Abstract 2186: Inflammation- and angiogenesis- related genes: Interaction with NSAID use, and serum inflammatory markers on colorectal cancer risk within the Women's Health Initiative
Authors: Habermann Nina , Brown Elissa , Toth Reka , Scherer Dominique , Buck Katharina , Cheng Ting-Yuan David , Makar Karen W. , Neuhouser Marian L. , Zheng Yingye , Duggan David J. , Beresford Shirley A. , Wener Mark , Ochs-Balcom Heather , Toriola Adetunji , Ulrich Cornelia M. 
Published: May 2015

Inflammation and angiogenesis are important pathways of colorectal carcinogenesis. We investigated interactions between genes related to both pathways and the use of NSAIDs on CRC risk. Furthermore, we assessed whether specific variants interact with the inflammation biomarkers C-reactive protein (CRP) and serum amyloid A (SAA).

From the Women's Health Initiative Observational Study of women aged 50-79 years, we selected 821 Caucasian case/control matched pairs (1993-2008). We genotyped 412 single nucleotide polymorphisms (SNPs) tagging 26 genes related to inflammation and angiogenesis (ALOX5, CRP, IL1B, IL6, PTGIS, PTGS1, PTGS2, TBXAS, TGFB1, TNF, ANGPT1, NGPT2, DKK4, DLL4, VEGFR1, IL10, KDR, MAPK1, NRP1, NRP2, PGF, IK3CA, PIK3CG, TEK, VEGFA) using the Illumina GoldenGate and Sequenom platforms. CRP and SAA were quantified in serum by latex-enhanced nephelometry. CRC risk was estimated by conditional logistic regression based on the co-dominant inheritance model (or dominant if allele count &lt;10). P-values were adjusted for correlated tests (pACT) unless genes were functional candidates. Global P-values were obtained by likelihood ratio tests. Additionally, in interaction analysis we controlled the false discovery rate on the gene level (p-intadj). Interactions between SNPs and serum inflammatory markers were evaluated by testing for different slopes of CRC risk associated with each biomarker across genotype.

One SNP in NRP1, rs7895812 was significantly associated with CRC risk (pACT=0.02). Nine of the examined SNPs modified the association between NSAID use and CRC risk, although only two interactions remained significant after multiple comparison adjustment. The protective association of NSAID use was limited to individuals who were wildtype for PTGS2 rs1886233 (rs2383529, intergenic: p-intadj=0.01), whereas for carriers of the variant allele in FLT1 NSAID use was associated with a decreased CRC risk (rs1886233, intronic: p-intadj=0.02). For serum CRP and SAA multiple interactions with genetic variants were observed as well.

We showed that genetic variation in inflammation- and angiogenesis-related genes modified the association between NSAID use and CRC risk; the genetic variants also interacted with serum concentrations of CRP and SAA. This information may aid in tailoring prevention strategies to individuals who will obtain the greatest benefit from NSAIDs.

Citation Format: Nina Habermann, Elissa Brown, Reka Toth, Dominique Scherer, Katharina Buck, Ting-Yuan David Cheng, Karen W. Makar, Marian L. Neuhouser, Yingye Zheng, David J. Duggan, Shirley A. Beresford, Mark Wener, Heather Ochs-Balcom, Adetunji Toriola, Cornelia M. Ulrich. Inflammation- and angiogenesis- related genes: Interaction with NSAID use, and serum inflammatory markers on colorectal cancer risk within the Women's Health Initiative. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2014-2186