title: Susceptibility loci for lung cancer are associated with mRNA levels of nearby genes in the lung.
abstract: Recent studies identified three genetic loci reproducibly associated with lung cancer in populations of European ancestry, namely 15q25, 5p15 and 6p21. The goals of this study are first to confirm whether these loci are associated with lung cancer in a French Canadian population and second to identify disease-associated single nucleotide polymorphisms (SNPs) influencing messenger RNA (mRNA) expression levels of genes in the lung, that is expression quantitative trait loci (eQTLs). SNPs were genotyped in 420 patients undergoing lung cancer surgery and compared with 3151 controls of European ancestry. Genome-wide gene expression levels in non-tumor lung tissues of the same 420 patients were also measured to identify eQTLs. Significant eQTLs were then followed-up in two replication sets (n = 339 and 363). SNPs found in the three susceptibility loci were associated with lung cancer in the French Canadian population. Strong eQTLs were found on chromosome 15q25 with the expression levels of CHRNA5 (P = 2.23 × 10(-) (22) with rs12907966). The CHRNA5-rs12907966 eQTL was convincingly validated in the two replication sets (P = 3.46 × 10(-) (16) and 2.01 × 10(-) (15)). On 6p21, a trend was observed for rs3131379 to be associated with the expression of APOM (P = 3.58 × 10(-) (4)) and validated in the replication sets (P = 1.11 × 10(-) (8) and 6.84 × 10(-) (4)). On 5p15, no significant eQTLs were found. This study confirmed that chromosomes 15q25, 5p15 and 6p21 harbored susceptibility loci for lung cancer in French Canadians. Most importantly, this study suggests that the risk alleles at 15q25 and 6p21 may mediate their effect by regulating the mRNA expression levels of CHRNA5 and APOM in the lung.
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec G1V 4G5, Canada.
authors.forename: Justin Dang Uy
authors.initials: JD
authors.lastname: Nguyen
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec G1V 4G5, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lamontagne
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec G1V 4G5, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec G1V 4G5, Canada.
authors.forename: Massimo
authors.initials: M
authors.lastname: Conti
authors.affiliation: UBC James Hogg Research Center and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada, Department of Medicine, Respiratory Division and.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: UBC James Hogg Research Center and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada, Department of Medicine, Respiratory Division and.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: UBC James Hogg Research Center and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.affiliation: Merck & Co. Inc., Rahway, NJ 08889, USA.
authors.forename: David
authors.initials: D
authors.lastname: Nickle
authors.affiliation: Department of Pulmonology and.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center, GRIAC Research Institute, Groningen FC41, The Netherlands and.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec G1V 4G5, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec G1V 4G5, Canada, Department of Molecular Medicine, Laval University, Québec G1V 0A6, Canada yohan.bosse@criucpq.ulaval.ca.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger