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1.  Symptom Clusters of Pain, Depressed Mood, and Fatigue in Lung Cancer: Assessing the Role of Cytokine Genes 
Symptom clusters, the multiple, co-occurring symptoms experienced by cancer patients, are debilitating and affects quality of life. We assessed if a panel of immune-response genes may underlie the co-occurrence of severe pain, depressed mood and fatigue and help identify patients with severe versus non-severe symptom clusters.
Symptoms were assessed at presentation, prior to cancer treatment in 599 newly diagnosed lung cancer patients. We applied cluster analyses to determine the patients with severe versus non-severe symptom clusters of pain, depressed mood, and fatigue.
Two homogenous clusters were identified. One hundred sixteen patients (19%) comprised the severe symptom cluster, reporting high intensity of pain, depressed mood and fatigue and 183 (30%) patients reported low intensity of these symptoms. Using Bayesian model averaging methodology, we found that of the 55 SNPs assessed, an additive effect of mutant alleles in ENOS (-1474 T/A) (Posterior Probability of Inclusion (PPI) = 0.78, OR = 0.54, 95% CI = (0.31, 0.93); IL1B T-31C (PPI = 0.72, OR = 0.55, 95% CI = (0.31, 0.97)); TNFR2 Met196Arg (PPI = 0.70; OR=1.85;95%CI=(1.03,3.36)); PTGS2 exon 10+837T>C (PPI = 0.69, OR = 0.54, 95%CI = (0.28, 0.99)); and IL10RB Lys47Glu (PPI = 0.68; OR=1.74; 95%CI=(1.04,2.92)) were predictive for symptom clusters.
Genetic polymorphisms may facilitate identification of high risk patients and development of individualized symptom therapies.
PMCID: PMC3923575  PMID: 23852407
pain; depression; fatigue; cytokines; symptoms; genes; epidemiology; lung cancer; SNPs
2.  Sensation seeking genes and physical activity in youth 
Genes, brain, and behavior  2012;12(2):181-188.
Many studies examining genetic influences on physical activity (PA) have evaluated the impact of single nucleotide polymorphisms (SNPs) related to the development of lifestyle-related chronic diseases, under the hypothesis that they would be associated with PA. However, PA is a multi-determined behavior and associated with a multitude of health consequences. Thus, examining a broader range of candidate genes associated with a boarder range of PA correlates may provide new insights into the genetic underpinnings of PA. In this study we focus on one such correlate – sensation seeking behavior. Participants (N=1,130 Mexican origin youth) provided a saliva sample and data on PA and sensation seeking tendencies in 2008–09. Participants were genotyped for 630 functional and tagging variants in the dopamine, serotonin, and cannabinoid pathways. Overall 30% of participants (males – 37.6%; females – 22.0%) reported ≥60 minutes of PA on five out of seven days. After adjusting for gender, age and population stratification, and applying the Bayesian False Discovery Probability approach for assessing noteworthiness, four gene variants were significantly associated with PA. In a multivariable model, being male, having higher sensation seeking tendencies and at least one copy of the minor allele for SNPs in ACE (rs8066276 OR=1.44; p=0.012) and TPH2 (rs11615016 OR=1.73; p=0.021) were associated with increased likelihood of meeting PA recommendations. Participants with at least one copy of the minor allele for SNPs in SNAP25 (rs363035 OR=0.53; p=0.005) and CNR1 (rs6454672 OR=0.62; p=0.022) have decreased likelihood of meeting PA recommendations. Our findings extend current knowledge of the complex relationship between PA and possible genetic underpinnings.
PMCID: PMC3581711  PMID: 23190435
Physical Activity; Genes; Sensation Seeking; Mexican origin youth
3.  Genetic Variants on 15q25.1, Smoking, and Lung Cancer: An Assessment of Mediation and Interaction 
American Journal of Epidemiology  2012;175(10):1013-1020.
Genome-wide association studies have identified variants on chromosome 15q25.1 that increase the risks of both lung cancer and nicotine dependence and associated smoking behavior. However, there remains debate as to whether the association with lung cancer is direct or is mediated by pathways related to smoking behavior. Here, the authors apply a novel method for mediation analysis, allowing for gene-environment interaction, to a lung cancer case-control study (1992–2004) conducted at Massachusetts General Hospital using 2 single nucleotide polymorphisms, rs8034191 and rs1051730, on 15q25.1. The results are validated using data from 3 other lung cancer studies. Tests for additive interaction (P = 2 × 10−10 and P = 1 × 10−9) and multiplicative interaction (P = 0.01 and P = 0.01) were significant. Pooled analyses yielded a direct-effect odds ratio of 1.26 (95% confidence interval (CI): 1.19, 1.33; P = 2 × 10−15) for rs8034191 and an indirect-effect odds ratio of 1.01 (95% CI: 1.00, 1.01; P = 0.09); the proportion of increased risk mediated by smoking was 3.2%. For rs1051730, direct- and indirect-effect odds ratios were 1.26 (95% CI: 1.19, 1.33; P = 1 × 10−15) and 1.00 (95% CI: 0.99, 1.01; P = 0.22), respectively, with a proportion mediated of 2.3%. Adjustment for measurement error in smoking behavior allowing up to 75% measurement error increased the proportions mediated to 12.5% and 9.2%, respectively. These analyses indicate that the association of the variants with lung cancer operates primarily through other pathways.
PMCID: PMC3353137  PMID: 22306564
gene-environment interaction; lung neoplasms; mediation; pathway analysis; smoking
4.  Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer 
PLoS ONE  2013;8(1):e53475.
Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions.
We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status.
Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers.
This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk.
PMCID: PMC3553105  PMID: 23372658
5.  Cigarette Experimentation and the Population Attributable Fraction for Associated Genetic and Non-Genetic Risk Factors 
PLoS ONE  2013;8(1):e53868.
We, and others, have shown that experimenting with cigarettes is a function of both non-genetic and genetic factors. In this analysis we ask: how much of the total risk of experimenting with cigarettes, among those who had not experimented with cigarettes when they enrolled in a prospective cohort, is attributable to genetic factors and to non-genetic factors?
Participants (N = 1,118 Mexican origin youth), recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Non-genetic data were elicited twice – baseline and follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways.
In the overall model, the adjusted combined non-genetic PAF was 71.2% and the adjusted combined genetic PAF was 58.5%. Among committed never smokers the adjusted combined non-genetic PAF was 67.0% and the adjusted combined genetic PAF was 53.5%. However, among cognitively susceptible youth, the adjusted combined non-genetic PAF was 52.0% and the adjusted combined genetic PAF was 68.4%.
Our results suggest there may be differences in genotypes between youth who think they will try cigarettes in the future compared to their peers who think they will not and underscore the possibility that the relative influence of genetic vs. non-genetic factors on the uptake of smoking may vary between these two groups of youth.
A clearer understanding of the relative role of genetic vs. non-genetic factors in the uptake of smoking may have implications for the design of prevention programs.
PMCID: PMC3547034  PMID: 23342024
6.  Cigarette Experimentation in Mexican Origin Youth: Psychosocial and Genetic Determinants 
Established psychosocial risk factors increase the risk for experimentation among Mexican-origin youth. Now we comprehensively investigate the added contribution of select polymorphisms in candidate genetic pathways associated with sensation seeking, risk taking, and smoking phenotypes to predict experimentation.
Participants, (N=1,118 Mexican origin youth) recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Psychosocial data were elicited twice—baseline and final follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways.
After adjusting for gender and age, with a Bayesian False Discovery Probability set at 0.8 and prior probability of 0.05, six gene variants were significantly associated with risk of experimentation. After controlling for established risk factors, multivariable analyses revealed that participants with six or more risk alleles were 2.25 (95%CI: 1.62–3.13) times more likely to have experimented since baseline compared to participants with five or fewer. Among committed never smokers (N=872), three genes (OPRM1, SNAP25, HTR1B) were associated with experimentation as were all psychosocial factors. Among susceptible youth (N=246) older age at baseline, living with a smoker, and three different genes (HTR2A, DRD2, SLC6A3) predicted experimentation.
Our findings, which have implications for development of culturally-specific interventions, need to be validated in other ethnic groups.
These results suggest that variations in select genes interact with a cognitive predisposition toward smoking. In susceptible adolescents, the impact of the genetic variants appears to be larger compared to committed never smokers.
PMCID: PMC3382046  PMID: 22028400
7.  Method for Evaluating Multiple Mediators: Mediating Effects of Smoking and COPD on the Association between the CHRNA5-A3 Variant and Lung Cancer Risk 
PLoS ONE  2012;7(10):e47705.
A mediation model explores the direct and indirect effects between an independent variable and a dependent variable by including other variables (or mediators). Mediation analysis has recently been used to dissect the direct and indirect effects of genetic variants on complex diseases using case-control studies. However, bias could arise in the estimations of the genetic variant-mediator association because the presence or absence of the mediator in the study samples is not sampled following the principles of case-control study design. In this case, the mediation analysis using data from case-control studies might lead to biased estimates of coefficients and indirect effects. In this article, we investigated a multiple-mediation model involving a three-path mediating effect through two mediators using case-control study data. We propose an approach to correct bias in coefficients and provide accurate estimates of the specific indirect effects. Our approach can also be used when the original case-control study is frequency matched on one of the mediators. We employed bootstrapping to assess the significance of indirect effects. We conducted simulation studies to investigate the performance of the proposed approach, and showed that it provides more accurate estimates of the indirect effects as well as the percent mediated than standard regressions. We then applied this approach to study the mediating effects of both smoking and chronic obstructive pulmonary disease (COPD) on the association between the CHRNA5-A3 gene locus and lung cancer risk using data from a lung cancer case-control study. The results showed that the genetic variant influences lung cancer risk indirectly through all three different pathways. The percent of genetic association mediated was 18.3% through smoking alone, 30.2% through COPD alone, and 20.6% through the path including both smoking and COPD, and the total genetic variant-lung cancer association explained by the two mediators was 69.1%.
PMCID: PMC3471886  PMID: 23077662
8.  The Influence of Tumor Necrosis Factor-α –308 G/A and IL-6 –174 G/C on Pain and Analgesia Response in Lung Cancer Patients Receiving Supportive Care 
We previously showed that select cytokine gene polymorphisms are a significant predictor for pain reported at initial presentation in 446 white patients newly diagnosed with non–small cell lung cancer. This follow-up study explores the extent to which polymorphisms in tumor necrosis factor-α (TNF- α-308 G/A), interleukin (IL)-6 −174G/C, and IL-8 −251T/A could explain variability in pain and analgesic response among those patients (n = 140) subsequently referred for pain treatment.
Pain severity (0, no pain; 10, worst pain) was assessed at initial consultation and at follow-up visit. The total dose of opioids at the time of first-follow up visit (30 days postconsult) was converted to an equivalent dose of parenteral morphine.
Forty-one percent (57 of 140) of the patients reported severe pain (score >7/10) at initial consultation (mean, 5.5), which significantly decreased to 25% (mean, 4) at first follow-up visit (McNemar = P < 0.001). Polymorphisms in TNF and IL-6 were significantly associated with pain severity (for TNF GG, 4.12; GA, 5.38; AA, 5.50; P = 0.04) and with morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P = 0.004), respectively. Adjusting for demographic and clinical variables, variant alleles in TNFα −308 G/A remained significantly associated with pain severity (b = 0.226; P = 0.036) and carriers of the IL-6 −174C/C genotypes required 4.7 times higher dose of opioids for pain relief (odds ratio, 4.7; 95% confidence interval, 1.2;15.0) relative to GG and GC genotypes.
We provide preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies.
PMCID: PMC3398799  PMID: 18990769
9.  Sensation seeking, risk behaviors and alcohol consumption among Mexican origin youth 
To examine factors associated with ever use of alcohol among Mexican origin youth.
Using a prospective study design, we followed 1053 Mexican origin adolescents. Participants completed two surveys in their homes and three follow-up telephone interviews, every six to eight months, in between. The second home survey was completed 30 months (SD=4.8 months) after baseline. Acculturation, subjective social status, and family cohesion were assessed at baseline and final home visit. Ever drinking, risk behaviors, and sensation seeking tendencies were assessed at the final home visit only.
Overall, 30% of the study participants reported ever drinking alcohol. Multivariate models revealed that being female, increasing age, lower levels of acculturation, family cohesion and subjective social status, higher sensation seeking tendencies and concomitantly engaging in three or four other risk behaviors were associated with ever drinking. Also, social disinhibition, an aspect of sensation seeking, mediated the relationship between engaging in other risk behaviors and alcohol use. This is consistent with previous research, suggesting that social disinhibition is a common factor that underlies the use of alcohol, tobacco, illicit drugs, and other problem behaviors.
The results of this study support taking a family-based approach to prevention that includes discussion of other risk behaviors, especially smoking, among Mexican origin youth. In addition, tailoring programs by gender, directly addressing both how changes in social norms resulting from acculturation can impact a youth’s decision to drink alcohol and underlying gender-based differences in why youth drink could improve the efficacy of preventive interventions.
PMCID: PMC3148938  PMID: 21185526
Cancer  2010;116(14):3458-3462.
Recent genome-wide association (GWA) studies of lung cancer have shown that the CHRNA5-A3 region on chromosome 15q24-25.1 is strongly associated with an increased risk of lung cancer and nicotine dependence, and thought to be associated with chronic obstructive airways disease as well. However, it has not been established whether the association between genetic variants and lung cancer risk is a direct one or one mediated by nicotine dependence.
In this paper we applied a rigorous statistical approach, mediation analysis, to examine the mediating effect of smoking behavior and self-reported physician-diagnosed emphysema (chronic obstructive pulmonary disease [COPD]) on the relationship between the CHRNA5-A3 region genetic variant rs1051730 and the risk of lung cancer.
Our results showed that rs1051730 is directly associated with lung cancer risk, but that it is also associated with lung cancer risk through its effect on both smoking behavior and COPD. Furthermore, we showed that COPD is a mediating phenotype that explains part of the effect of smoking behavior on lung cancer. Our results also suggested that smoking behavior is a mediator of the relationship between rs1051730 and COPD risk.
Smoking behavior and COPD are mediators of the association between the SNP rs1051730 and the risk of lung cancer. Also, COPD is a mediator of the association between smoking behavior and lung cancer. Finally, smoking behavior also has mediating effects on the association between the SNP and COPD.
PMCID: PMC3073819  PMID: 20564069
Lung Cancer; COPD; Mediation analysis; smoking behavior; genetic variants
11.  Exposure to Smoking Imagery in the Movies and Experimenting with Cigarettes among Mexican Heritage Youth 
There is growing evidence that an adolescent’s decision to try cigarettes is influenced by level of exposure to movies in which smoking is portrayed. Less is known about how ethnicity affects this process. We examined whether acculturation and/or country of birth influence the relationship between exposure to smoking imagery in the movies and experimenting with cigarettes among Mexican origin youth. We prospectively followed 1,328 Mexican origin adolescents aged 11–13 at baseline. We assessed which of 50 movies (randomly selected from a pool of 250 popular contemporary movies released from 1999–2004 and content analyzed for smoking) adolescents had seen. Smoking behavior was assessed at baseline and at 6-month intervals over 24 months. 10% of the adolescents had experimented at baseline; 17% tried subsequently. Multivariate analyses revealed, as exposure to smoking imagery in the movies increased, the chances of having ever experimented (AOR=1.27; 95% CI: 1.10–1.48) and of being a new experimenter (AOR=1.19; 95% CI: 1.01–1.40) increased, equivalent to a 4.2% increased risk of ever and a 3.0% increased risk of new experimenting for each additional quartile of movie exposure. This effect was moderated by country of birth. For Mexican-born youth, exposure to smoking imagery in the movies was the strongest independent predictor of new experimentation (AOR=1.52; 95% CI: 1.14–2.05). For US-born youth, we observed a ceiling effect: the percent of experimenters increased with increasing exposure, and then flattened. Among Mexican-born youth exposure to smoking imagery in the movies may be an important part of the acculturation process associated with smoking initiation.
PMCID: PMC2791895  PMID: 19959693
Experimenting with cigarettes; exposure to smoking imagery; Mexican origin youth
12.  Genetic and Non-Genetic Covariates of Pain Severity in Patients with Adenocarcinoma of the Pancreas: Assessing the Influence of Cytokine Genes 
We previously demonstrated that select cytokine gene polymorphisms in interleukin (IL)-8 are a significant predictor for pain and analgesia in patients with lung cancer. This study explores the role of thirteen potentially functional polymorphisms in cytokine genes including IL-1β, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor (TNF-α), and nuclear factor kappa-B subunit 1 (NFkappaB1) in pain severity in patients with pancreatic cancer. We evaluated a series opatients with histologically-confirmed adenocarcinoma of the pancreas (n=484) who had completed a self-administered survey of pain prior to initiating any cancer treatment. DNA (n=156) available for a subset of white patients was assayed and assessed for association with pain severity. Results showed that 26% (128/484) reported experiencing severe pain (score of > 7 on a 0–10 scale). Severe pain varied by stage of disease (odds ratio [OR] Stage II=4.02, 95% confidence interval (CI)=1.07, 15.07; Stage III=5.02, 95% CI=1.28, 19.61; Stage IV=6.90, 95% CI=1.96, 24.29), ethnicity (OR non-Hispanic blacks=3.67; 95% CI=1.44, 9.38), reports of depressed mood (OR=1.94; 95% CI=1.09, 3.43), and female sex (OR=1.78; 95% CI=1.04, 3.05). Controlling for these covariates, IL8-251T/A (OR=2.43, 95% CI=1.3, 4.7, P<0.009) significantly predicted severe pain in a subset of white patients. When we adjusted for reported analgesic use, we found that IL8-251T/A persisted as a predictor for severe pain, with carriers of TT and AT genotypes having more than a threefold risk (OR=3.23, 95% CI=1.4, 4.7) for severe pain relative to the AA genotypes. We provide preliminary evidence of the role of IL-8 in the severity of pain in pancreatic cancer patients. Additional studies are needed in larger cohorts of patients.
PMCID: PMC2795073  PMID: 19692203
Pain; genes; cytokines; epidemiology; cancer; analgesia; molecular epidemiology
13.  The role of inflammation gene polymorphisms on pain severity in lung cancer patients 
Many of the same inflammatory factors that promote tumor growth are also hypothesized to function as pain modulators. There is substantial interindividual variation in pain severity in cancer patients. Therefore, we evaluated 59 SNPs in 37 inflammation genes in newly diagnosed non-Hispanic Caucasian lung cancer patients (n=667) and assessed their association with pain severity. Patients rated their pain “during the past week” on an 11-point numeric scale, (0= ‘no pain’ and 10= ‘pain as bad as you can imagine’) at presentation, prior to initiating cancer therapy. Reported analgesic use was abstracted from charts and converted to an equivalent dose of morphine (MEDD). Results showed that 16% of the patients reported severe pain (score ≥ 7). Advanced stage of disease (OR=2.34; 95% CI=1.50-3.65, p-value=0.001), age≤ 50 (OR=2.10; 95%CI=1.32-3.30, p-value=0.002), reports of depressed mood (OR=3.68; 95%CI=1.96-6.93, p-value=0.001); fatigue (OR=3.72; 95% CI=2.36-5.87, p-value=0.001) and MEDD (OR=1.02; 95% C.I=1.01, 1.03) were significantly correlated with severe pain. Controlling for these non-genetic covariates, we found that patients with CC genotypes for PTGS2 exon10+837T>C (rs5275) were at lower risk for severe pain (OR=0.33; 95% Confidence Interval=0.11-0.97) and an additive model for TNF α -308GA (rs1800629) (OR=1.67, 95% CI=1.08,2.58) and NFKBIA Ex6+50C>T (rs8904) was predictive of severe pain (OR=0.64, 95% CI=0.43,0.93). In a multi-gene analysis, we found a gene-dose effect, with each protective genotype reducing the risk for severe pain by as much as 38%. This study suggests the importance of inflammation gene polymorphisms in modulating pain severity. Additional studies are needed to validate our findings.
PMCID: PMC2759856  PMID: 19773451
Pain; Genes; Inflammation; Epidemiology; Cancer
14.  The influence of subjective social status on the relationship between positive outcome expectations and experimentation with cigarettes 
In Texas, Mexican American (MA) adolescents, and in particular boys, are at increased risk of experimenting with cigarettes compared to their black or white counterparts. Positive outcome expectations (POE), the functional social significance ascribed to cigarettes, and subjective social status (SSS), the adolescents’ subjective views of where they lie in the school-based social hierarchy, are independent predictors of smoking. The goal of this study was to test the hypothesis that SSS moderates the relationship between POE and experimentation with cigarettes.
Moderating effects of SSS were examined using a between-subjects 2 by 2 ANOVA and unconditional logistic regression analyses. Using a prospective study design, we followed 1,142 MA adolescents aged 11 to 13. Participants completed a baseline survey at home, which assessed POE, SSS, and smoking and were followed via telephone at 6 monthly intervals over a 12 month period to assess changes in smoking behavior.
At follow-up, there were 99 new experimenters. Consistent with our hypothesis, adolescents who reported moderate-low SSS and who held POE at baseline were more likely to have experimented with cigarettes at either follow-up than their peers with moderate-low SSS who held less POE (OR=1.92, CI: 1.02–3.58). There was no association between outcome expectations and experimenting among adolescents with high SSS (OR=1.79, CI: 0.73–4.36). Low SSS boys were more likely to experiment than girls and high SSS boys.
The results of this study indicate that adolescents with moderate-low SSS hold different outcome expectations about smoking than their higher SSS peers. The results underscore the possibility that moderate-low SSS adolescents view behaviors such as smoking as a way to achieve higher SSS and thereby increase their peer social standing. Our results suggest that, in addition to tailoring intervention efforts by gender, placing adolescents of similar social standing to one another within the school into intervention groups that are led by a peer-nominated peer may increase the overall effectiveness of these peer-led prevention efforts.
PMCID: PMC2705959  PMID: 19306792
15.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 
Nature genetics  2008;40(5):616-622.
To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 × 10−17) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.
PMCID: PMC2713680  PMID: 18385676

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