Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk

Thorunn Rafnar*, Patrick Sulem, Soren Besenbacher, Daniel F. Gudbjartsson, Carlo Zanon, Julius Gudmundsson, Simon N. Stacey, Jelena P. Kostic, Thorgeir E. Thorgeirsson, Gudmar Thorleifsson, Hjordis Bjarnason, Halla Skuladottir, Tomas Gudbjartsson, Helgi J. Isaksson, Dolores Isla, Laura Murillo, Maria D. García-Prats, Angeles Panadero, Katja K.H. Aben, Sita H. VermeulenHenricus F.M. Van Der Heijden, William J. Feser, York E. Miller, Paul A. Bunn, Augustine Kong, Holly J. Wolf, Wilbur A. Franklin, Jose I. Mayordomo, Lambertus A. Kiemeney, Steinn Jonsson, Unnur Thorsteinsdottir, Kari Stefansson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

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 genomewide 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.

Original languageEnglish
Pages (from-to)1356-1361
Number of pages6
JournalCancer Research
Volume71
Issue number4
DOIs
Publication statusPublished - 15 Feb 2011

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