Abstract 933: Glutathione peroxidase (GPX) candidate and tagSNPs and risk of colorectal neoplasia
Authors: Haug Ulrike , Poole Elizabeth M. , Xiao Liren , Slattery Marty L. , Galbraith Rachel L. , Duggan David , Hsu Li , Makar Karen W. , Peters U , Kulmacz Richard J. , Curtin Karen , Potter John D. , Caan Bette J. , Koepl Lisel , Coghill Anna E. , Muehling Jill , Taverna Darin , Carlson Christopher S. , Ulrich Cornelia M. 
Published: February 2011

Introduction: Glutathione peroxidases (GPXs) are selenium-dependent enzymes that scavenge hydroperoxides linked to oxidative stress, prostaglandin synthesis, inflammation and proliferation. Because these processes are important in carcinogenesis, we hypothesized that genetic variability in the GPXs may influence colorectal neoplasia risk. We investigated candidate polymorphisms and tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis.

Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 24 tagSNPs, including the candidates (GPX1 P200L and GPX4 2573 C&gt;T), representing common genetic variation in Europeans. We used an identical Illumina platform to investigate GPX SNPs in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal components analysis (PCA). Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (&gt;90% of all study populations).

Results: In PCA, GPX3 was significant for rectal cancer at p=0.03. Without correction for multiple testing, five polymorphisms in GPX2 and GPX3 were associated with significant differences in rectal cancer risk at α=0.05 (see Table). GPX3 rs8177406 also reduced risk in rectal polyps. The candidate GPX1 P200L showed a marginally increased risk for LP/LL vs. PP (1.22, 0.98-1.52, p=0.06). No other SNPs in GPX1-4 showed significant associations for rectal cancer or adenomas. No associations were observed for colon cancer.

Conclusion: These data provide evidence that genetic variability in GPX2 and GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for unique etiological mechanisms for colon and rectal cancer.Table.Selected tagSNPs in GPX1, GPX2 and GPX3 and risk of rectal cancer, adjusted for age, sex, and study center*SNPGenotypeCasesControlsOR95%CIp (2df)p-trendGPX1rs105045**CC252367     2834 C&gt;T, P200LCT or TT3013601.220.981.520.06NAGPX2rs2277502**GG4595741.00..  2834 G&gt;AGA or AA1141890.770.600.990.04NA         rs4902347**GG4565741.00..  1756 G&gt;AGA or AA1141880.780.601.000.05NAGPX3rs3828599CC3404091.00..  1580 C-&gt;TCT2142980.850.681.07   TT29660.520.330.830.010.01         rs736775CC2372821.00    9133 C-&gt;TCT2753540.910.721.15   TT701380.590.420.830.010.01         rs8177447CC4135001.00    7241 C-&gt;TCT1552350.790.621.01   TT14350.480.260.910.020.01* r2 &lt; 0.70, except rs2277502 and rs4902347 (r2 &gt; 0.90)** Dominant model is shown because there were 10 or fewer subjects with the homozygous variant model

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 933.