| 1. |
- Falcone, Guido J., et al.
(författare)
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Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage
- 2020
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 88:1, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively. Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020.
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| 2. |
- Bouras, Emmanouil, et al.
(författare)
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Identification of potential mediators of the relationship between body mass index and colorectal cancer : a Mendelian randomization analysis
- 2024
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 53:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC.Methods: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR–Egger, Contamination Mixture). We used multivariable MR for the mediation analyses.Results: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) ¼ 1.17, 95% CI: 1.08–1.24, P-value ¼ 1.4 × 10−5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2–13%) of the association], smoking (31%, 4–57%) and PA (7%, 2–11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA.Conclusions: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI–CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.
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| 3. |
- Chen, Jie, et al.
(författare)
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Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis : A Mendelian Randomization Study
- 2023
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 46:4, s. 828-835
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs).RESEARCH DESIGN AND METHODS: Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia.RESULTS: Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03-1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07-1.17) for gastric ulcer, 1.11 (95% CI, 1.03-1.20) for acute gastritis, 1.07 (95% CI, 1.01-1.13) for chronic gastritis, 1.08 (95% CI, 1.03-1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01-1.07) for diverticular disease, 1.08 (95% CI, 1.02-1.14) for acute pancreatitis, 1.09 (95% CI, 1.05-1.12) for cholelithiasis, 1.09 (95% CI, 1.05-1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17-1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03-1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89-0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively.CONCLUSIONS: Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.
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| 4. |
- Chen, Jie, et al.
(författare)
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Sedentary lifestyle, physical activity, and gastrointestinal diseases : evidence from mendelian randomization analysis
- 2024
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 103
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Tidskriftsartikel (refereegranskat)abstract
- Background: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations.Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 x 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures.Findings: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases.Interpretation: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases.
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| 5. |
- Cronjé, Héléne T., et al.
(författare)
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Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk : a Mendelian randomization study
- 2023
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Ingår i: BMC Medicine. - 1741-7015. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods: Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. Results: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. Conclusions: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling.
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| 6. |
- Gill, Dipender, et al.
(författare)
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ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels : a Mendelian randomization study
- 2020
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Ingår i: Royal Society Open Science. - : ROYAL SOC. - 2054-5703. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 x 10(-4)) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
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| 7. |
- Gill, Dipender, et al.
(författare)
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Genetically Determined Risk of Depression and Functional Outcome After Ischemic Stroke
- 2019
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Ingår i: Stroke. - 1524-4628. ; 50:8, s. 2219-2222
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose- Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods- Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results- There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions- We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possible effect on functional outcome after ischemic stroke. Given the widespread prevalence of depression-related morbidity, these findings could have implications for prognostication and personalized rehabilitation after stroke.
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| 8. |
- Giontella, Alice, et al.
(författare)
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Association of thyroid function with blood pressure and cardiovascular disease : A mendelian randomization
- 2021
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Ingår i: Journal of Personalized Medicine. - : MDPI AG. - 2075-4426. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper-or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper-and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.
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| 9. |
- Giontella, Alice, et al.
(författare)
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Caffeine Intake, Plasma Caffeine Level, and Kidney Function : A Mendelian Randomization Study
- 2023
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 15:20
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Tidskriftsartikel (refereegranskat)abstract
- Caffeine is a psychoactive substance widely consumed worldwide, mainly via sources such as coffee and tea. The effects of caffeine on kidney function remain unclear. We leveraged the genetic variants in the CYP1A2 and AHR genes via the two-sample Mendelian randomization (MR) framework to estimate the association of genetically predicted plasma caffeine and caffeine intake on kidney traits. Genetic association summary statistics on plasma caffeine levels and caffeine intake were taken from genome-wide association study (GWAS) meta-analyses of 9876 and of >47,000 European ancestry individuals, respectively. Genetically predicted plasma caffeine levels were associated with a decrease in estimated glomerular filtration rate (eGFR) measured using either creatinine or cystatin C. In contrast, genetically predicted caffeine intake was associated with an increase in eGFR and a low risk of chronic kidney disease. The discrepancy is likely attributable to faster metabolizers of caffeine consuming more caffeine-containing beverages to achieve the same pharmacological effect. Further research is needed to distinguish whether the observed effects on kidney function are driven by the harmful effects of higher plasma caffeine levels or the protective effects of greater intake of caffeine-containing beverages, particularly given the widespread use of drinks containing caffeine and the increasing burden of kidney disease.
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| 10. |
- Giontella, Alice, et al.
(författare)
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Calcium, Its Regulatory Hormones, and Their Causal Role on Blood Pressure : A Two-Sample Mendelian Randomization Study
- 2022
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 107:11, s. 3080-3085
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Vitamin D (Vit-D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) are the major calciotropic hormones involved in the regulation of blood calcium levels from the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of calcium itself or through the effect of its regulatory hormones could affect blood pressure (BP), but the exact mechanisms remain unclear. OBJECTIVE: To evaluate whether a causal relationship exists between serum calcium level and/or the regulatory hormones involved in its homeostasis with BP, we performed a two-sample Mendelian randomization (MR) study. METHODS: From 4 large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) single nucleotide polymorphisms (SNPs) associated with serum calcium (119 SNPs), Vit-D (78 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with systolic BP (SBP) and diastolic BP (DBP) in a Swedish urban-based study, the Malmö Diet and Cancer study (n = 29 298). Causality was evaluated by the inverse variance weighted method (IVW) and weighted median, while MR Egger and MR-PRESSO were used as sensitivity analyses. RESULTS: Genetically predicted serum calcium level was found to be associated with DBP (IVW: beta = 0.10, SE = 0.04, P = 0.007) and SBP (IVW: beta = 0.07, SE = 0.04, P = 0.04). Genetically predicted Vit-D and PTH showed no association with the traits, while FGF23 was inversely associated with SBP (IVW: beta = -0.11, SE = 0.04, P = 0.01), although this association lost statistical significance in sensitivity analysis. CONCLUSION: Our study shows a direct association between genetically predicted calcium level and DBP, and a weaker association with SBP. No such clear association was found for genetically predicted calciotropic hormone levels. It is of interest to detect which target genes involved in calcium homeostasis mediate the effect of calcium on BP, particularly for improving personalized intervention strategies.
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| 11. |
- Giontella, Alice, et al.
(författare)
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Causal effect of adiposity measures on blood pressure traits in 2 urban swedish cohorts : A mendelian randomization study
- 2021
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 10:13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Different adiposity traits may be causally related to hypertension in different ways. By using genetic variants as randomly allocated proxies for studying the effect of modifying adiposity traits, the Mendelian randomization approach can be used to investigate this. METHODS AND RESULTS: In this study, we used 4 different genetic risk scores (GRS; GRS-BMI 565, GRS-WHR 324, GRS-VAT 208, GRS-BF 81) including hundreds of single nucleotide polymorphisms associated with body mass index, waist-to-hip ratio, visceral adipose tissue, and body fat, respectively. These were applied as instrumental variables in Mendelian randomization analyses. Two Swedish urban-based cohort studies, the Malmö Diet and Cancer, and the Malmö Preventive Projects were used to obtain genetic association estimates with blood pressure (BP). In both the Malmö Preventive Projects and Malmö Diet and Cancer studies, except for that for body fat, all of the genetic risk scores were significantly associated with systolic BP and diastolic BP, but with different magnitudes. In particular, in both cohorts, each standard deviation increase in the genetic risk score made up by the 324 single nucleotide polymorphisms associated with waist-to-hip ratio was associated with doubling of the likelihood of hypertension prevalence at baseline. However, only the genetic risk score made up by the 565 SNPs associated with body mass index was significantly associated with hypertension incidence during 23.6±4.3 years of follow-up in the Malmö Preventive Project. CONCLUSIONS: We support a causal link between genetically mediated adiposity, especially waist-to-hip ratio and body mass index, and BP traits including hypertension prevalence and, for the first time to our knowledge, hypertension incidence. The differences in magnitude between these associations might suggest different mechanisms by which different adiposity affects BP/hypertension and consequently may indicate that tailored interventions are needed to reduce cardiovascular risk.
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| 12. |
- Giontella, Alice, et al.
(författare)
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Renoprotective effects of genetically proxied fibroblast growth factor 21 : Mendelian randomization, proteome-wide and metabolome-wide association study
- 2023
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Ingår i: Metabolism. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 145
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD).Methods: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites).Results: We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 x 10(-4)), higher urinary sodium excretion (p = 5.1 x 10(-11)), and lower urine albumin-creatinine ratio (p = 3.6 x 10(-5)). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94-0.98; p = 3.2 x 10(-4)). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 x 10(- 07)) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 x 10(-24)) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction.Conclusion: This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to
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| 13. |
- Higgins, Hannah, et al.
(författare)
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Estimating the Population Benefits of Blood Pressure Lowering : A Wide-Angled Mendelian Randomization Study in UK Biobank
- 2021
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Ingår i: Journal of the American Heart Association. - : Wolters Kluwer. - 2047-9980. ; 10:17
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe causal relevance of elevated blood pressure for several cardiovascular diseases (CVDs) is uncertain, as is the population impact of blood pressure lowering. This study systematically assesses evidence of causality for various CVDs in a 2‐sample Mendelian randomization framework, and estimates the potential reduction in the prevalence of these diseases attributable to long‐term population shifts in the distribution of systolic blood pressure (SBP).Methods and ResultsWe investigated associations of genetically predicted SBP as predicted by 256 genetic variants with 21 CVDs in UK Biobank, a population‐based cohort of UK residents. The sample consisted of 376 703 participants of European ancestry, aged 40 to 69 years at recruitment. Genetically predicted SBP was positively associated with 14 of the outcomes (P<0.002), including dilated cardiomyopathy, endocarditis, peripheral vascular disease, and rheumatic heart disease. Using genetic variation to estimate the long‐term impact of blood pressure lowering on disease in a middle‐aged to early late‐aged UK‐based population, population reductions in SBP were predicted to result in an overall 16.9% (95% CI, 12.2%–21.3%) decrease in morbidity for a 5–mm Hg decrease from a population mean of 137.7 mm Hg, 30.8% (95% CI, 22.8%–38.0%) decrease for a 10–mm Hg decrease, and 56.2% (95% CI, 43.7%–65.9%) decrease for a 22.7–mm Hg decrease in SBP (22.7 mm Hg represents a shift from the current mean SBP to 115 mm Hg).ConclusionsRisk of many CVDs is influenced by long‐term differences in SBP. The burden of a broad range of CVDs could be substantially reduced by long‐term population‐wide reductions in the distribution of blood pressure.
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| 14. |
- Karhunen, Ville, et al.
(författare)
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Genetically proxied growth-differentiation factor 15 levels and body mass index
- 2021
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Ingår i: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 87:10, s. 4036-4039
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Tidskriftsartikel (refereegranskat)abstract
- Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis that is being pursued as a drug target for obesity. Its circulating levels are acutely increased by the type 2 diabetes medication metformin, resulting in reduced appetite and weight loss. We identified a genetic variant at the GDF15 gene to proxy a small, lifelong increase in circulating GDF15 levels, and leveraged it in colocalization and Mendelian randomization analyses to investigate the effects of chronically elevated GDF15 levels on body mass index (BMI) and type 2 diabetes liability. The results provide human genetic evidence supporting that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI-lowering effects of an acute increase in GDF15 levels observed after metformin use. These findings have direct implications for informing pharmacological strategies aimed at targeting GDF15 levels for weight loss.
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| 15. |
- Karhunen, Ville, et al.
(författare)
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Modifiable Risk Factors for Intracranial Aneurysm and Aneurysmal Subarachnoid Hemorrhage : A Mendelian Randomization Study
- 2021
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Ingår i: Journal of the American Heart Association. - : Wolters Kluwer. - 2047-9980. ; 10:22
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe aim of this study was to assess the associations of modifiable lifestyle factors (smoking, coffee consumption, sleep, and physical activity) and cardiometabolic factors (body mass index, glycemic traits, type 2 diabetes, systolic and diastolic blood pressure, lipids, and inflammation and kidney function markers) with risks of any (ruptured or unruptured) intracranial aneurysm and aneurysmal subarachnoid hemorrhage using Mendelian randomization.Methods and ResultsSummary statistical data for the genetic associations with the modifiable risk factors and the outcomes were obtained from meta‐analyses of genome‐wide association studies. The inverse‐variance weighted method was used as the main Mendelian randomization analysis, with additional sensitivity analyses conducted using methods more robust to horizontal pleiotropy. Genetic predisposition to smoking, insomnia, and higher blood pressure was associated with an increased risk of both intracranial aneurysm and aneurysmal subarachnoid hemorrhage. For intracranial aneurysm, the odds ratios were 3.20 (95% CI, 1.93–5.29) per SD increase in smoking index, 1.24 (95% CI, 1.10–1.40) per unit increase in log‐odds of insomnia, and 2.92 (95% CI, 2.49–3.43) per 10 mm Hg increase in diastolic blood pressure. In addition, there was weak evidence for associations of genetically predicted decreased physical activity, higher triglyceride levels, higher body mass index, and lower low‐density lipoprotein cholesterol levels with higher risk of intracranial aneurysm and aneurysmal subarachnoid hemorrhage, with 95% CI overlapping the null for at least 1 of the outcomes. All results were consistent in sensitivity analyses.ConclusionsThis Mendelian randomization study suggests that smoking, insomnia, and high blood pressure are major risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage.
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| 16. |
- Larsson, Susanna C., et al.
(författare)
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Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease : two sample mendelian randomisation study
- 2023
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Ingår i: BMJ medicine. - : BMJ Publishing Group Ltd. - 2754-0413. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the potential causal effects of long term plasma caffeine concentrations on adiposity, type 2 diabetes, and major cardiovascular diseases.DESIGN: Two sample mendelian randomisation study.SETTING: Genome-wide association study summary data for associations of two single nucleotide polymorphisms associated with plasma caffeine at the genome-wide significance threshold (rs2472297 near the CYP1A2 gene and rs4410790 near the AHR gene) and their association with the outcomes.PARTICIPANTS: Primarily individuals of European ancestry participating in cohorts contributing to genome-wide association study consortia.MAIN OUTCOME MEASURES: Outcomes studied were body mass index, whole body fat mass, whole body fat-free mass, type 2 diabetes, ischaemic heart disease, atrial fibrillation, heart failure, and stroke.RESULTS: Higher genetically predicted plasma caffeine concentrations were associated with lower body mass index (beta -0.08 standard deviation (SD) (95% confidence interval -0.10 to -0.06), where 1 SD equals about 4.8 kg/m2 in body mass index, for every standard deviation increase in plasma caffeine) and whole body fat mass (beta -0.06 SD (-0.08 to -0.04), 1 SD equals about 9.5 kg; P<0.001) but not fat-free mass (beta -0.01 SD (-0.02 to -0.00), 1 SD equals about 11.5 kg; P=0.17). Higher genetically predicted plasma caffeine concentrations were associated with a lower risk of type 2 diabetes in two consortia (FinnGen and DIAMANTE), with a combined odds ratio of 0.81 ((95% confidence interval 0.74 to 0.89); P<0.001). Approximately half (43%; 95% confidence interval 30% to 61%) of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index reduction. No strong associations were reported between genetically predicted plasma caffeine concentrations and a risk of any of the studied cardiovascular diseases.CONCLUSIONS: Higher plasma caffeine concentrations might reduce adiposity and risk of type 2 diabetes. Further clinical study is warranted to investigate the translational potential of these findings towards reducing the burden of metabolic disease.
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| 17. |
- Larsson, Susanna C., et al.
(författare)
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Association of Serum Magnesium Levels With Risk of Intracranial Aneurysm : A Mendelian Randomization Study
- 2021
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 97:4, s. E341-E344
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Magnesium has been implicated in regulating blood pressure and vascular endothelial cell function, but its role in the pathophysiology of intracranial aneurysm is not known. Here we performed a Mendelian randomization analysis to investigate the association between serum magnesium concentration and risk of intracranial aneurysm.Methods: Five single-nucleotide polymorphisms strongly associated with serum magnesium concentrations in a genome-wide association study in 23,829 individuals of European ancestry were used as genetic instruments. Genetic association estimates for intracranial aneurysm were obtained from a genome-wide association study in 79,429 individuals (7,495 cases and 71,934 controls). The inverse variance weighted method was used in the primary analyses to obtain the causal estimates.Results: Higher genetically predicted serum magnesium concentrations were associated with lower risk of intracranial aneurysm. The odds ratios per 0.1 mmol/L increment in genetically predicted serum magnesium concentrations were 0.66 (95% confidence interval [CI] 0.49-0.91) for intracranial aneurysm (unruptured and ruptured combined), 0.57 (95% CI 0.30-1.06) for unruptured intracranial aneurysm, and 0.67 (95% CI 0.48-0.92) for aneurysmal subarachnoid hemorrhage.Conclusion: This study provides evidence to support that increased serum magnesium concentrations reduce the risk of intracranial aneurysm and associated hemorrhage.
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| 18. |
- Larsson, Susanna C., et al.
(författare)
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Genetic Evidence Supporting Fibroblast Growth Factor 21 Signalling as a Pharmacological Target for Cardiometabolic Outcomes and Alzheimer's Disease
- 2021
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Fibroblast growth factor 21 (FGF21) is a human metabolic hormone whose effects include modification of macronutrient preference and energy homeostasis. In animal models, FGF21 has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer's disease risk and lifespan. In this study, the single-nucleotide polymorphism rs838133 in the FGF21 gene region was leveraged to investigate the potential clinical effects of targeting FGF21. The FGF21 G allele was associated with lower intakes of total sugars and alcohol, and higher intakes of protein and fat as well as favourable with lipid levels, blood pressure traits, waist-to-hip ratio, systemic inflammation, cardiovascular outcomes, Alzheimer's disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling.
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| 21. |
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| 22. |
- Larsson, Susanna C., et al.
(författare)
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Plasma Caffeine Levels and Risk of Alzheimer's Disease and Parkinson's Disease : Mendelian Randomization Study
- 2022
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- We leveraged genetic variants associated with caffeine metabolism in the two-sample Mendelian randomization framework to investigate the effect of plasma caffeine levels on the risk of Alzheimer's disease and Parkinson's disease. Genetic association estimates for the outcomes were obtained from the International Genomics of Alzheimer's Project, the International Parkinson's Disease Genomics consortium, the FinnGen consortium, and the UK Biobank. Genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer's disease (odds ratio 0.87; 95% confidence interval 0.76, 1.00; p = 0.056). A suggestive association was observed for genetically predicted higher plasma caffeine levels and lower risk of Parkinson's disease in the FinnGen consortium. but not in the International Parkinson's Disease Genomics consortium; no overall association was found (odds ratio 0.92; 95% confidence interval 0.77, 1.10; p = 0.347). This study found possible suggestive evidence of a protective role of caffeine in Alzheimer's disease. The association between caffeine and Parkinson's disease requires further study.
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| 23. |
- Malik, Rainer, et al.
(författare)
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Relationship between Blood Pressure and Incident Cardiovascular Disease : Linear and Nonlinear Mendelian Randomization Analyses
- 2021
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Ingår i: Hypertension. - 0194-911X. ; 77:6, s. 2004-2013
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Tidskriftsartikel (refereegranskat)abstract
- Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38-1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38-1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22-1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD.
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| 24. |
- Rogers, Miranda, et al.
(författare)
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Genetically proxied impaired GIPR signaling and risk of 6 cancers
- 2023
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Ingår i: iScience. - 2589-0042. ; 26:6
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.
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