Mendelian randomization analysis rules out disylipidaemia as colorectal cancer cause

Dyslipidemia and statin use have been associated with colorectal cancer (CRC), but prospective studies have shown mixed results. We aimed to determine whether dyslipidemia is causally linked to CRC risk using a Mendelian randomization approach and to explore the association of statins with CRC. A casecontrol study was performed including 1336 CRC cases and 2744 controls (MCC-Spain). Subjects were administered an epidemiological questionnaire and were genotyped with an array which included polymorphisms associated with blood lipids levels, selected to avoid pleiotropy. Four genetic lipid scores specific for triglycerides (TG), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), or total cholesterol (TC) were created as the count of risk alleles. The genetic lipid scores were not associated with CRC. The ORs per 10 risk alleles, were for TG 0.91 (95%CI: 0.72–1.16, p = 0.44), for HDL 1.14 (95%CI: 0.95–1.37, p = 0.16), for LDL 0.97 (95%CI: 0.81–1.16, p = 0.73), and for TC 0.98 (95%CI: 0.84–1.17, p = 0.88). The LDL and TC genetic risk scores were associated with statin use, but not the HDL or TG. Statin use, overall, was a non-significant protective factor for CRC (OR 0.84; 95%CI: 0.70–1.01, p = 0.060), but lipophilic statins were associated with a CRC risk reduction (OR 0.78; 95%CI 0.66–0.96, p = 0.018). Using the Mendelian randomization approach, our study does not support the hypothesis that lipid levels are associated with the risk of CRC. This study does not rule out, however, a possible protective effect of statins in CRC by a mechanism unrelated to lipid levels.This work was supported by the 'Accion Transversal del Cancer', approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds - 'a way to build Europe' [grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, PI17/00092 and PI15/00069]. Support was also provided by the Fundacion Marques de Valdecilla (grant API 10/09]; the Junta de Castilla y Leon [grant LE22A10-2]; the Consejeria de Salud of the Junta de Andalucia [2009-S0143]; the Conselleria de Sanitat of the Generalitat Valenciana [grant AP 061/10]; the Recercaixa [grant 2010ACUP 00310]; the Regional Government of the Basque Country; the Consejeria de Sanidad de la Region de Murcia; European Commission grants FOOD-CT-2006-036224-HIWATE; the Spanish Association Against Cancer (AECC) Scientific Foundation; the Catalan Government DURSI [grants 2017SGR723 and 2014SGR850]; the Fundacion Caja de Ahorros de Asturias; the University of Oviedo; Societat Catalana de Digestologia; and COST action CA17118 Transcoloncan. ISGlobal and IDIBELL are members of the CERCA Programme, Generalitat de Catalunya