| 1. |
- Allara, Elias, et al.
(författare)
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Genetically predicted cortisol levels and risk of venous thromboembolism
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:8
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: In observational studies, venous thromboembolism (VTE) has been associated with Cushing's syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization.METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed.RESULTS: Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62-0.87, p<0.001). The association was stronger for deep vein thrombosis (OR 0.69, 95% CI 0.55-0.88, p = 0.003) than for pulmonary embolism which did not achieve statistical significance (OR 0.83, 95% CI 0.63-1.09, p = 0.184). Adjusting for genetically predicted systolic blood pressure inverted the direction of the point estimate for VTE, although the resulting CI was wide (OR 1.06, 95% CI 0.70-1.61, p = 0.780).CONCLUSIONS: This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.
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| 2. |
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| 3. |
- Gaziano, Liam, et al.
(författare)
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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19
- 2021
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data for 1,263 actionable druggable genes, which encode protein targets for approved drugs or drugs in clinical development, identify IFNAR2 and ACE2 as the most promising therapeutic targets for early management of COVID-19. Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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| 4. |
- Gaziano, Liam, et al.
(författare)
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Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
- 2022
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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| 5. |
- Larsson, Susanna C., et al.
(författare)
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Assessing the role of cortisol in cancer : a wide-ranged Mendelian randomisation study
- 2021
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Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 125:7, s. 1025-1029
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Tidskriftsartikel (refereegranskat)abstract
- Background Cortisol’s immunosuppressive, obesogenic, and hyperglycaemic effects suggest that it may play a role in cancer development. However, whether cortisol increases cancer risk is not known. We investigated the potential causal association between plasma cortisol and risk of overall and common site-specific cancers using Mendelian randomisation.Methods Three genetic variants associated with morning plasma cortisol levels at the genome-wide significance level (P < 5 × 10−8) in the Cortisol Network consortium were used as genetic instruments. Summary-level genome-wide association study data for the cancer outcomes were obtained from large-scale cancer consortia, the UK Biobank, and the FinnGen consortium. Two-sample Mendelian randomisation analyses were performed using the fixed-effects inverse-variance weighted method. Estimates across data sources were combined using meta-analysis.Results A standard deviation increase in genetically predicted plasma cortisol was associated with increased risk of endometrial cancer (odds ratio 1.50, 95% confidence interval 1.13–1.99; P = 0.005). There was no significant association between genetically predicted plasma cortisol and risk of other common site-specific cancers, including breast, ovarian, prostate, colorectal, lung, or malignant skin cancer, or overall cancer.Conclusions These results indicate that elevated plasma cortisol levels may increase the risk of endometrial cancer but not other cancers. The mechanism by which this occurs remains to be investigated.
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| 6. |
- Larsson, Susanna C., et al.
(författare)
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Plasma Cortisol and Risk of Atrial Fibrillation : A Mendelian Randomization Study
- 2021
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 106:7, s. E2521-E2526
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Tidskriftsartikel (refereegranskat)abstract
- Context: Atrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing's syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally.Objective: To determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design.Methods: Three genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants).Results: One standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38).Conclusion: Evidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.
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| 7. |
- Larsson, Susanna C., et al.
(författare)
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Thyroid Function and Dysfunction in Relation to 16 Cardiovascular Diseases : A Mendelian Randomization Study
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:3, s. 121-126
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subclinical thyroid dysfunction, defined as thyroidstimulating hormone levels outside the reference range with normal free thyroxine levels in asymptomatic patients, is associated with alterations in cardiac hemodynamics. We used Mendelian randomization to assess the role of thyroid dysfunction for cardiovascular disease (CVD).METHODS: Single-nucleotide polymorphisms associated with thyroid function were identified from a genome-wide association meta-analysis in up to 72 167 individuals. Data for genetic associations with CVD were obtained from meta-analyses of genome-wide association studies of atrial fibrillation (n= 537 409 individuals), coronary artery disease (n= 184 305 individuals), and ischemic stroke (n= 438 847) as well as from the UK Biobank (n= 367 703 individuals).RESULTS: Genetically predicted thyroid-stimulating hormone levels and hyperthyroidism were statistically significantly associated with atrial fibrillation but no other CVDs at the Bonferroni-corrected level of significance (P< 7.8x10-4). The odds ratios of atrial fibrillation were 1.15 (95% CI, 1.11-1.19; P= 2.4x10-14) per genetically predicted 1 SD decrease in thyroid-stimulating hormone levels and 1.05 (95% CI, 1.03-1.08; P= 5.4x10-5) for genetic predisposition to hyperthyroidism. Genetically predicted free thyroxin levels were not statistically significantly associated with any CVD.CONCLUSIONS: This Mendelian randomization study supports evidence for a causal association of decreased thyroid-stimulating hormone levels in the direction of a mild form of hyperthyroidism with an increased risk of atrial fibrillation but no other CVDs.
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| 8. |
- Lee, Wei-Hsuan, et al.
(författare)
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Genetically predicted plasma cortisol and common chronic diseases : A Mendelian randomization study.
- 2023
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Ingår i: Clinical Endocrinology. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cushing's syndrome is characterized by hypercortisolaemia and is frequently accompanied by comorbidities such as type 2 diabetes, hypertension, osteoporosis, depression and schizophrenia. It is unclear whether moderate but lifelong hypercortisolaemia is causally associated with these diseases in the general population. We aimed to address this research gap using a Mendelian randomization approach.METHODS: We used three cortisol-associated genetic variants in the SERPINA6/SERPINA1 region as genetic instruments in a two-sample, inverse-variance-weighted Mendelian randomization analysis. We obtained summary-level statistics for cortisol and disease outcomes from publicly available genetic consortia, and meta-analysed them as appropriate. We conducted a multivariable Mendelian randomization analysis to assess potential mediating effects.RESULTS: A 1 standard deviation higher genetically predicted plasma cortisol was associated with greater odds of hypertension (odds ratio: 1.12; 95% confidence interval [CI]: 1.05-1.18) as well as higher systolic blood pressure (mean difference [MD]: 0.03 SD change; 95% CI: 0.01-0.05) and diastolic blood pressure (MD: 0.03 SD change; 95% CI: 0.01-0.04). There was no evidence of association with type 2 diabetes, osteoporosis, depression and schizophrenia. The association with hypertension was attenuated upon adjustment for waist circumference, suggesting potential mediation through central obesity.CONCLUSION: There is strong evidence for a causal association between plasma cortisol and greater risk for hypertension, potentially mediated by obesity.
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