A blood sample was obtained and a survey about smoking habits was answered by 319 university students aged 18 to 35 years (127 women, 171 smokers), living in Northeastern Mexico. Genetic variants were studied by polymerase chain reaction/restriction fragment length polymorphism and their frequencies were associated with smoking and BMI. Results: No associations were found between the analyzed variants and smoking in the study groups. However, there was an association among non-smoking subjects between the A allele of rs16969968 and high a BMI (p < 0.01). Conclusions: This last variant may be involved in food-addiction disorders.

Efeitos da exposição à nicotina e à fumaça de cigarro durante a lactação sobre o sistema de recompensa cerebral em ratos / Effects of exposure to nicotine and cigarette smoke during lactation on the brain reward system in rats

Crianças de mães fumantes são mais suscetíveis a se tornarem adultos obesos e se viciarem em drogas ou alimentos palatáveis. Drogas e alimentos ativam a via mesolímbica de recompensa, causando sensação de prazer que induz ainda mais o consumo. Assim, avaliamos a relação entre a exposição apenas à nicotina ou à fumaça do cigarro durante a lactação com a preferência alimentar e sistema dopaminérgico de recompensa cerebral das proles, em dois modelos de programação: Modelo I: no 2o dia pós-natal (PN), lactantes receberam implante de minibombas osmóticas que liberam nicotina (NIC) ou salina (C), durante 14 dias. Em PN150 e novamente em PN160, as proles foram divididas em 4 grupos para um desafio alimentar: N-SC e C-SC que receberam ração padrão; N-SSD e C-SSD que podiam escolher livremente entre as dietas hiperlipídica e hiperglicídica. A ingestão alimentar foi avaliada após 12 h. As mães foram sacrificadas apenas na 21ª da lactação (desmame) e as proles em PN15 (com nicotina), PN21 e PN170 (ausência da NIC). Ao desmame, as ratas lactantes NIC apresentaram menor conteúdo de tirosina hidroxilase (TH), maior OBRb e SOCS3 na area tegmentar ventral (VTA); menor TH, maior receptor de dopamina 1 (D1R), receptor de dopamina 2 (D2R) e transportador de dopamina (DAT) no núcleo accumbens (NAc); maior conteúdo de TH no estriado dorsal (DS); e maior D2R e SOCS3 no núcleo arqueado (ARC). Em PN15, os filhotes NIC apresentaram maior conteúdo de D1R, D2R e menor DAT no NAc, enquanto em PN21, apresentaram apenas menor DAT no DS, e menor conteúdo de pSTAT3 em ARC. Aos 170 dias, as proles SSD demonstraram maior preferência para a ração hiperlipídica. No entanto, os animais N-SSD consumiram mais ração hiperglicidica do que as proles C-SSD...

Children from smoking mothers are more susceptible to become obese adults and to become drug or food addicts. Drugs and food activate the mesolimbic reward pathway, causing a sense of pleasure that induces further consumption.Thus, we studied the relationship between only nicotine or tobacco smoke exposure during lactation with feeding behavior and brain dopaminergic reward system at adulthood, in two programming models: Model I, on the postnatal day (PN) 2, lactating rats were implanted with minipumps releasing nicotine (NIC) or saline (C) for 14 days. On PN150 and again on PN160, offspring were divided into 4 groups for a food challenge: N-SC and C-SC received standard chow; N-SSD and C-SSD could freely select between hyperlipidic and hyperglicidic diets. Mothers were euthanized only in 21ª of lactation and offspring were euthanized in PN15 (with nicotine), PN21 and PN170 (withdraw). At weaning (PN21), NIC dams had: lower tyrosine hydroxylase (TH), higher OBRb and SOCS3 contents in ventral tegmental area (VTA); lower TH, higher dopamine receptor 1 (D1R), dopamine receptor 2 (D2R) and dopamine transporter (DAT) contents in nucleus accumbens (NAc); higher TH content in dorsal striatum (DS); and higher D2R and SOCS3 contents in arcuate nucleus (ARC). On PN15, NIC pups had higher D1R, D2R and lower DAT contents in NAc, while on PN21 they had lower DAT in DS, and lower pSTAT3 content in ARC. On PN170, SSD animals showed an increased food intake compared with SC ones and a preference for the hyperlipidic chow. However, N-SSD animals consumed relatively more hyperglicidic chow than C-SSD ones. N offspring presented lower D2R and DAT contents in the NAc, and lower D2R in the ARC. Model II, nursing rats and their pups were divided into: tobacco smoke-exposed (S group: 4 times/day, from the 3rd to the 21th day of lactation), and ambient air-exposed (C group)...

Variantes genéticas de CYP2A6 y su relación con la dependencia tabáquica y el hábito de fumar en una muestra individuos chilenos: Un estudio piloto / Relation of genetic variants of CYP2A6 with tobacco dependence and smoking habit in Chilean subjects: A pilot study

Background: Genetic and metabolic factors associated with nicotine metabolism may be related to smoking behavior. Aim: To assess the prevalence of allelic and genotype variants of CYP2A6 in a sample of Chilean subjects and to evaluate their relationship with smoking and tobacco dependence. Material and Methods: The genotype frequencies for *2, *3 and *4 of CYP2A6*1 (wild type) gene were determined by polymerase chain reaction (PCR) in 54 volunteers. Addiction to tobacco was evaluated using the Fagerstrom Test. The association between the presence of allelic variants of CYP2A6 and smoking and tobacco dependence was evaluated with chi square test. Results: The prevalence of *1, *2 (wt/*2), *3 (wt/*3 or *31*3) and *4 (del/del) were 92.6%, 3.7%, 0% y 3.7%, respectively. No significant association was observed between being a carrier of a variant genotype of CYP2A6 and smoking or tobacco dependence. Conclusions: In this sample of Chilean individuals we did not find a relation between any CYP2A6 genotype with smoking or tobacco dependence.

Effect of a disintegrin and metalloprotease 33 [ADAMSS] gene polymorphisms and smoking in COPD

COPD is characterized by air flow limitation that is not fully reversed and associated with an influx of neutrophils, macrophages and CD8 T lymphocytes in the airways. The disease is characterized by airflow limitation and is associated with an abnormal inflammatory response of the lungs in response to noxious particles or gases and associated with systemic manifestation. Sixty consecutive patients with COPD and 40 normal healthy individuals were included. All cases and controls were subjected to detection of 2 polymorphic loci [S1 AND Q1] of ADAM33 by PCR-RFLP technique. The percentage of S1 and Q1 AA genotype and A allele were significantly increased in control than in COPD patients while there was significant increase in S1 and Q1 GG genotype and G allele in COPD patients than in control [p < 0.001]. No significant difference was found between smoker and non-smoker among the two studied groups in genotype and alleles distribution of ADAM33 SNPs S1 and Q1 p > 0.05, whereas there was significant increase in ADAM33 S1 G allele and Q1 G allele in smoker and non-smoker in COPD patients as compared to their corresponding fellows in control group [p < 0.05]. As regard to Pulmonary function test there was significant decrease in% of FEV1 in COPD patients as compared to control group for both smokers and non-smokers [p < 0.001]. Within both control and COPD groups smokers had significant decrease in FEV1% as compared to non-smokers [p < 0.001]. There was a significant decrease in FEV1% among all genotypes in smoker as compared to non-smoker COPD patients [p < 0.001], the most prominent decrease was found in smoker GG genotype for both ADAM33 S1 and Q1 in COPD patients. In conclusion, we found that polymorphisms in the SNPs [Q1 and S1] of ADAM33 gene are associated with COPD in the general population. In addition, smoker patients with GG genotype in [S1 and Q1] ADAM33 will have more pronounced decline in the pulmonary function test [FEV1]

Serotonin transporter gene polymorphisms: a case-control study

Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter, are involved in alcoholism and tobacco use and are influenced by polymorphism of the promoter region of 5HTT (5-HTTLPR). As alcohol and tobacco consumption have been implicated in the pathogenesis of oral cancer, the purpose of this study was to investigate 5-HTTLPR polymorphism in patients with oral squamous cell carcinoma (OSCC) compared with a control group in a sample of Brazilian patients. One hundred and three patients affected by OSCC and 103 volunteers without OSCC were genotyped for 5-HTTLPR. Both groups were matched for age, sex and tobacco use. The chi-squared test was used for statistical analysis (α=0.05). There was no statistically significant difference in 5-HTTLPR genotypes between case and control group (p= 0.408). In conclusion, the present investigation demonstrated that serotonin transporter polymorphisms are not implicated in the OSSC development.

Consideráveis evidências indicam que mecanismos serotoninérgicos, particularmente o transportador de serotonina, estão envolvidos no alcoolismo e no uso de fumo e são influenciados pelo polimorfismo da região promotora do 5HTT (5-HTTLPR). Como o consumo de álcool e fumo está implicado na patogênese do câncer, o objetivo deste estudo foi investigar o polimorfismo 5-HTTLPR em pacientes com carcinoma bucal de células escamosas (CBCE) comparado com um grupo controle em uma amostra de pacientes brasileiros. Cento e três pacientes afetados por CBCE e 103 voluntários sem história de CBCE foram genotipados para 5-HTTLPR. Ambos os grupos foram pareados pela idade, gênero e uso de fumo. O teste do qui-quadrado foi usado para análise estatística. Não houve diferença estatística entre os genótipos dos grupos caso e controle (p= 0,408). Concluindo, a presente investigação demonstrou que os polimorfismos do transportador de serotonina não estão implicados no desenvolvimento do CBCE.

Epidermal growth factor receptor and KRAS mutations in Brazilian lung cancer patients

OBJECTIVE: Epidermal growth factor receptor is involved in the pathogenesis of non-small cell lung cancer and has recently emerged as an important target for molecular therapeutics. The KRAS oncogene also plays an important role in the development of lung cancer. The aim of this study was to evaluate the frequency of epidermal growth factor receptor and KRAS mutations in a population of Brazilian patients with non-small cell lung cancer. METHODS: A total of 207 specimens from Brazilian patients with non-small cell lung cancer were analyzed for activating epidermal growth factor receptor and KRAS somatic mutations, and their associations with clinicopathological characteristics (including age, gender, ethnicity, smoking habits, and histological subtype) were examined. RESULTS: We identified 63 cases (30.4%) with epidermal growth factor receptor mutations and 30 cases (14.6%) with KRAS mutations. The most frequent epidermal growth factor receptor mutation we detected was a deletion in exon 19 (60.3%, 38 patients), followed by an L858R amino acid substitution in exon 21 (27%, 17 patients). The most common types of KRAS mutations were found in codon 12. There were no significant differences in epidermal growth factor receptor or KRAS mutations by gender or primary versus metastatic lung cancer. There was a higher prevalence of KRAS mutations in the non-Asian patients. Epidermal growth factor receptor mutations were more prevalent in adenocarcinomas than in non-adenocarcinoma histological types. Being a non-smoker was significantly associated with the prevalence of epidermal growth factor receptor mutations, but the prevalence of KRAS mutations was significantly associated with smoking. CONCLUSIONS: This study is the first to examine the prevalence of epidermal growth factor receptor and KRAS mutations in a Brazilian population sample with non-small cell lung cancer.

P21 [Waf1/Cip1] gene polymorphisms and possible interaction with cigarette smoking in esophageal squamous cell carcinoma in northeastern iran: a preliminary study

The incidence of esophageal squamous cell carcinoma [ESCC] is very high in northeastern Iran. However, the genetic predisposing factors to ESCC in this region have not been clearly defined. The P21 [waf1/cip1] gene is involved in the arrest of cellular growth, as induced by the p53 tumor suppressor gene. Two polymorphisms of p21 gene in codon 31 [p21 C98A, dbSNP rs1801270] and the 3'UTR [p21 C70T, dbSNP rs1059234] ma-y affect protein expression and play a role in cancer susceptibility. The present study aimed to investigate the association of p21 polymorphisms in codon 31 and the 3'UTR, and cigarette smoking on the risk of ESCC in northeastern Iran. A case-control study was carried out to detect the p21 polymorphism in the 3'UTR and codon 31 of samples from 126 ESCC cases and 100 controls from 2006 to 2007. There were no significant differences of age and sex between cases and controls. Genotyping of p21 polymorphisms were determined with the PCR-RFLP method. Conditional logistic regression was used to adjust for potential confounders. None of the p21 genotypes were significantly associated with risk of ESCC, even after adjusting for age and gender [P=0.52, OR=1.24; 95%CI: 0.63-2.42]. However, the presence of these polymorphisms in combination with cigarette smoking had a synergistic interaction in ESCC carcinogenesis in northeastern Iran [P=0.02, OR=8.38; 95%CI: 1.03-67.93]. Our data suggests that these two p21 polymorphisms, both alone and in combination, are not genetic susceptibility biomarkers for ESCC. However, their interaction with cigarette smoking may influence the susceptibility to ESCC development in northeastern Iran

Estrogen receptor 1 gene polymorphisms in premenopausal women: interaction between genotype and smoking on lipid levels

Estrogen has multiple effects on lipid and lipoprotein metabolism. We investigated the association between the four common single nucleotide polymorphisms in the estrogen receptor 1 (ESR1) gene locus, -1989T>G, +261G>C, IVS1-397T>C and IVS1-351A>G, and lipid and lipoprotein levels in southern Brazilians. The sample consisted in 150 men and 187 premenopausal women. The women were considered premenopausal if they had regular menstrual bleeding within the previous 3 months and were 18-50 years of age. Exclusion criteria were pregnancy, secondary hyperlipidemia due to renal, hepatic or thyroid disease, and diabetes. Smoking status was self-reported; subjects were classified as never smoked and current smokers. DNA was amplified by PCR and was subsequently digested with the appropriate restriction enzymes. Statistical analysis was carried out for men and women separately. In the study population, major allele frequencies were _1989*T (0.83), +261*G (0.96), IVS1-397*T (0.58), and IVS1-351*A (0.65). Multiple linear regression analyses indicated that an interaction between +261G>C polymorphism and smoking was a significant factor affecting high-density lipoprotein cholesterol (HDL-C) levels (P = 0.028) in women. Nonsmoking women with genotype G/C of +261G>C polymorphism had mean HDL-C levels higher than those with G/G genotype (1.40 ± 0.33 vs 1.22 ± 0.26 mmol/L; P = 0.033). No significant associations with lipid and lipoprotein levels in women and men were detected for other polymorphisms. In conclusion, the +261G>C polymorphism might influence lipoprotein and lipid levels in premenopausal women, but these effects seem to be modulated by smoking, whereas in men ESR1 polymorphisms were not associated with high lipoprotein levels.

A influência da genética na dependência tabágica e o papel da farmacogenética no tratamento do tabagismo / The influence of genetics on nicotine dependence and the role of pharmacogenetics in treating the smoking habit

Mesmo com os esforços intensivos para o controle do tabagismo nas últimas décadas, uma proporção substancial de pessoas inicia a fumar ou mantém-se fumando apesar do pleno conhecimento dos malefícios do hábito. Os estudos têm focado atualmente as bases genéticas da adição nicotínica. O tabagismo tem sido associado a vários polimorfismos genéticos, mas os fatores ambientais também devem ser enfatizados. Esta revisão apresenta alguns dos principais dados disponíveis dos estudos genéticos sobre o comportamento tabágico. Esta linha de pesquisa poderá, no futuro, ajudar os clínicos a individualizar o tipo, a dosagem e a duração do tratamento da dependência tabágica, conforme o genótipo de cada fumante, maximizando a eficácia do esquema proposto.

Despite the considerable efforts made in the fight against smoking in the last decades, there are still substantial numbers of people who, in full knowledge of the health hazards, begin smoking or continue smoking. Recent studies have focused on the genetic bases of the nicotine addiction. Various genetic polymorphisms have been associated with smoking. However, environmental factors have also been shown to play a role. In this review, we present some of the principal data collected in genetic studies of smoking behavior. The results obtained through this line of research will eventually aid clinicians in individualizing the type, dosage and duration of treatment for patients with nicotine dependence in accordance with the genotype of each smoker, thereby maximizing the efficacy of the proposed treatment regimen.

Variantes alélicas de CYP1A1 y GSTM1 como biomarcadores de susceptibilidad a cáncer gástrico: influencia de los hábitos tabáquico y alcohólico / Cytochrome P4501A1 (CYP1A1), glutathione S transferase M1 (GSTM1) polymorphisms and their association with smoking and alcohol consumption as gastric cancer susceptibility biomarkers

Background: Gastric cancer (GaC) is the second cause of death by cancer in the world and one of the first causes in Chile. However, the burden of this disease shows remarkable worldwide variation probably explained by environmental and genetic factors. The role of susceptibility low penetrance genes and environmental and dietary factors in the etiology of gastric cancer is not well-known. Aim: To analyze the possible association between CaG susceptibility, genetic (CYP1A1 and GSTM1 polymorphisms) and environmental (tobacco and alcohol) factors. Patients and Methods: In a case-control study, we included 73 patients with a pathologically diagnosed GaC and 263 controls. DNA was extracted from peripheral blood to detect allele variants for CYP1A1 and GSTM1, using polymerase chain reactions and digestion with restriction enzymes. Results: There was a clear association of smoking and alcohol ingestion with GaC with odds ratios (OR) of 2.54 (95 percent confidence intervals (CI) of 1.45-4.46 and OR of 3.36 (95 percent CI 1.76-6.41), respectively. Polymorphic variants of CYP1A1 and GSTM1 had no association with GaC. However, the m2 variant of CYP1A1 significantly modifies the risk induced by tobacco or alcohol (OR 13.65; 95 percent CI 3.15-59.05 y 8.37; 95 percent CI 1.86-37.64, respectively). Conclusions: Subjects that carry the m2 allelic variant of CYP1A1 and are exposed to tobacco smoke or alcohol have a significantly higher risk of developing gastric cancer.

Smoking increases dna damage in male infertile patients in Egypt

Environmental factors, have been shown to have a deleterious effect on spermatogenesis. Cigarette smoking is a major source of environmental pollution. Many studies have suggested that cigarette smoking is associated with altered semen quality, but conclusions about the extent of the deleterious effects vary widely. Sperm nuclear chromatin abnormalities /DNA damage could occur at the time of, or be the result of, DNA packing at spermatogenesis. Environmental stress, gene mutations, and chromosomal abnormalities can disturb the highly refined biochemical events that occur during spermatogenesis. This can ultimately lead to an abnormal chromatin structure that is incompatible with fertility. However, the exact mechanism by which chromatin abnormalities/DNA damage arise in human spermatozoa are not precisely understood. We have conducted a study on 50 infertile males, of whom 25 are smokers, to assess the degree of sperm DNA damage using the COMET assay and correlate our findings with other semen parameters. Conclusion: In the present study, the percentage of severe DNA fragmentation was significantly higher in smoker infertile group compared to no smokers and control groups

Modulatory effects of different doses of alpha-tocopherol on benzo(a)pyrene-DNA adduct formation in the pulmonary tissue of cigarette smoke inhaling mice.

Cigarette smoke (CS) has been established as one of the major risk factors for many pathologies including lung cancer in humans and experimental animals. In view of the discrepancy about the role of alpha-tocopherol (AT) in carcinogenesis, the present study was designed to investigate the effects of different doses of AT on benzo(a)pyrene-DNA [B(a)P-DNA] adduct formation in lungs of CS inhaling mice. Extent of carcinogen-DNA adduct formation has been considered as an index for carcinogenesis. Feeding of 35 IU AT/kg body weight increased B(a)P-DNA adducts formation significantly whereas feeding of 5 IU AT/kg body weight did not altered much the B(a)P-DNA adduct levels when both were compared to the control counterparts. With CS inhalation, the B(a)P-DNA adducts formation increased in all the groups when compared to their respective sham counterparts. Interestingly, in CS exposed groups, there was least increase in B(a)P-DNA adducts formation in 5 IU AT/kg fed animals followed by the control and 35 IU AT/kg body weight fed groups respectively. The results suggest that higher doses of AT accentuate DNA adduct formation in CS inhaling mice.

Surfactant protein B 1580 polymorphism is associated with susceptibility to chronic obstructive pulmonary disease in Chinese Han population / 华中科技大学学报（医学）（英德文版）

Whether surfactant protein B (SP-B)-18A/C and 1580C/T polymorphism were associated with susceptibility to chronic obstructive pulmonary disease (COPD) in Chinese Han population was investigated. After genomic DNA was isolated from blood of COPD smokers and control smokers, the genotypes of SP-B-18A/C and SP-B1580C/T polymorphism loci were determined by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) respectively. The results showed that there was significant difference in genotypes distribution frequency of SP-B1580C/T polymorphism locus between COPD smokers and control smokers. C-->T mutation rate (including TT homozygote and CT heterozygote) in COPD smokers was higher than in control smokers (57.9% vs 41.7%, chi2 = 4.93, P<0.05), whereas there was no significant difference in genotypes distribution frequency of SP-B1580-18A/C locus between COPD smokers and control smokers. The allele frequency (29.1%) of SP-B1580-18A/C locus is lower than T allele (70.9%) in Chinese Han Population, and the distribution was different from that in Mexican, in which, the A and T allele frequencies were 85% and 15% respectively. It was concluded that SP-B1580 T allele was probably associated with increased susceptibility to COPD in Chinese Han population; The polymorphism of SP-B-18A/C locus maybe varied with race.

El impacto del tabaquismo sobre el riñón y el aparato genitourinario / The impact of smoking on the kidney and genitourinary system

El tabaquismo tiene múltiples efectos sobre el aparato genitourinario. El más conocido es su efecto carcinogénico, pues es una causa importante de cáncer de riñón, vejiga, pelvis renal y ureteros. Los agentes causales son las aminas aromáticas del tabaco, y parece existir una susceptibilidad variable a estas sustancias que depende del genotipo de cada persona. En el sexo masculino el tabaquismo se ha relacionado con la impotencia sexual, infertilidad, desbalances hormonales y teratogenicidad. También se han observado alteraciones en el control del balance de agua, así como un mayor deterioro de algunos padecimientos glomerulares