Abstract 5223: Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium

Abstract Background Conventional observational studies have reported conflicting results regarding the association between low density lipoprotein cholesterol (LDL-C) and risk of colorectal cancer (CRC). We conducted a Mendelian randomization analysis to address this association. Methods Single-nucleotide polymorphisms (SNPs) associated with five blood lipids (total cholesterol, HDL-C, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and triglyceride) were obtained from a genome-wide association study (GWAS) meta-analysis of European ancestry in the Global Lipids Genetics Consortium (GLGC, N ≤ 1 319 982), and two lipids (apolipoprotein A1 and apolipoprotein B) from a GWAS in the UK Biobank (UKB, N ≤ 441 016). Summary statistics were obtained for these SNPs from a GWAS of CRC in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) including 34,869 cases and 29,051 controls. Associations with CRC risk per one standard deviation increase in the genetically predicted lipids level were generated using inverse-variance weighted random-effects models. Results No overall association was observed between genetically predicted levels of blood lipids and CRC risk. However, increased risks were observed for all LDL-C related traits among women, including total cholesterol (OR = 1.10; 95%CI = 1.02, 1.18), LDL-C (1.07; 1.00, 1.14), non-HDL-C (1.09; 1.02, 1.16), and apolipoprotein B (1.11; 1.02, 1.21); whereas no significant association was found among men. Similar but ostensibly stronger associations of these traits were seen with distal colon cancer cases, with no significant association showing on proximal colon or rectum cancer cases. We also observed similar positive associations of LDL-C related traits among those having CRC before their 50 years. Of note, risk reduction was found for apolipoprotein A1, a major component of HDL-C, in these early-onset cases (0.87; 0.78, 0.98). Conclusion Results from this study suggest that high circulating LDL-C levels may increase the risk of CRC, particularly cancer of the distal colon, and the association may differ by sex and age at CRC onset. Key words: Blood lipids; colorectal cancer; Mendelian randomization. Citation Format: Lili Liu, Wanqing Wen, Jirong Long, Themistocles L Assimes, Luis Bujanda, Stephen B Gruber, Sébastien Küry, Brigid Lynch, Conghui Qu, Minta Thomas, Emily White, Michael O. Woods, Ulrike Peters, Wei Zheng. Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5223.