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. 2012 Mar 1;21(5):1190-200.
doi: 10.1093/hmg/ddr551. Epub 2011 Nov 23.

The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma

Summer S Han  1 , Meredith Yeager, Lee E Moore, Ming-Hui Wei, Ruth Pfeiffer, Ousmane Toure, Mark P Purdue, Mattias Johansson, Ghislaine Scelo, Charles C Chung, Valerie Gaborieau, David Zaridze, Kendra Schwartz, Neonilia Szeszenia-Dabrowska, Faith Davis, Vladimir Bencko, Joanne S Colt, Vladimir Janout, Vsevolod Matveev, Lenka Foretova, Dana Mates, M Navratilova, Paolo Boffetta, Christine D Berg, Robert L Grubb 3rd, Victoria L Stevens, Michael J Thun, W Ryan Diver, Susan M Gapstur, Demetrius Albanes, Stephanie J Weinstein, Jarmo Virtamo, Laurie Burdett, Antonin Brisuda, James D McKay, Joseph F Fraumeni Jr, Nilanjan Chatterjee, Philip S Rosenberg, Nathaniel Rothman, Paul Brennan, Wong-Ho Chow, Margaret A Tucker, Stephen J Chanock, Jorge R Toro
Affiliations

The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma

Summer S Han et al. Hum Mol Genet. .

Abstract

In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10(-8), per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17-1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10(-14)) and rs12617313 (P = 7.48 × 10(-12)), both highly correlated with rs9679290 (r(2) > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r(2) < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10(-9), per-allele OR = 1.28, 95% CI: 1.18-1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.

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Figures

Figure 1.
Figure 1.
Study design, sample sizes and stages of analyses. *The numbers in the parentheses next to each study in ‘Initial Genotyping Analysis’ and ‘Validation’ correspond to the number of cases and the number of controls, respectively.
Figure 2.
Figure 2.
Association results and LD plots for the 2p21 region. (A) The P-values (–log 10 scale) of association tests from the SNPs of the initial genotyping analysis (red dots) and from the analysis using imputed SNPs (blue dots). (B) The P-values of the four genotyped validated SNPs (green triangles) and SNPs in the initial genotyping analysis (red dots). (C) The LD structure (pairwise r2) and the location of the recombination hotspots (the black arrows) in the region. (D) EPAS1 gene structure, location of the SNPs genotyped and transcription factor binding sites in the region.
Figure 3.
Figure 3.
Forest plots and heterogeneity tests for the four validated EPAS1 SNPs.
See this image and copyright information in PMC

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