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Genetic polymorphisms and susceptibility to lung disease
Pauline L Lee, Carol West, Karen Crain, Lei Wang
Journal of Negative Results in BioMedicine , 2006, DOI: 10.1186/1477-5751-5-5
Abstract: Since October 2001, when Bacillus anthracis was released in the United States as an act of bioterrorism, there has been a greater interest in determining if there are risk factors for inhalation anthrax infection. Exposure to Bacillus anthracis spores does not cause infection in all exposed individuals [1]. Epidemiologic studies of individuals infected by inhalation anthrax have suggested that a weakened immune system might increase susceptibility to infection by Bacillus anthracis [2]. Some of the infected individuals had a history of chronic pulmonary disease, including asthma, sarcoidosis, and tuberculosis [2-4]. Studies in mice have demonstrated a genetic basis for anthrax sensitivity [5,6]. For example, macrophages from C3H mice are 100,000 times more sensitive to the Bacillus anthracis toxin than macrophages from A/J mice [6]. The current study examines whether there are genetic polymorphisms in humans associated with increased susceptibility to lung disease. Identification of genes associated with an increased risk of lung disease might identify individuals who might also be of increased susceptibility to inhalation anthrax infection.The NAD(P)H oxidases (NOX) are a family of enzymes that are essential in host defense against microbial infection, as reviewed by Quinn and Gauss [7]. The central enzyme of the NAD(P)H oxidase is a flavin and heme-containing protein, the most well known being the phagocytic gp91phox (CYBB, NOX2) protein. gp91phox, and a number of related proteins including DUOX1 and DUOX2, are transmembrane proteins which transport electrons and generate reactive oxygen species (ROS) at the expense of NADH or NADPH. The activity of the oxidases are highly regulated by accessory proteins, including p22phox (CYBA), p47phox (NOXO1, NCF1), p67phox (NOXA2, NCF2), and p40phox (NCF4). Chronic Granulomatous Disease (CGD), associated with severe, recurrent, and chronic non-specific bacterial and fungal infections, is most commonly caused by mutations in p
Genetic polymorphisms in lung disease: bandwagon or breakthrough?
Michael C Iannuzzi, Mary Maliarik, Benjamin Rybicki
Respiratory Research , 2002, DOI: 10.1186/rr164
Abstract: Genetic polymorphisms are defined as variations in DNA that are observed in 1% or more of the population. Genetic polymorphisms may alter protein structure and function through a single nucleotide base substitution in a gene's coding region, and may increase or decrease gene expression either by affecting mRNA stability when occurring in a gene's 3′ untranslated region or by altering transcription factor binding when occurring in the 5′ promoter region. Alternatively, a polymorphism may have no discernable effect on the protein product and may lie within DNA regions that are not involved in gene transcription or translation. Polymorphisms that exist in these regions as variations in repeat sequences throughout the genome have served the basis for genetic linkage analysis [1].The study of genetic polymorphisms promises to help define pathophysiologic mechanisms, to identify individuals at risk for disease and to suggest novel targets for drug treatment. The methodology to study polymorphisms is simple, requiring only access to a polymerase chain reaction machine, funding for reagents, and DNA samples from cases and controls (Fig. 1 illustrates the methods used to detect polymorphisms). The seemingly unlimited potential of genetics to help predict who will get lung disease or who, once diagnosed with disease, will have an unfavorable prognosis has inspired many investigators to jump on the bandwagon of studying genetic polymorphisms. While progress in understanding and treating pulmonary diseases has occurred through investigating genetic polymorphisms, the limitations and potential pitfalls of this approach may be under-appreciated.Polymorphisms are most often assessed as contributing to disease susceptibility or progression using association studies [2]. We will thus focus on factors affecting the quality of association study design. To identify susceptibility loci, association studies involve typing a genetic polymorphism in unrelated affected individuals and in a
Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population
Lian-Hua Cui, Min-Ho Shin, Hee Kim, Hye-Rim Song, Jin-Mei Piao, Sun-Seog Kweon, Jin-Su Choi, Woo-Jun Yun, Young-Chul Kim, In-Jae Oh, Kyu-Sik Kim
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-28
Abstract: We conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung cancer and 1700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. Statistical significance was estimated by logistic regression analysis.The MTHFR C677T frequencies of CC, CT, and TT genotypes were 34.5%, 48.5%, and 17% among lung cancer patients, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677CT and TT genotype showed a weak protection against lung cancer compared with the homozygous CC genotype, although the results did not reach statistical significance. The age- and gender-adjusted odds ratio (OR) of overall lung cancer was 0.90 (95% confidence interval (CI), 0.77-1.04) for MTHFR 677 CT and 0.88 (95% CI, 0.71-1.07) for MTHFR 677TT. However, after stratification analysis by histological type, the MTHFR 677CT genotype showed a significantly decreased risk for squamous cell carcinoma (age- and gender-adjusted OR, 0.78; 95% CI, 0.64-0.96). The combination of 677 TT homozygous with 677 CT heterozygous also appeared to have a protection effect on the risk of squamous cell carcinoma. We observed no significant interaction between the MTHFR C677T polymorphism and age and gender or smoking habit.This is the first reported study focusing on the association between MTHFR C677T polymorphisms and the risk of lung cancer in a Korean population. The T allele was found to provide a weak protective association with lung squamous cell carcinoma.Lung cancer is the leading cause of cancer-related death worldwide. The incidence and mortality of lung cancer have been significantly and constantly increasing over the past two decades in Korea [1-3]. According to the Korean National Cancer Registry, the age-standardized incidence rate for lung cancer of Korean population was 47.5/100,000 for men and 13.3/100,000 for women in 2007 [2], it has become the second most common malignant tumor following gastric cancer. The r
Genetic Association of NPY Gene Polymorphisms with Dampness-Phlegm Pattern in Korean Stroke Patients
Mi Mi Ko,Byoung Kab Kang,Ji Hye Lim,Myeong Soo Lee,Min Ho Cha
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/109796
Abstract: Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in a variety of biological fields. In this study, we analyzed the distribution of NPY polymorphisms in dampness-phlegm pattern and non-dampness-phlegm pattern in elderly Korean subjects with cerebral infarction (CI). A total of 1.097 subjects (498 normal subjects and 599 CI patients, including 198 with dampness-phlegm pattern and 401 with non-dampness-phlegm pattern) participated in this study. Genotyping for five SNPs (G-1484A, C-1471T, C-399T, A1201G, and C5325T) was conducted by primer extension. The results were statistically analyzed for genetic association of NPY-polymorphisms with normal versus dampness-phlegm pattern or non-dampness-phlegm pattern subjects. Among the five SNPs tested, the T allele of C-399T has a negative association with the dampness-phlegm pattern and is marked by a decrease in serum cholesterol levels. Furthermore, serum cholesterol levels were significantly higher in dampness-phlegm pattern patients than in non-dampness-phlegm pattern patients.In this study, for the first time, the association of NPY polymorphisms with pattern identification (PI) of traditional Korean medicine (TKM) was analyzed in a large CI patient population.
Genetic polymorphisms in MMP 2, 9 and 3 genes modify lung cancer risk and survival
Patricia González-Arriaga, Teresa Pascual, Arturo García-Alvarez, Ana Fernández-Somoano, M Felicitas López-Cima, Adonina Tardón
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-121
Abstract: The case-control study includes 879 lung cancer patients and 803 controls from a Caucasian population in Spain (CAPUA study). Genotypes were determined by PCR-RFLP. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. The Kaplan-Meier method, long-rank test and Cox's were used for the survival analysis.The MMP9 -1562 T/T genotype was associated with a statistically significant decreased risk of developing lung cancer (OR = 0.23; 95% CI: 0.06-0.85), whereas no association was found for the MMP2 -735 C/T and MMP3 -1171 5A/6A polymorphisms. The MMP2 -735 T/T genotype was statistically significantly associated with a decreased survival in non-small cell lung cancer (NSCLC) patients, identified as an independent prognosis factor of survival (hazard ratio (HR) = 1.79; 95% CI: 1.00-3.20). In contrast, no association was found between the MMP3 -1171 5A/6A and the MMP9 -1562 C/T polymorphisms and survival.These findings support the hypothesis that the MMP9 -1562 C/T polymorphism is associated with a protective effect against the development of lung cancer and suggest that the MMP2 -735 C/T polymorphism modify the length of survival in NSCLC patients.Lung cancer is one of the leading causes of death worldwide. Approximately one million people, 850,000 men and 330,000 women [1], die from lung cancer per year. In Spain, lung cancer caused more than 20,000 deaths in 2008; of these, 17,135 were men, and 3,035 were women [2]. Despite some advances in the diagnosis and treatment of lung cancer in the last several decades, the prognosis of lung cancer remains poor. The 5-year overall survival rate of lung cancer is approximately 12% in Spain and < 9% in developing countries [3]. The discovery and application of specific prognostic biomarkers could improve the survival rate of lung cancer [4]. Although some efforts have been made in this field [5-9], stable biomarkers for both risk assessment and clinical outcome predictors of lu
Synergistic Association of PTGS2 and CYP2E1 Genetic Polymorphisms with Lung Cancer Risk in Northeastern Chinese  [PDF]
Shujie Guo, Xiaobo Li, Min Gao, Hong Kong, Yuqiong Li, Mingliang Gu, Xiaoqun Dong, Wenquan Niu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039814
Abstract: Background Lung cancer is the most common cause of cancer-related deaths worldwide. The aim of this study was to investigate the association of five extensively-studied polymorphisms in PTGS2 (rs689466, rs5275, rs20417) and CYP2E1 (rs2031920, rs6413432) genes with lung cancer risk in a large northeastern Chinese population. Methodology/Principal Findings This is a hospital-based case-control study involving 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR method. Data were analyzed using Haplo.stats and MDR programs. There were significant differences between patients and controls in allele/genotype distributions of rs5275 (P = 0.002/0.003) and rs6413432 (P = 0.037/0.044), as well as in genotype distributions of rs689466 (P = 0.02). The risk for lung cancer associated with the rs5275-C mutant allele was decreased by 60% (95% CI [confidence interval]: 0.21–0.74; P = 0.004) under the recessive model. Carriers of rs689466-G mutant allele had a 28% (95% CI: 0.57–0.92; P = 0.008) reduced risk of developing lung cancer relative to the AA genotype carriers. In haplotype analysis, haplotype G-C-C-T (in order of rs689466, rs5275, rs2031920 and rs6413432) decreased the odds of lung cancer by 28% (95% CI: 0.51–0.93; P = 0.019) after adjusting for confounding factors, whereas haplotype A-T-T-T had 1.49-fold (95% CI: 1.21–1.79; P = 0.012) increased risk for lung cancer. Using MDR method, the overall best model including rs5275, rs689466 and rs6413432 polymorphisms was identified with a maximal testing accuracy of 66.1% and a maximal cross-validation consistency of 10 out of 10 (P = 0.003). Conclusions/Significance Our findings demonstrated a potentially synergistic association of PTGS2 and CYP2E1 polymorphisms with the underlying cause of lung cancer in northeastern Chinese.
The Associations between Two Vital GSTs Genetic Polymorphisms and Lung Cancer Risk in the Chinese Population: Evidence from 71 Studies  [PDF]
Kui Liu, Xialu Lin, Qi Zhou, Ting Ma, Liyuan Han, Guochuan Mao, Jian Chen, Xia Yue, Huiqin Wang, Lu Zhang, Guixiu Jin, Jianmin Jiang, Jinshun Zhao, Baobo Zou
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0102372
Abstract: Background The genetic polymorphisms of glutathione S-transferase (GSTs) have been suspected to be related to the development of lung cancer while the current results are conflicting, especially in the Chinese population. Methods Data on genetic polymorphisms of glutathione S-transferase Mu 1 (GSTM1) from 68 studies, glutathione S-transferase theta 1 (GSTT1) from 17 studies and GSTM1-GSTT1 from 8 studies in the Chinese population were reanalyzed on their association with lung cancer risk. Odds ratios (OR) were pooled using forest plots. 9 subgroups were all or partly performed in the subgroup analyses. The Galbraith plot was used to identify the heterogeneous records. Potential publication biases were detected by Begg's and Egger's tests. Results 71 eligible studies were identified after screening of 1608 articles. The increased association between two vital GSTs genetic polymorphisms and lung cancer risk was detected by random-effects model based on a comparable heterogeneity. Subgroup analysis showed a significant relationship between squamous carcinoma (SC), adenocarcinoma (AC) or small cell lung carcinoma (SCLC) and GSTM1 null genotype, as well as SC or AC and GSTT1 null genotype. Additionally, smokers with GSTM1 null genotype had a higher lung cancer risk than non-smokers. Our cumulative meta-analysis demonstrated a stable and reliable result of the relationship between GSTM1 null genotype and lung cancer risk. After the possible heterogeneous articles were omitted, the adjusted risk of GSTs and lung cancer susceptibility increased (fixed-effects model: ORGSTM1 = 1.23, 95% CI: 1.19 to 1.27, P<0.001; ORGSTT1 = 1.18, 95% CI: 1.10 to 1.26, P<0.001; ORGSTM1-GSTT1 = 1.33, 95% CI: 1.10 to 1.61, P = 0.004). Conclusions An increased risk of lung cancer with GSTM1 and GSTT1 null genotype, especially with dual null genotype, was found in the Chinese population. In addition, special histopathological classification of lung cancers and a wide range of gene-environment and gene-gene interaction analysis should be taken into consideration in future studies.
CYP1A1 m1 and m2 polymorphisms: genetic susceptibility to lung cancer
Mota,Paula; Moura,David Silva; Vale,Maria Gra?a; Coimbra,Henriqueta; Carvalho,Lina; Regateiro,Fernando;
Revista Portuguesa de Pneumologia , 2010,
Abstract: lung cancer is considered an environment-related disease that develops as a consequence of exposure to mutagenic agents, namely those present in tobacco. the cyp1a1 gene codifies the phase i enzyme aryl hydrocarbon hydroxilase (ahh) belonging to the cytochrome p450 system that plays a major role in the bio-activation of tobacco procarcinogenes. two cyp1a1 polymorphisms, m1 (t6235c transition) and m2 (a4889g transition), are associated with greater enzymatic activity and have been described as genetic susceptibility factors for lung cancer. the aim of this study was to verify if this association holds true in blood samples of 175 lung cancer patients and 217 non-cancer patients from portugal?s midlands region. the samples were studied by restriction fragment length polymorphism (rflp) assay. the allelic frequencies of the mutant alleles were 0.12 for allele c and 1.14 for allele g in the control population. the results were not statistically different from those alleles in the patient population. there was also no statistically significant difference in genotype distribution in lung cancer patients and controls even when combining high risk genotypes. in our control sample, as in other populations of different ethnic origin, both polymorphisms also seem to be in linkage disequilibrium. we conclude that in this sample of the portuguese population, cyp1a1 m1 and m2 polymorphisms are too rare to be of clinical relevance, and do not seem to be associated with susceptibility to lung cancer.
Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk: A meta-analysis
Chikako Kiyohara, Kouichi Yoshimasu
International Journal of Medical Sciences , 2007,
Abstract: Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, can result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent lung cancer studies have focused on identifying the effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly being studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide excision repair pathway genes, focusing on xeroderma pigmentosum group A (XPA), excision repair cross complementing group 1 (ERCC1), ERCC2/XPD, ERCC4/XPF and ERCC5/XPG. We found an increased risk of lung cancer among subjects carrying the ERCC2 751Gln/Gln genotype (odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.14 - 1.49). We found a protective effect of the XPA 23G/G genotype (OR = 0.75, 95% CI = 0.59 - 0.95). Considering the data available, it can be conjectured that if there is any risk association between a single SNP and lung cancer, the risk fluctuation will probably be minimal. Advances in the identification of new polymorphisms and in high-throughput genotyping techniques will facilitate the analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples.
Significant association of SREBP-2 genetic polymorphisms with avascular necrosis in the Korean population
Tae-Ho Kim, Jeong-In Baek, Jung Hong, Su-Jin Choi, Hye-Jin Lee, Hyun-Ju Cho, Eui Park, Un-Kyung Kim, Shin-Yoon Kim
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-94
Abstract: Four single nucleotide polymorphisms (SNP) in the SREBP-2 gene, IVS1+8408 T>C (rs2267439), IVS3-342 G>T (rs2269657), IVS11+414 G>A (rs1052717) and IVS12-1667 G>A (rs2267443), were selected from public databases and genotyped in 443 AVN patients and 273 control subjects by using single-based extension (SBE) genotyping.The minor allele (C) frequency of rs2267439 showed a significant protective effect on AVN (P = 0.01, OR; 0.75, 95% CI; 0.604–0.935), and the genotype frequencies of this polymorphism were also different from the controls in all alternative analysis models (P range, 0.009–0.03, OR; 0.647–0.744). In contrast, rs1052717 and rs2267443 polymorphisms were significantly associated with AVN risk. Further analysis based on pathological etiology showed that the genotypes of rs2267439, rs1052717 and rs2267443 were also significantly associated with AVN susceptibility in each subgroup.This study is the first report to evaluate the association between SREBP-2 gene polymorphisms and the susceptibility of AVN in the Korean population.Avascular necrosis (AVN), also known as osteonecrosis of the femoral head (ONFH), is a devastating bone disease that develops symptoms of articular destruction and bone collapse of the femoral head due to a disturbance in the supply of blood [1]. This disease mainly occurs in middle aged men, between 30 and 50 years of age. The pathogenic factor of AVN is not definite, but many previous studies have suggested that long term steroid usage [1-5] and alcohol abuse [6,7] are associated with AVN, and in some case it can also be idiopathic. These factors have a harmful influence on oxygen and nutrient supply to the bone through blood vessels in direct or indirect pathways. Steroid administration and alcohol abuse induce an increase of fatty vesicles in the circulation of the blood, causing fat embolism and increased lipid precipitation in osteocytes within the femoral head. Some previous experiments using animal models verified that alcohol fac
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