title: Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk.
abstract: Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.
authors.affiliation: deCODE genetics, Department of Medical Oncology, Landspitali-University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Thorunn
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authors.lastname: Rafnar
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authors.lastname: Sulem
authors.forename: Soren
authors.initials: S
authors.lastname: Besenbacher
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
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authors.lastname: Zanon
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authors.lastname: Gudmundsson
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authors.initials: SN
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authors.forename: Jelena P
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authors.lastname: Kostic
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authors.lastname: Thorgeirsson
authors.forename: Gudmar
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authors.lastname: Thorleifsson
authors.forename: Hjordis
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authors.lastname: Bjarnason
authors.forename: Halla
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authors.lastname: Skuladottir
authors.forename: Tomas
authors.initials: T
authors.lastname: Gudbjartsson
authors.forename: Helgi J
authors.initials: HJ
authors.lastname: Isaksson
authors.forename: Dolores
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authors.lastname: Isla
authors.forename: Laura
authors.initials: L
authors.lastname: Murillo
authors.forename: Maria D
authors.initials: MD
authors.lastname: García-Prats
authors.forename: Angeles
authors.initials: A
authors.lastname: Panadero
authors.forename: Katja K H
authors.initials: KK
authors.lastname: Aben
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Henricus F M
authors.initials: HF
authors.lastname: van der Heijden
authors.forename: William J
authors.initials: WJ
authors.lastname: Feser
authors.forename: York E
authors.initials: YE
authors.lastname: Miller
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Wolf
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Jose I
authors.initials: JI
authors.lastname: Mayordomo
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Steinn
authors.initials: S
authors.lastname: Jonsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000502:physiology; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology; D000071857:Tumor Suppressor p53-Binding Protein 1; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1