Genetically predicted plasma phospholipid arachidonic acid concentrations and 10 site-specific cancers in UK biobank and genetic consortia participants: A mendelian randomization study

Susanna C Larsson; Paul Carter; Mathew Vithayathil; Amy M Mason; Karl Michaëlsson; John A Baron; Stephen Burgess

doi:10.1016/j.clnu.2020.11.004

Genetically predicted plasma phospholipid arachidonic acid concentrations and 10 site-specific cancers in UK biobank and genetic consortia participants: A mendelian randomization study

Clin Nutr. 2021 May;40(5):3332-3337. doi: 10.1016/j.clnu.2020.11.004. Epub 2020 Nov 7.

Authors

Susanna C Larsson¹, Paul Carter², Mathew Vithayathil³, Amy M Mason⁴, Karl Michaëlsson⁵, John A Baron⁶, Stephen Burgess⁷

Affiliations

¹ Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: susanna.larsson@surgsci.uu.se.
² Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Electronic address: paul_richard_carter@outlook.com.
³ MRC Cancer Unit, University of Cambridge, Cambridge, UK. Electronic address: mat2k89@gmail.com.
⁴ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK. Electronic address: am2609@medschl.cam.ac.uk.
⁵ Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. Electronic address: karl.michaelsson@surgsci.uu.se.
⁶ Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA. Electronic address: jabaron@med.unc.edu.
⁷ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK. Electronic address: sb452@medschl.cam.ac.uk.

Abstract

Background & aims: Arachidonic acid (AA) is metabolized by cyclooxygenases and lipoxygenases to pro-inflammatory eicosanoids, which according to experimental research modulate tumor cell proliferation, differentiation, and apoptosis. We employed the Mendelian randomization design to test the hypothesis that higher plasma phospholipid AA concentrations are associated with increased risk of 10 site-specific cancers.

Methods: Two genetic variants associated with plasma phospholipid concentrations of AA (rs174547 in FADS1 [P = 3.0 × 10^-971] and rs16966952 in PDXDC1 [P = 2.4 × 10^-10]) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium were used as genetic instruments. The associations of those variants with cancer were taken from the UK Biobank (n = 367,643), FinnGen consortium (n = 135,638), International Lung Cancer Consortium (n = 27,209), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254), Breast Cancer Association Consortium (n = 228,951), Ovarian Cancer Association Consortium (n = 66,450), and BioBank Japan (n = 212,453).

Results: Higher genetically predicted plasma phospholipid AA concentrations were associated with increased risk of colorectal and lung cancer. Results were consistent across data sources and variants. The combined odds ratios per standard deviation increase of AA concentrations were 1.08 (95% CI 1.05-1.11; P = 6.3 × 10^-8) for colorectal cancer and 1.07 (95%CI 1.05-1.10; P = 3.5 × 10^-7) for lung cancer. Genetically predicted AA concentrations had a suggestive positive association with esophageal cancer (odds ratio 1.09; 95% CI 1.02-1.17; P = 0.016) but were not associated with cancers of the stomach, pancreas, bladder, prostate, breast, uterus, or ovary.

Conclusion: These results indicate that AA may be implicated in the development of colorectal and lung cancer and possibly esophageal cancer. Treatments with plasma AA-lowering properties should be evaluated for clinical benefit.

Keywords: Arachidonic acid; Cancer; Fatty acids; Mendelian randomization; Polymorphisms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arachidonic Acid* / blood
Arachidonic Acid* / genetics
Databases, Factual
Delta-5 Fatty Acid Desaturase
Humans
Mendelian Randomization Analysis
Neoplasms* / blood
Neoplasms* / epidemiology
Neoplasms* / genetics
Polymorphism, Single Nucleotide / genetics
United Kingdom

Substances

Delta-5 Fatty Acid Desaturase
Arachidonic Acid
FADS1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding