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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年11月23日

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  • 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

摘要

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.