Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study

Nutrients. 2020 Jul 28;12(8):2261. doi: 10.3390/nu12082261.


Estimated Δ5-desaturase (D5D) and Δ6-desaturase (D6D) are key enzymes in metabolism of polyunsaturated fatty acids (PUFA) and have been associated with cardiometabolic risk; however, causality needs to be clarified. We applied two-sample Mendelian randomization (MR) approach using a representative sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) genome-wide association studies (GWAS). Furthermore, we addressed confounding by linkage disequilibrium (LD) as all instruments from FADS1 (encoding D5D) are in LD with FADS2 (encoding D6D) variants. Our univariable MRs revealed risk-increasing total effects of both, D6D and D5D on type 2 diabetes (T2DM) risk; and risk-increasing total effect of D6D on risk of coronary artery disease (CAD). The multivariable MR approach could not unambiguously allocate a direct causal effect to either of the individual desaturases. Our results suggest that D6D is causally linked to cardiometabolic risk, which is likely due to downstream production of fatty acids and products resulting from high D6D activity. For D5D, we found indication for causal effects on T2DM and CAD, which could, however, still be confounded by LD.

Keywords: FADS-gene-cluster; Mendelian randomization; coronary artery disease; fatty acids; multivariable Mendelian randomization; type 2 diabetes; Δ5-desaturase; Δ6-desaturase.

MeSH terms

  • Adult
  • Aged
  • Cardiometabolic Risk Factors
  • Coronary Artery Disease / genetics*
  • Delta-5 Fatty Acid Desaturase
  • Diabetes Mellitus, Type 2 / genetics*
  • Fatty Acid Desaturases / genetics*
  • Fatty Acids, Unsaturated / metabolism
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Linoleoyl-CoA Desaturase / genetics*
  • Male
  • Mendelian Randomization Analysis
  • Meta-Analysis as Topic
  • Middle Aged
  • Prospective Studies


  • Delta-5 Fatty Acid Desaturase
  • Fatty Acids, Unsaturated
  • Fatty Acid Desaturases
  • FADS1 protein, human
  • Linoleoyl-CoA Desaturase