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

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. LiAndrew T. Chan, Hermann Brenner, Konstantinos K. Tsilidis , Wei Zheng

^*Corresponding author for this work

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

2 Citations (Scopus)

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.

Original language	English
Article number	13407
Pages (from-to)	103-110
Number of pages	8
Journal	British Journal of Cancer
Volume	132
Issue number	1
Early online date	23 Nov 2024
DOIs	https://doi.org/10.1038/s41416-024-02900-7
Publication status	Published - 31 Jan 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research

Cite this

Ching Chan, W., Liu, L., Bouras, E., Zuber, V., Wen, W., Long, J., Gill, D., Murphy, N., Gunter, M. J., Assimes, T. L., Bujanda, L., Gruber, S. B., Küry, S., Lynch, B. M., Qu, C., Thomas , M., White, E., Woods , M. O., Peters, U., ... Zheng, W. (2025). Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study. British Journal of Cancer, 132(1), 103-110. Article 13407. https://doi.org/10.1038/s41416-024-02900-7

@article{c20306b195974012b96d11e4777fe42e,

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

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.",

author = "\{Ching Chan\}, Wing and Lili Liu and Emmanouil Bouras and Verena Zuber and Wanqing Wen and Jirong Long and Dipender Gill and Neil Murphy and Gunter, \{Marc J\} and Assimes, \{Themistocles L\} and Luis Bujanda and Gruber, \{Stephen B.\} and S{\'e}bastien K{\"u}ry and Lynch, \{Brigid M\} and Conghui Qu and Minta Thomas and Emily White and Woods, \{Michael O\} and Ulrike Peters and Li, \{Christopher I.\} and Chan, \{Andrew T.\} and Hermann Brenner and Tsilidis, \{Konstantinos K.\} and Wei Zheng",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2025",

month = jan,

day = "31",

doi = "10.1038/s41416-024-02900-7",

language = "English",

volume = "132",

pages = "103--110",

journal = "British Journal of Cancer",

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Ching Chan, W, Liu, L, Bouras, E, Zuber, V, Wen, W, Long, J, Gill, D, Murphy, N, Gunter, MJ, Assimes, TL, Bujanda, L, Gruber, SB, Küry, S, Lynch, BM, Qu, C, Thomas , M, White, E, Woods , MO, Peters, U, Li, CI, Chan, AT, Brenner, H, Tsilidis , KK & Zheng, W 2025, 'Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study', British Journal of Cancer, vol. 132, no. 1, 13407, pp. 103-110. https://doi.org/10.1038/s41416-024-02900-7

TY - JOUR

T1 - Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk:

T2 - a Mendelian randomisation study

AU - Ching Chan, Wing

AU - Liu, Lili

AU - Bouras, Emmanouil

AU - Zuber, Verena

AU - Wen, Wanqing

AU - Long, Jirong

AU - Gill, Dipender

AU - Murphy, Neil

AU - Gunter, Marc J

AU - Assimes, Themistocles L

AU - Bujanda, Luis

AU - Gruber, Stephen B.

AU - Küry, Sébastien

AU - Lynch, Brigid M

AU - Qu, Conghui

AU - Thomas , Minta

AU - White, Emily

AU - Woods , Michael O

AU - Peters, Ulrike

AU - Li, Christopher I.

AU - Chan, Andrew T.

AU - Brenner, Hermann

AU - Tsilidis , Konstantinos K.

AU - Zheng, Wei

PY - 2025/1/31

Y1 - 2025/1/31

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-024-02900-7

DO - 10.1038/s41416-024-02900-7

M3 - Article (Academic Journal)

C2 - 39580580

SN - 0007-0920

VL - 132

SP - 103

EP - 110

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 1

M1 - 13407

ER -