Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization
Background Observational associations between type 2 diabetes (T2D) and atrial fibrillation (AF) have been established, but causality remains undetermined. We performed Mendelian randomization (MR) to study causal effects of genetically predicted T2D on AF risk, independent of cardiometabolic risk f...
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.030298 |
| _version_ | 1797689817534824448 |
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| author | Rohin K. Reddy Maddalena Ardissino Fu Siong Ng |
| author_facet | Rohin K. Reddy Maddalena Ardissino Fu Siong Ng |
| author_sort | Rohin K. Reddy |
| collection | DOAJ |
| description | Background Observational associations between type 2 diabetes (T2D) and atrial fibrillation (AF) have been established, but causality remains undetermined. We performed Mendelian randomization (MR) to study causal effects of genetically predicted T2D on AF risk, independent of cardiometabolic risk factors. Methods and Results Instrumental variables included 182 uncorrelated single nucleotide polymorphisms associated with T2D at genome‐wide significance (P <5×10−8). Genetic association estimates for cardiometabolic exposures were obtained from genome‐wide association studies including 188 577 individuals for low‐density lipoprotein‐C, 694 649 individuals for body mass index, and 757 601 for systolic blood pressure. Two‐sample, inverse‐variance weighted MR formed the primary analyses. The MR‐TRYX approach was used to dissect potential pleiotropic pathways, with multivariable MR performed to investigate cardiometabolic mediation. Genetically predicted T2D associated with increased AF liability in univariable MR (odds ratio [OR], 1.08 [95% CI, 1.02–1.13], P=0.003). Sensitivity analyses indicated potential pleiotropy, with radial MR identifying 4 outlier single nucleotide polymorphisms that were likely contributors. Phenomic scanning on MR‐base and subsequent least absolute shrinkage and selection operator regression allowed prioritization of 7 candidate traits. The outlier‐adjusted effect estimate remained consistent with the original inverse‐variance weighted estimate (OR, 1.07 [95% CI, 1.02–1.12], P=0.008). On multivariable MR, T2D remained associated with increased AF liability after adjustment for low‐density lipoprotein‐C and body mass index. Following adjustment for systolic blood pressure, the relationship between T2D and AF became nonsignificant (OR, 1.04 [95% CI, 0.95–1.13], P=0.40). Conclusions These data provide novel genetic evidence that while T2D likely causally associates with AF, mediation via systolic blood pressure exists. Endeavoring to lower systolic blood pressure alongside achieving normoglycemia may provide particular benefit on AF risk in patients with T2D. |
| first_indexed | 2024-03-12T01:50:53Z |
| format | Article |
| id | doaj.art-049a2df2543d4de78d66181c25a26899 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-12T01:50:53Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-049a2df2543d4de78d66181c25a268992023-09-08T12:39:35ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-09-01121710.1161/JAHA.123.030298Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian RandomizationRohin K. Reddy0Maddalena Ardissino1Fu Siong Ng2National Heart and Lung Institute, Imperial College London London United KingdomNational Heart and Lung Institute, Imperial College London London United KingdomNational Heart and Lung Institute, Imperial College London London United KingdomBackground Observational associations between type 2 diabetes (T2D) and atrial fibrillation (AF) have been established, but causality remains undetermined. We performed Mendelian randomization (MR) to study causal effects of genetically predicted T2D on AF risk, independent of cardiometabolic risk factors. Methods and Results Instrumental variables included 182 uncorrelated single nucleotide polymorphisms associated with T2D at genome‐wide significance (P <5×10−8). Genetic association estimates for cardiometabolic exposures were obtained from genome‐wide association studies including 188 577 individuals for low‐density lipoprotein‐C, 694 649 individuals for body mass index, and 757 601 for systolic blood pressure. Two‐sample, inverse‐variance weighted MR formed the primary analyses. The MR‐TRYX approach was used to dissect potential pleiotropic pathways, with multivariable MR performed to investigate cardiometabolic mediation. Genetically predicted T2D associated with increased AF liability in univariable MR (odds ratio [OR], 1.08 [95% CI, 1.02–1.13], P=0.003). Sensitivity analyses indicated potential pleiotropy, with radial MR identifying 4 outlier single nucleotide polymorphisms that were likely contributors. Phenomic scanning on MR‐base and subsequent least absolute shrinkage and selection operator regression allowed prioritization of 7 candidate traits. The outlier‐adjusted effect estimate remained consistent with the original inverse‐variance weighted estimate (OR, 1.07 [95% CI, 1.02–1.12], P=0.008). On multivariable MR, T2D remained associated with increased AF liability after adjustment for low‐density lipoprotein‐C and body mass index. Following adjustment for systolic blood pressure, the relationship between T2D and AF became nonsignificant (OR, 1.04 [95% CI, 0.95–1.13], P=0.40). Conclusions These data provide novel genetic evidence that while T2D likely causally associates with AF, mediation via systolic blood pressure exists. Endeavoring to lower systolic blood pressure alongside achieving normoglycemia may provide particular benefit on AF risk in patients with T2D.https://www.ahajournals.org/doi/10.1161/JAHA.123.030298atrial fibrillationdiabetes, type 2genesMendelian randomization |
| spellingShingle | Rohin K. Reddy Maddalena Ardissino Fu Siong Ng Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atrial fibrillation diabetes, type 2 genes Mendelian randomization |
| title | Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization |
| title_full | Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization |
| title_fullStr | Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization |
| title_full_unstemmed | Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization |
| title_short | Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization |
| title_sort | type 2 diabetes and atrial fibrillation evaluating causal and pleiotropic pathways using mendelian randomization |
| topic | atrial fibrillation diabetes, type 2 genes Mendelian randomization |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.030298 |
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