title: A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood.
abstract: Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3'UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60-0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62-0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47-0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53-0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62-0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3'UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Robles
authors.affiliation: Mayo Clinic, Department of Health Sciences Research, Rochester, Minnesota.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Laboratory Medicine and Pathology and Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Department of Pathology, Stanford University Hospital and Clinics, Stanford, California.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McClary
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Kara
authors.initials: K
authors.lastname: Calhoun
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Elise D
authors.initials: ED
authors.lastname: Bowman
authors.affiliation: School of Pharmacy/Toxicology, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Vähäkangas
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: K Leigh
authors.initials: KL
authors.lastname: Greathouse
authors.affiliation: Division of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, China. Division of Epidemiology, Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Epidemiology, College of Public Health, Ohio State University, Columbus, Ohio.
authors.forename: Susan
authors.initials: S
authors.lastname: Olivo-Marston
authors.affiliation: Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Wenzlaff
authors.affiliation: Division of Epidemiology, Health Sciences Research, Mayo Clinic, Rochester, Minnesota. Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Deng
authors.affiliation: Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. ryanb@mail.nih.gov.
authors.forename: Bríd M
authors.initials: BM
authors.lastname: Ryan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D004198:Disease Susceptibility; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D020413:3' Untranslated Regions; C523021:CHRNA1 protein, human; C436489:CHRNA2 protein, human; C583260:DRD1 protein, human; D035683:MicroRNAs; D017447:Receptors, Dopamine D1; D011978:Receptors, Nicotinic; D014028:Tobacco Smoke Pollution; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6