Abstract 294: Blood lipids, colorectal adenomas, and non-adenomatous polyps: A comparison of associations from clinical measurements and Mendelian randomization
Authors: Passarelli Michael N. , Newcomb Polly A. , Makar Karen W. , Burnett-Hartman Andrea N. , Potter John D. , Upton Melissa P. , Zhu Lee-Ching , Rosenfeld Michael E. , Schwartz Stephen M. , Rutter Carolyn M. 
Published: May 2015

Abstract
Background: Numerous studies have assessed associations between lipid levels and risk of colorectal neoplasia, but findings have been inconsistent. Recent genetic studies have identified &gt;100 loci associated with lipid levels. Knowledge of the magnitude and direction of genetic effects permits evaluation of allele scores that can serve as proxies for phenotypes.
Methods: We collected information on blood lipids as part of a colonoscopy study among enrollees, ages 25-79, of Group Health, a large healthcare system in Washington State. Low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC) measurements were extracted from electronic medical records for 98% of participants. For each participant, we identified the highest LDL, TG, and TC measurement (zenith) and lowest HDL measurement (nadir) prior to colonoscopy. All participants were genotyped for 96 single-nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium. For each lipid trait, we estimated 3 associations: 1) phenotype-polyp odds ratios (OR) with 95% confidence intervals (CI) comparing non-advanced adenoma cases to controls, advanced adenoma cases (≥10 mm in diameter, with villous components, or high-grade dysplasia) to controls, and non-adenomatous polyp cases to controls from polytomous logistic regression; 2) genotype-phenotype associations from linear regression; and 3) genotype-polyp ORs from two-stage linear-logistic regression.
Results: In total, 1,791 participants had information on phenotype and genotype (518 non-advanced adenoma cases, 139 advanced adenoma cases, 380 non-adenomatous polyp cases, and 754 polyp-free controls). Individuals with advanced adenomas were more likely than controls to have higher LDL and TG (adjusted OR per 20 mg/dL increase in zenith LDL: 1.16, CI 1.03-1.30 and OR per 40 mg/dL increase in zenith TG: 1.09, 1.03-1.16). Associations from allele scores were in the same direction (OR per increase in allele score scaled to be comparable to a 20 mg/dL LDL increase: 1.17, CI 0.78-1.75, and OR per increase in allele score scaled to be comparable to a 40 mg/dL TG increase: 1.12, 0.91-1.38). SNPs most strongly related to phenotype, however, were not associated with polyps, and SNPs that were, including variants of NAT2, MC4R, and APOE, may function through alternative pathways. Analyses among statin-naïve participants were not meaningfully different.
Conclusions: Mendelian randomization estimates did not achieve statistical significance, but the direction of associations suggests that polyps are more prevalent among those with inherited susceptibility to increased LDL and TG. Results also highlight difficulties interpreting results from Mendelian randomization analyses of traits with complex biology, given that variants may be pleiotropic and not suitable for use as instrumental variables.
Citation Format: Michael N. Passarelli, Polly A. Newcomb, Karen W. Makar, Andrea N. Burnett-Hartman, John D. Potter, Melissa P. Upton, Lee-Ching Zhu, Michael E. Rosenfeld, Stephen M. Schwartz, Carolyn M. Rutter. Blood lipids, colorectal adenomas, and non-adenomatous polyps: A comparison of associations from clinical measurements and Mendelian randomization. [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 294. doi:10.1158/1538-7445.AM2014-294