Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.1.1. Individual-Level Data from EPIC-Potsdam
2.1.2. Summary-Level Data from DIAGRAM and CARDIoGRAM
2.2. DNA-Extraction, Genotyping and Quality Control
2.3. Determination of Desaturase Activities
2.4. Statistical Analysis
2.4.1. Selecting Genetic Instruments in Genome-Wide Association Study
2.4.2. Mendelian Randomization
2.4.3. Investigation of LD within the FADS-Gene Cluster
3. Results
3.1. Selection of Genetic Instruments
3.2. Mendelian Randomization
3.2.1. Univariable Mendelian Randomization
Causal Estimates for Desaturase Activities on Risk of Type 2 Diabetes
Causal Estimates for Desaturase Activities on Risk of Coronary Artery Disease
Sensitivity Analyses
3.2.2. Multivariable Mendelian Randomization
Estimates for Causal Direct Effects of Desaturase Activities on Risk of Type 2 Diabetes and Coronary Artery Disease
Sensitivity Analyses
3.2.3. Investigation of Confounding by Linkage Disequilibrium
4. Discussion
4.1. D6D and Risk of Type 2 Diabetes and Coronary Artery Disease
4.2. D5D and Risk of Type 2 Diabetes and Coronary Artery Disease
4.3. Biological Mechanisms
4.4. Strengths and Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Ethics Approval and Consent to Participate
Availability of Data and Materials
Code Availability
References
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EPIC-Potsdam | |
---|---|
N | 1853 |
Sex (% men) | 37.1 |
Age in years; median (interquartile range) | 49.0 (15.5) |
Waist circumference in cm; mean (SD) | 85.3 (12.6) |
Δ6-desaturase activity (18:3n-6/18:2n-6); median (interquartile range) | 0.005 (0.003) |
Δ5-desaturase activity (20:4n-6/20:3n-6); mean (SD) | 8.80 (1.91) |
Lipid medication (%) | 3.72 |
T2DM | CAD | |||||||
---|---|---|---|---|---|---|---|---|
Method | N (SNPs) * | OR (95% CI) | p-Value | N (SNPs) † | OR (95% CI) | p-Value | ||
D6D | instruments from FADS | IVW | 6 | 1.08 (1.06–1.09) | <0.001 | 6 | 1.06 (1.02–1.11) | 0.008 |
MVIVW | 10 | 1.03 (0.94–1.12) | 0.528 | 10 | 1.00 (0.93–1.07) | 0.971 | ||
MVIVW ‡ | 10 | 1.03 (0.99–1.16) | 10 | 1.01 (0.91–1.12) | ||||
instruments from FADS and genome-wide hits | MVIVW | 12 | 1.03 (0.95–1.10) | 0.514 | 12 | 1.00 (0.95–1.06) | 0.907 | |
MVIVW ‡ | 12 | 1.01 (0.94–1.10) | 12 | 1.00 (0.96–1.15) | ||||
D5D | instruments from FADS | IVW | 9 | 1.03 (1.01–1.04) | <0.001 | 9 | 1.03 (1.01–1.05) | 0.017 |
MVIVW | 10 | 1.00 (0.96–1.04) | 0.824 | 10 | 1.04 (1.01–1.08) | 0.021 | ||
MVIVW ‡ | 10 | 1.02 (0.98–1.04) | 10 | 1.04 (1.01–1.15) | ||||
instruments from FADS and genome-wide hits | IVW | 11 | 1.04 (1.02–1.06) | <0.001 | 11 | 1.03 (1.01–1.06) | 0.017 | |
MVIVW | 12 | 1.00 (0.96–1.03) | 0.845 | 12 | 1.03 (0.99–1.06) | 0.108 | ||
MVIVW ‡ | 12 | 1.02 (0.99–1.05) | 12 | 1.04 (0.99–1.07) |
T2DM | CAD | ||||||||
---|---|---|---|---|---|---|---|---|---|
Method | N (SNPs) | OR (95% CI) | p-Value | Intercept (SE), p-Value | N (SNPs) | OR (95% CI) | p-Value | Intercept (SE), p-Value | |
D6D | MR-Egger | 3 † | 0.87 (0.55–1.37) | 0.538 | 0.050 (0.045), 0.267 | 3 † | 1.26 (0.21–7.70) | 0.804 | −0.022 (0.176), 0.902 |
IVW * | 3 † | 1.12 (1.06–1.18) | <0.001 | 3 † | 1.12 (1.04–1.21) | 0.002 | |||
MVIVW * | 3 † | 0.74 (0.34–1.62) | 0.453 | 3 † | 1.12 (0.34–3.69) | 0.850 | |||
D5D | IVW * | 2 ‡ | 1.04 (0.99–1.08) | 0.087 | 2 ‡ | 1.04 (0.98–1.11) | 0.236 | ||
MVIVW * | 2 ‡ | 1.01 (0.95–1.07) | 0.790 | 2 ‡ | 1.00 (0.93–1.08) | 0.996 | |||
MVIVW * | 3 † | 1.29 (0.75–2.21) | 0.362 | 3 † | 1.00 (0.48–2.09) | 1.000 |
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Jäger, S.; Cuadrat, R.; Hoffmann, P.; Wittenbecher, C.; Schulze, M.B. Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study. Nutrients 2020, 12, 2261. https://doi.org/10.3390/nu12082261
Jäger S, Cuadrat R, Hoffmann P, Wittenbecher C, Schulze MB. Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study. Nutrients. 2020; 12(8):2261. https://doi.org/10.3390/nu12082261
Chicago/Turabian StyleJäger, Susanne, Rafael Cuadrat, Per Hoffmann, Clemens Wittenbecher, and Matthias B. Schulze. 2020. "Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study" Nutrients 12, no. 8: 2261. https://doi.org/10.3390/nu12082261
APA StyleJäger, S., Cuadrat, R., Hoffmann, P., Wittenbecher, C., & Schulze, M. B. (2020). Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study. Nutrients, 12(8), 2261. https://doi.org/10.3390/nu12082261