Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study

Wing Ching Chan; Lili Liu; Emmanouil Bouras; Verena Zuber; Wanqing Wen; Jirong Long; Dipender Gill; Neil Murphy; Marc J Gunter; Themistocles L Assimes; Luis Bujanda; Stephen B Gruber; Sébastien Küry; Brigid M Lynch; Conghui Qu; Minta Thomas; Emily White; Michael O Woods; Ulrike Peters; Christopher I Li; Andrew T Chan; Hermann Brenner; Konstantinos K Tsilidis; Wei Zheng

doi:10.1038/s41416-024-02900-7

Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study

Br J Cancer. 2024 Nov 23. doi: 10.1038/s41416-024-02900-7. Online ahead of print.

Authors

Wing Ching Chan^#¹, Lili Liu^#², Emmanouil Bouras³, Verena Zuber^{4

5

6}, Wanqing Wen², Jirong Long², Dipender Gill⁴, Neil Murphy⁷, Marc J Gunter^{4

7}, Themistocles L Assimes^{8

9}, Luis Bujanda¹⁰, Stephen B Gruber¹¹, Sébastien Küry¹², Brigid M Lynch^{13

14}, Conghui Qu¹⁵, Minta Thomas¹⁵, Emily White^{15

16}, Michael O Woods¹⁷, Ulrike Peters^{15

16}, Christopher I Li^{15

16}, Andrew T Chan¹⁸, Hermann Brenner^{19

20

21}, Konstantinos K Tsilidis^{4

3}, Wei Zheng²

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. w.chan21@imperial.ac.uk.
² Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
⁴ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁵ MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁶ UK Dementia Research Institute at Imperial College, Imperial College London, London, UK.
⁷ Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁸ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Department of Gastroenterology, Biodonostia Health Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain.
¹¹ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
¹² Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France.
¹³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁶ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁷ Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL, Canada.
¹⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²¹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

^# Contributed equally.

PMID: 39580580
DOI: 10.1038/s41416-024-02900-7

Abstract

Background: Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear.

Methods: Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed.

Results: Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02-1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05-1.21) or diabetes (OR = 1.09; 95%CI 1.02-1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets.

Conclusions: We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.