David P Miller

Harvard University, Cambridge, Massachusetts, United States

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Publications (24)135.88 Total impact

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    ABSTRACT: Exposure to second hand smoke (SHS) has been identified as a risk factor for lung cancer for three decades. It is also known that the lung continues to grow from birth to adulthood, when lung growth stops. We hypothesize that after adjusting for active cigarette smoking, if SHS exposure took place during the period of growth, i.e. in the earlier part of life (0-25 years of age) the risk of lung cancer is greater compared to an exposure occurring after age 25. Second hand smoke exposure was self-reported for three different activities (leisure, work and at home) for this study population of 1669 cases and 1263 controls. We created variables that captured location of exposure and timing of first exposure with respect to a study participant's age (0-25, >25 years of age). Multiple logistic regressions were used to study the association between SHS exposure and lung cancer, adjusting for age, gender and active smoking variables. For study participants that were exposed to SHS at both activities (work and leisure) and compared to one or no activity, the adjusted odds ratio (AOR) for lung cancer was 1.30 (1.08-1.57) when exposure occurred between birth and age 25 and 0.66 (0.21-1.57) if exposure occurred after age 25 years. Respective results for non-smokers were 1.29 (0.82-2.02) and 0.87 (0.22-3.38), and current and ex-smokers combined 1.28 (1.04-1.58) and 0.66 (0.15-2.85). All individuals exposed to SHS have a higher risk of lung cancer. Furthermore, this study suggests that subjects first exposed before age 25 have a higher lung cancer risk compared to those for whom first exposure occurred after age 25 years.
    Lung Cancer 07/2008; 61(1):13-20. DOI:10.1016/j.lungcan.2007.11.013 · 3.96 Impact Factor
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    ABSTRACT: Case-control and observational studies are popular choices for evaluating molecular prognostic/pharmacogenetic outcomes, but data quality is rarely tested. Using clinical trial and epidemiologic methods, we assessed the quality of prognostic and outcomes data obtainable from a large case-control study of lung cancer. We developed an explicit algorithm (set of standard operating procedures forming a rapid outcomes ascertainment system) that encompassed multiple tests of quality assurance, and quality of data for a range of prognostic and outcomes variables, in several cancers, across several centers and two countries were assessed. Based on these assessments, the algorithm was revised and physicians' clinical practice changed. We reevaluated the quality of outcomes after these revisions. Development of an algorithm with internal quality controls showed specific patterns of data collection errors, which were fixable. Although the major discrepancy rate in retrospective data collection was low (0.6%) when compared with external validated sources, complete data were found in <50% of patients for treatment response rate, toxicity, and documentation of patient palliative symptoms. Prospective data collection and changes to clinical practice led to significantly improved data quality. Complete data on response rate increased from 45% to 76% (P = 0.01, Fisher's exact test), for toxicity data, from 26% to 56% (P = 0.02), and for palliative symptoms, from 25% to 70% (P < 0.05), in one large lung cancer case-control study. Observational studies can be a useful source for studying molecular prognostic and pharmacogenetic outcomes. A rapid outcomes ascertainment system with strict ongoing quality control measures is an excellent means of monitoring key variables.
    Cancer Epidemiology Biomarkers & Prevention 01/2008; 17(1):204-11. DOI:10.1158/1055-9965.EPI-07-0470 · 4.13 Impact Factor
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    ABSTRACT: Polymorphisms in GSTT1, GSTM1 and GSTP1 impact detoxification of carcinogens by GSTs and have been reported to increase susceptibility to environmentally related health outcomes. Individual factors in arsenic biotransformation may influence disease susceptibility. GST activity is involved in the metabolism of endogenous and exogenous compounds, including catalyzing the formation of arsenic-GSH conjugates. We investigated whether polymorphisms in GSTT1, GSTP1 and GSTM1 were associated with risk of skin lesions and whether these polymorphisms modify the relationship between drinking water arsenic exposure and skin lesions in a case control study of 1200 subjects frequency matched on age and gender in community clinics in Pabna, Bangladesh in 2001-2002. GSTT1 homozygous wildtype status was associated with increased odds of skin lesions compared to the null status (OR1.56 95% CI 1.10-2.19). The GSTP1 GG polymorphism was associated with greater odds of skin lesions compared to GSTP1 AA, (OR 1.86 (95%CI 1.15-3.00). No evidence of effect modification by GSTT1, GSTM1 or GSTP1 polymorphisms on the association between arsenic exposure and skin lesions was detected. GSTT1 wildtype and GSTP1 GG are associated with increased risk of skin lesions.
    Environmental Health 02/2007; 6(1):5. DOI:10.1186/1476-069X-6-5 · 3.37 Impact Factor
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    ABSTRACT: Second hand smoke (SHS) exposure is associated with higher risk of lung cancer. However, the role of SHS in lung cancer survival is not clear. We examined the association between self-reported SHS exposure before diagnosis and overall survival and recurrence-free survival in 393 early-stage non-small-cell lung cancer patients. SHS exposure was analyzed by both duration and location of exposure using log-rank test and Cox proportional hazard models, adjusting for covariates including pack-years of smoking. The median follow-up time was 66 months (range, 0.2-140 months). There were 135 recurrences and 213 deaths. The 5-year overall survival rates were 71% [95% confidence interval (95% CI), 62-81%], 61% (51-72%), 49% (38-60%), and 47% (37-58%), respectively, for patients with the lowest to highest quartile of SHS exposure durations (P < 0.001, log-rank test), with the adjusted hazard ratio (AHR) of 1.57 (95% CI, 1.02-2.41) for the highest versus lowest quartile of SHS exposure durations (P(trend) = 0.04). For different SHS exposure locations, a stronger association was found for SHS exposure at work (AHR of the highest versus lowest quartile, 1.71; 95% CI, 1.12-2.61; P(trend) = 0.03) than for exposure at home (AHR, 1.26; 95% CI, 0.86-1.86; P(trend) = 0.20) or leisure places (AHR, 1.28; 95% CI, 0.83-1.95; P(trend) = 0.16). Similar associations were observed when SHS exposure durations were dichotomized into two or three groups and between SHS exposure and recurrence-free survival. SHS exposure is associated with worse survival in early-stage non-small-cell lung cancer patients, especially for SHS exposure at the work.
    Clinical Cancer Research 01/2007; 12(23):7187-93. DOI:10.1158/1078-0432.CCR-06-1460 · 8.72 Impact Factor
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    ABSTRACT: Among the genes that encode the glutathione S-transferase (GST) superfamily of Phase 2 metabolizing enzymes, GSTP1 has the highest expression in the lung. The polymorphic GSTP1 gene encodes glutathione S-transferase pi, which is an enzyme that detoxifies cigarette carcinogens, such as benzo-[a]-pyrene. The variant GSTP1 GG genotype is associated with lower enzymatic activity and higher DNA adduct levels in human lymphocytes compared with the AA genotype. The authors evaluated the association of GSTP1 genotypes with lung cancer in 1921 cases and 1343 controls of Caucasian descent by using polymerase chain reaction-restriction fragment length polymorphism techniques. The results were analyzed with multiple logistic regression adjusting for age, gender, smoking status, and pack-years. To investigate specifically the subset of younger lung cancer patients and controls, the effect of age (either as a dichotomous or continuous variable in separate models) was analyzed as a modifying factor of the association between the GSTP1 polymorphism and lung cancer. The GSTP1 GG genotype was not associated with an overall increased risk of lung cancer (adjusted odds ratio, 1.02; 95% confidence interval [95% CI], 0.78-1.34) compared with the GSTP1 AA genotype. In both models that evaluated the gene-age interaction, an overall statistically significant interaction (P < .01) was observed between age and the GG genotype. However, for the model that included age as a dichotomous variable, the odds ratio of lung cancer risk with the GG genotype compared with the AA among individuals age </=50 years was 2.67 (95% CI, 1.36-5.22); in older individuals, the risk was 0.87 (95% CI, 0.65-1.2). The GSTP1 GG genotype was associated with increased lung cancer susceptibility among younger study participants.
    Cancer 10/2006; 107(7):1570-7. DOI:10.1002/cncr.22124 · 4.89 Impact Factor
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    ABSTRACT: Iron, zinc, and calcium are all involved in the metabolism of reactive oxygen species and may compete with each other for similar binding sites. Dietary intakes of these micronutrients have been associated with altered risks of colorectal, breast, and prostate cancers. In this Massachusetts hospital-based case-control study of 923 patients with lung cancer and 1125 healthy controls, we studied the associations between dietary iron, zinc, and calcium intake and the risk of lung cancer. Dietary intake was assessed at the time of recruitment (1992 to 2000) with the use of a 126-item semiquantitative food-frequency questionnaire. We analyzed the data using multiple logistic regression models adjusting for smoking history and other potential risk factors. The adjusted odds ratios of dietary iron, zinc, and calcium from food sources were 1.45 (95% confidence interval=1.03-2.06), 0.71 (0.50-0.99), and 1.64 (1.17-2.29), respectively, for the highest quintile versus the lowest quintile of each micronutrient. Stronger associations between micronutrients and lung cancer risk were found when iron, zinc, and calcium were included together in the same model. The associations between dietary micronutrients intake and lung cancer risk were stronger among current smokers than among former smokers. When we examined intake from supplements as well as diet, associations were similar to those for diet alone. Dietary iron, zinc, and calcium may play an important role in the development of lung cancer, especially among current smokers. These results need to be confirmed in large prospective studies.
    Epidemiology 12/2005; 16(6):772-9. DOI:10.1097/01.ede.0000181311.11585.59 · 6.20 Impact Factor
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    ABSTRACT: Many approaches have been taken to adjust for smoking in modeling cancer risk. In case-control studies, these metrics are often used arbitrarily rather than being based on the properties of the metric in the context of the study. Depending on the underlying study design, hypotheses, and base population, different metrics may be deemed most appropriate. We present our approach to evaluating different smoking metrics. We examine the properties of a new metric, "logcig-years", that we initially derived from using a biological model of DNA adduct formation. We compare this metric to three other smoking metrics, namely pack-years, square-root pack-years, and a model in which smoking duration and intensity are separate variables. Our comparisons use generalized additive models and logistic regression to examine the relationship between the logit probability of cancer and each of the metrics, adjusting for other covariates. All models were fit using data from a lung cancer study of 1,275 cases and 1,269 controls that has focused on gene-smoking relationships. There was a very significant, linear relationship between logcig-years and the logit probability of lung cancer in this sample, without any need to adjust for smoking status. These properties together were not shared by the other metrics. In this sample, logcig-years captured more information about smoking that is important in lung cancer risk than the other metrics. In conclusion, we provide a general framework for evaluating different smoking metrics in studies where smoking is a critical variable.
    Cancer Epidemiology Biomarkers & Prevention 11/2005; 14(10):2296-302. DOI:10.1158/1055-9965.EPI-04-0393 · 4.13 Impact Factor
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    ABSTRACT: Manganese superoxide dismutase (SOD2) and myeloperoxidase (MPO) are polymorphic enzymes involved in reactive oxidative species metabolism. In this case-control study (830 non-small cell lung carcinoma (NSCLC) patients; 1119 controls) we evaluated whether the MPO -G463A polymorphism (associated with a novel estrogen receptor binding site) modifies the association between the SOD2 Ala16Val polymorphism and NSCLC risk differently by gender. For women carrying the MPO variant genotypes, the adjusted odds ratio of the SOD2 polymorphism (Val/Val vs. Ala/Ala) was 3.26 (95% CI, 1.55-6.83). No associations were found in men or in women carrying the MPO GG wildtype genotype.
    Cancer Letters 11/2004; 214(1):69-79. DOI:10.1016/j.canlet.2004.06.027 · 5.62 Impact Factor
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    ABSTRACT: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are rare disorders characterized by platelet aggregation, microthrombi, and resulting tissue damage. We studied the incidence and possible risk factors for these diseases in 3 large populations in the United States, United Kingdom, and Canada. Data were derived from a large health insurer in the United States, general practices in the United Kingdom, and the Province of Saskatchewan. We identified potential cases of thrombotic thrombocytopenia purpura and hemolytic uremic syndrome in computerized data and verified them by medical record review. We estimated incidence rates for thrombotic thrombocytopenia purpura and hemolytic uremic syndrome together and separately, and we conducted a case-control study to evaluate potential risk factors. The age-sex standardized incidence of thrombotic thrombocytopenia purpura and hemolytic uremic syndrome was higher than previously reported (6.5, 2.2, and 3.2 per million per year in the United States, United Kingdom, and Saskatchewan, respectively), but there was no secular trend. The incidence of thrombotic thrombocytopenia purpura and hemolytic uremic syndrome was higher in women than men. Most cases of hemolytic uremic syndrome occurred before 20 years of age. We confirmed several known risk factors for thrombotic thrombocytopenia purpura and hemolytic uremic syndrome (cancer, bone marrow transplantation, pregnancy). The incidence of thrombotic thrombocytopenia purpura and hemolytic uremic syndrome is higher than previously reported but does not appear to be rising. Apparent international differences in incidence could be the result of imprecision in identifying thrombotic thrombocytopenia purpura and hemolytic uremic syndrome in large research databases.
    Epidemiology 04/2004; 15(2):208-15. DOI:10.1097/01.ede.0000113273.14807.53 · 6.20 Impact Factor
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    ABSTRACT: In November 2000, alosetron HCl (Lotronex), a treatment for irritable bowel syndrome (IBS), was removed from the U.S. market in part because of the occurrence of colon ischemia in treated patients. Since the relation between colon ischemia and IBS is poorly understood, we evaluated the incidence of colon ischemia among people with and without IBS. Using medical claims data from a large health care organization in the United States, we identified 87,449 people with an IBS diagnosis between January 1995 and December 1999. We calculated age- and sex-specific incidence rates in the general population and in IBS patients. There were 740 cases of colon ischemia during 8.5 million person-years of observation in 5.4 million persons. The crude incidence rate was 42.8 cases per 100,000 person-years for IBS patients. By comparison, the incidence rate was 7.2 per 100,000 person-years in the general population. After adjustment for age, sex, and calendar year, the incidence of colon ischemia in people with IBS was 3.4 times higher than in persons without (95% CI 2.6-4.5). Rates of colon ischemia among patients carrying a diagnosis of IBS are substantially higher than in the general population. Colon ischemia, though unusual in IBS patients, may nonetheless constitute a distinct part of the IBS natural history. Alternatively, it may be a consequence of therapy, or a manifestation of other bowel pathology that is sometimes confused with IBS.
    The American Journal of Gastroenterology 04/2004; 99(3):486-91. DOI:10.1111/j.1572-0241.2004.04097.x · 10.76 Impact Factor
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    ABSTRACT: Major risk factors for ARDS have been identified. However, only a minority of patients with such risks develops ARDS. It is likely that, given the same type and degree of insult, there are heritable determinants of susceptibility to ARDS. To investigate the possibility of variable genetic susceptibility to ARDS, we examined the association between ARDS and a polymorphism in intron 4 of the surfactant protein-B (SP-B) gene. Nested case-control study conducted from September 1999 to March 2001. Four adult medical and surgical ICUs at a tertiary academic center. One hundred eighty-nine patients meeting study criteria for a defined risk factor for ARDS were enrolled and prospectively followed. Measurements and results: Seventy-two patients (38%) developed ARDS. After stratification by gender and adjustment for potential confounders, there was a significantly increased odds for women with the variant SP-B gene to develop ARDS compared to women homozygous for the wild-type allele (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.1 to 18.8; p = 0.03). Women with the variant SP-B polymorphism also had significantly increased odds of having a direct pulmonary injury such as aspiration or pneumonia as a risk factor for ARDS as opposed to an indirect pulmonary risk for ARDS (OR, 4.6; 95% CI, 1.1 to 19.9; p = 0.04). No such association with ARDS or direct pulmonary injury was found for men. The variant polymorphism of the SP-B gene is associated with ARDS and with direct pulmonary injury in women, but not in men. Further study is needed to confirm the association between the variant SP-B gene, and gender, ARDS, and direct pulmonary injury.
    Chest 02/2004; 125(1):203-11. · 7.48 Impact Factor
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    ABSTRACT: GSTP1 is a gene that helps detoxify foreign substances in the body. Functional polymorphisms of GSTP1 have been studied as risk factors for lung cancer. Past studies have compared the effect of the "at risk" polymorphism in two strata of smoking pack-years (usually defined by the median among controls). We examined the interaction between GSTP1 polymorphisms and cumulative exposure to smoking and their association with lung cancer risk. Data are from a large hospital-based case-control study of persons treated for primary lung cancer at the Massachusetts General Hospital since 1992. Controls were drawn from friends and nonrelated family members. We genotyped 1,042 cases and 1,161 controls for GSTP1 using polymerase chain reaction-restriction fragment length polymorphism techniques. The GSTP1 GG genotype approximately doubled the lung cancer risk associated with pack-years. This interaction was stronger among current smokers. At 26 pack-years (median among controls with a smoking history), the adjusted odds ratio for the association between pack-years and lung cancer risk was 13 (95% confidence interval = 6.5-25) among current smokers with the GSTP1 GG genotype compared with 6.1 (95% confidence interval = 4.9-7.5) among those with the GSTP1 AA genotype. GSTP1 GG increases the lung cancer risk associated with pack-years of smoking.
    Epidemiology 10/2003; 14(5):545-51. DOI:10.1097/01.ede.0000073120.46981.24 · 6.20 Impact Factor
  • Lung Cancer 08/2003; 41. DOI:10.1016/S0169-5002(03)91829-0 · 3.96 Impact Factor
  • Lung Cancer 08/2003; 41. DOI:10.1016/S0169-5002(03)91742-9 · 3.96 Impact Factor
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    ABSTRACT: p21 (Waf1/Cip1) is a downstream target of p53. We evaluated the association between p21 polymorphism (codon 31), p53 polymorphism (codon 72) and their corresponding in vivo mRNA expression. In this study, p21 and p53 genetic polymorphisms (using standard PCR-RFLP techniques) and p21 and p53 gene expressions (using a radiolabelled ribonuclease protection assay (RPA) technique) were evaluated in the peripheral leukocytes of 84 individuals (63 with lung cancer). Log-transformed values of mRNA expression by RPA, which approximated a normal distribution, were analyzed. p53 genotypes did not correlate with p53 mRNA log-expression (P>0.05 for all comparisons), but the Pro allele variants of p53 were associated with a significant decrease in mRNA log-expression of its downstream target, p21. The variant Arg allele of p21 was also associated with a significant decrease in p21 mRNA log-expression. When individuals with at least one variant allele of both p53 and p21 (double-variants) were compared with all other genotype groups, these double-variants had significantly lower log-expression of p21 (P<0.005 by both t-tests (crude) and linear regression analyses (adjusted)). This is translated into an approximate 48% reduction in the geometric mean of the mRNA expression of the double-variants, when compared with all other groups. Results were consistent in both patients with lung cancer (n=63) and in normal controls (n=21). In conclusion, the presence of a p53 Pro allele and/or p21 Arg allele is associated with lower downstream target gene expression of p21.
    Lung Cancer 07/2003; 40(3):259-66. DOI:10.1016/S0169-5002(03)00081-3 · 3.96 Impact Factor
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    ABSTRACT: Alosetron hydrochloride (Lotronex), a potent selective 5-hydroxytryptamine(3) receptor antagonist, was approved in February, 2000 in the United States for the treatment of diarrhea-predominant irritable bowel syndrome (IBS) in women. Marketing was suspended in November, 2000, after reports of colonic ischemia and serious complications of constipation. We sought to compare the incidence of colonic ischemia, hospitalized complications of constipation, and bowel surgery among alosetron users and a cohort of patients with IBS who did not use alosetron. We sought outcomes of colonic ischemia, hospitalized complications of constipation, and bowel surgery in 3,631 Lotronex users and 2,480 comparison IBS subjects using diagnoses, procedures, and drugs recorded in the UnitedHealthcare insurance claims database, and validated these by chart review. The initial assessment was to last for 3 yr beginning with the start of alosetron treatment and was to include 10,000 Lotronex users; however, the observation period ended by December 31, 2000, after suspension of marketing. There were 3631 alosetron users among members of UnitedHealthcare from March through December, 2000, and we identified 2480 comparison IBS-only patients; follow-up time averaged about 5 months in both groups. There were no instances of colonic ischemia in either cohort. Thirty instances of bowel surgery occurred, giving rates of 10.2/1000 person-yr in the alosetron cohort and 11.8/1000 person-yr in the IBS/no alosetron cohort. There were three cases of hospitalized complications of constipation. The incidence rates were essentially the same in alosetron users (1.24/1000 person-yr) and in IBS patients with no alosetron use (0.92/1000 person-yr). Alosetron users did not differ from IBS patients not using alosetron in the incidence of bowel surgery or hospitalized complications of constipation; there were no cases of colonic ischemia. The statistical upper limit of colonic ischemia rates in alosetron users was 2.28/1000 person-yr. Because of the market withdrawal, the size of the cohort and the duration of follow-up were smaller than originally planned; consequently, the statements about the safety of alosetron were necessarily limited. On June 7, 2002, the Food and Drug Administration approved alosetron for reintroduction in the U.S. market for women with severe diarrhea-related IBS.
    The American Journal of Gastroenterology 06/2003; 98(5):1117-22. DOI:10.1111/j.1572-0241.2003.07418.x · 10.76 Impact Factor
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    ABSTRACT: Environmental Tobacco Smoke (ETS) exposure has been associated with lung cancer risk. ETS is composed of emissions from cigarette smoke and contains a higher concentration of tobacco smoke carcinogens than mainstream smoke. Polymorphisms in genes that metabolize tobacco smoke carcinogens have been studied as effect modifiers of the association between active smoking and lung cancer risk. GSTP1 is a polymorphic gene that encodes for GST pi, a detoxification enzyme and has a high expression in the lung. We investigated the association between ETS and lung cancer risk and the modification of this association by the GSTP1 polymorphism. Using a case-control design, individuals were genotyped for GSTP1 using PCR-RFLP techniques. All analyses were carried out using multiple logistic regression. The association between ETS exposure and lung cancer risk was evaluated in different strata based on smoking habits to evaluate the consistency of results. The effect of the GSTP1 polymorphisms on lung cancer risk was evaluated by considering the joint effect of having both an ETS exposure and the GSTP1 GG genotype compared to the absence of ETS exposure and the GSTP1 AA genotype as a reference group as well as doing stratified analysis by genotype. ETS exposure was associated consistently with higher lung cancer risk in all the strata considered. The adjusted odds ratios (AOR) evaluating the association between ETS and lung cancer risk for the different strata were: nonsmokers (Cases/Controls 66/413; AOR = 1.38; 95% CI = 0.78-2.43), ex-smokers (Cases/Controls 560/527; AOR = 1.66; 95% CI = 1.22-2.25), current smokers (Cases/Controls 415/219; AOR = 1.56; 95% CI = 1.00-2.41). The AORs for ex-smokers and light smoking subgroups were: ex-smokers who quit for 19 years or more (Cases/Controls 144/244; AOR = 2.64; 95% CI = 1.55-4.50), ex-smokers who quit for 10-19 years (Cases/Controls 141/128; AOR = 1.16; 95% CI = 0.66-2.04), ex-smokers who quit for 10 years or less (Cases/Controls 247/122; AOR = 1.45; 95% CI = 0.83-2.55) and participants who had <15 packyears and nonsmokers combined (Cases/Controls 143/640; AOR = 1.52; 95% CI = 1.02-2.28). Among those with the GSTP1 GG genotype the ETS-lung cancer risk association was greater than those with the GSTP1 AA genotype: nonsmokers (GSTP1 GG AOR = 7.84; 95% CI = 0.80-76.68; GSTP1 AA AOR = 1.15; 95% CI = 0.46-2.90), ex-smokers (GSTP1 GG AOR = 2.32; 95% CI = 0.90-5.96; GSTP1 AA AOR = 2.15; 95% CI = 1.34-3.44), current smokers (GSTP1 GG AOR = 1.75; 95% CI = 0.42-7.32; GSTP1 AA AOR = 1.32; 95% CI = 0.67-2.58) and participants who had <15 packyears and nonsmokers (GSTP1 GG AOR = 1.93; 95% CI = 0.54-6.97; GSTP1 AA AOR = 1.58; 95% CI = 0.83-3.01). We found that ETS exposure is associated with higher lung cancer risk. Furthermore, the presence of the GSTP1 GG genotype appears to enhance the magnitude of the association between ETS exposure and lung cancer. Larger studies will be needed to confirm these preliminary findings.
    International Journal of Cancer 05/2003; 104(6):758-63. DOI:10.1002/ijc.10989 · 5.09 Impact Factor
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    ABSTRACT: XRCC1 (X-ray cross-complementing group 1) and ERCC2 (excision repair cross-complementing group 2) are two major DNA repair proteins. Polymorphisms of these two genes have been associated with altered DNA repair capacity and cancer risk. We have described statistically significant interactions between the ERCC2 polymorphisms (Asp312Asn and Lys751Gln) and smoking in lung cancer risk. In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer. The results were analyzed using logistic regression models, adjusting for relevant covariates. Overall, the adjusted odds ratio (OR) of XRCC1 Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was 1.3 [95% confidence interval (CI), 1.0-1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For nonsmokers, the adjusted OR was 2.4 (95% CI, 1.2-5.0), whereas for heavy smokers (>/=55 pack-years), the OR decreased to 0.5 (95% CI, 0.3-1.0). When the three polymorphisms were evaluated together, the adjusted ORs of the extreme genotype combinations of variant alleles (individuals with 5 or 6 variant alleles) versus wild genotype (individuals with 0 variant alleles) were 5.2 (95% CI, 1.7-16.6) for nonsmokers and 0.3 (95% CI, 0.1-0.8) for heavy smokers, respectively. Similar gene-smoking interaction associations were found when pack-years of smoking (or smoking duration and smoking intensity) was fitted as a continuous variable. In conclusion, cumulative cigarette smoking plays an important role in altering the direction and magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk.
    Cancer Epidemiology Biomarkers & Prevention 04/2003; 12(4):359-65. · 4.13 Impact Factor
  • Cancer Epidemiology Biomarkers & Prevention 03/2003; 12(2):174-5. · 4.13 Impact Factor
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    ABSTRACT: The myeloperoxidase (MPO) G-to-A substitution polymorphism in the promoter region of the MPO gene has been associated with a 40-70% reduction in lung cancer risk in several studies, although a recent nested case-control study disputes these findings. MPO is involved in the activation of a number of procarcinogens, including benzo(a)pyrene. The variant A allele has been shown to reduce MPO mRNA expression, thus potentially decreasing carcinogen activation. To confirm results from smaller studies, we evaluated this MPO polymorphism in 988 incident Caucasian lung cancer cases and 1128 controls. Logistic regression evaluated the association between MPO genotype and lung cancer risk, adjusting for age, gender, smoking status, time since quitting smoking, and pack-years of smoking. In the controls, the A allele frequency was 21%, and genotype distribution was in the Hardy-Weinberg equilibrium. Compared with the wild-type G/G genotype, the adjusted odds ratios for the A/A and A/G genotypes were 1.15 (95% confidence interval 0.7-1.9, P > 0.2) and 1.03 (95% confidence interval 0.8-1.3, P > 0.20), respectively. A similar lack of association was seen in analyses stratified by smoking status, median age, a number of smoking variables, disease stage, tumor grade, and histological subtype. These findings are in contrast with earlier studies suggesting a protective effect of carrying the variant A allele.
    Cancer Epidemiology Biomarkers & Prevention 01/2003; 11(12):1555-9. · 4.13 Impact Factor

Publication Stats

934 Citations
135.88 Total Impact Points


  • 2004–2008
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
  • 2005
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2003–2004
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States