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1.  GSTM1 null genotype in COPD and lung cancer: evidence of a modifier or confounding effect? 
Studies over the past two decades have reported associations between GSTM1 (glutathione S-transferase mu 1) null genotype and chronic obstructive pulmonary disease (COPD) or lung cancer. However, a modifier or confounding effect from COPD mediating the GSTM1 association with lung cancer has not been previously explored.
Aim and methods
This variant was examined in a case-control study of current or former smokers with COPD (n = 669), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups.
The GSTM1 null genotype was found to be more frequent in smokers with COPD alone (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.02–1.66, P = 0.031) and lung cancer (OR 1.26, 95% CI 0.96–1.65, P = 0.083) than in matched smokers with normal lung function (62%, 61%, and 56%, respectively). However, when smokers with lung cancer were subgrouped according to the presence of COPD, then the association with all COPD subjects (OR 1.34, 95% CI 1.07–1.70, P = 0.010) and with COPD and lung cancer (OR 1.50, 95% CI 1.06–2.12, P = 0.018) continued to be significant while that with lung cancer only was reduced (OR 1.11, 95% CI 0.78–1.56, P = 0.55). These associations were independent of age, sex, height, lung function, and smoking history.
Findings suggest that COPD is an important subphenotype of lung cancer and may underlie previously reported associations with the GSTM1 null genotype.
PMCID: PMC3681185  PMID: 23776374
lung cancer; chronic obstructive pulmonary disease; GSTM1; association study; polymorphism; copy number variant
2.  Individual and Cumulative Effects of GWAS Susceptibility Loci in Lung Cancer: Associations after Sub-Phenotyping for COPD 
PLoS ONE  2011;6(2):e16476.
Epidemiological studies show that approximately 20–30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10–15% develop lung cancer. COPD pre-exists lung cancer in 50–90% of cases and has a heritability of 40–77%, much greater than for lung cancer with heritability of 15–25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV1, appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV1 is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the “risk genotypes” derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.
PMCID: PMC3033394  PMID: 21304900
3.  FAM13A locus in COPD is independently associated with lung cancer – evidence of a molecular genetic link between COPD and lung cancer 
Recent genome-wide association studies have reported a FAM13A variant on chromosome 4q22.1 is associated with lung function and COPD. We examined this variant in a case-control study of current or former smokers with chronic obstructive pulmonary disease (COPD, n = 458), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. We confirmed the FAM13A variant (rs7671167) confers a protective effect on smoking-related COPD alone (C allele odds ratio [OR] = 0.79, P = 0.013, and CC genotype OR = 0.71, P = 0.024) and those with COPD, both with and without lung cancer (C allele OR = 0.80, P = 0.008, and CC genotype OR = 0.70, P = 0.007). The FAM13A variant also confers a protective effect on lung cancer overall (C allele OR = 0.75, P = 0.002, and CC genotype OR = 0.64, P = 0.003) even after excluding those with co-existing COPD (C allele OR = 0.67, P = 0.0007, and CC genotype OR = 0.58, P = 0.006). This was independent of age, sex, height, lung function, and smoking history. This protective effect was confined to those with nonsmall cell lung cancer (C allele OR = 0.72, P = 0.0009, and CC genotype OR = 0.61, P = 0.003). This study suggests that genetic predisposition to COPD is shared with lung cancer through shared pathogenetic factors such as the 4q22.1 locus implicating the Rho-kinase pathway.
PMCID: PMC3681173  PMID: 23776362
lung cancer; chronic obstructive pulmonary disease; FAM13A; association study; polymorphism; GTPase
4.  Lung Cancer Susceptibility Model Based on Age, Family History and Genetic Variants 
PLoS ONE  2009;4(4):e5302.
Epidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer.
Methodology/Principal Findings
We screened 157 candidate single nucleotide polymorphisms (SNP) in a discovery cohort of 439 subjects (200 controls and 239 lung cancer cases) and identified 30 SNPs associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping this 30 SNP panel in a validation cohort of 491 subjects (248 controls and 207 lung cancers) and, using the same protective and susceptibility genotypes from our discovery cohort, a 20 SNP panel was selected based on replication of SNP associations in the validation cohort. Following multivariate logistic regression analyses, including the selected SNPs from runs 1 and 2, we found age and family history of lung cancer to be significantly and independently associated with lung cancer. Numeric scores were assigned to both the SNP and demographic data, and combined to form a simple algorithm of risk.
Significant differences in the distribution of the lung cancer susceptibility score was found between normal controls and lung cancer cases, which remained after accounting for differences in lung function. Validation in other case-control and prospective cohorts are underway to further define the potential clinical utility of this model.
PMCID: PMC2668761  PMID: 19390575

Results 1-4 (4)