scholarly journals Low-density lipoprotein cholesterol and atrial fibrillation; A Mendelian randomization study using UK-Biobank data

2017 ◽  
Vol 1 (1) ◽  
Author(s):  
Michail Katsoulis ◽  
Spiros Denaxas ◽  
Riyaz Patel ◽  
Harry Hemingway
Keyword(s):  
Atrial Fibrillation ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hospital Episode Statistics ◽  
Uk Biobank ◽  
Low Density Lipoprotein Cholesterol ◽  
Hospital Episode ◽  
The Uk

ABSTRACTObjectivesWe used data from UK-Biobank that were linked with Hospital Episode Statistics and Office for National Statistics to assess the relationship between low-density lipoprotein cholesterol (LDL-C) and atrial fibrillation (AF). In this study, we applied Mendelian randomization in order to find out whether there is a causal effect of LDL-C to AF. ApproachWe used data from the UK Biobank (~500,000 subjects) which is linked with electronic health records. At baseline (2006-2010), participants from across the UK took part in this project. They have undergone measures, provided blood, urine and saliva samples for future analysis, detailed information about themselves and agreed to have their health followed. Information in relation to the development of atrial fibrillation was derived from a) the enrollment of the participants (self-reported events), b) their hospitalization before and after their recruitment to UK-Biobank (confirmed events from Hospital Episode Statistics) and c) the death certificates [confirmed events from Office for National Statistics]. We also used genetic data from the analyses of the participants’ blood sample that have been stored. We used Mendelian randomization to capture the effect of LDL-C to AF. As instruments, we used a genetic predisposition risk score (GPRs) for LDL-C, which was created as a weighted sum of the 18 most significant SNPs related to LDL-C, as there were documented in Global Lipid Consortium, in 18 out of 22 chromosomes. We ran a logistic regression model, using AF as outcome and GPRs as exposure. ResultsOur final sample consisted of 144,092 individuals, for which we have valid information for their genetic data. The AF cases in this sample were 3207, most of which were identified from Hospital Episode Statistics (hospitalization of the participants). From the Mendelian randomization study, from our preliminary results, we found a weak positive relationship between GPRs and AF, when we did not adjust for any covariate [OR per one unit increase of GPRs=1.08, 95% CI= (0.95-1.22)] and results remained practically the same when we adjusted for age and sex [OR=1.09, 95% CI= (0.96-1.24 )]. ConclusionWe observed a weak positive association between LDL-C and AF in this study. This is the first Mendelian randomization approach that focuses on this relationship. More Mendelian randomization studies should be performed in order to identify the causal effect of LDL-C to AF. The use of electronic health records will facilitate the conduction of similar studies.

scholarly journals Causal Associations Between Blood Lipids and COVID-19 Risk: A Two-Sample Mendelian Randomization Study

2021 ◽  
Author(s):  
Kun Zhang ◽  
Shan-Shan Dong ◽  
Yan Guo ◽  
Shi-Hao Tang ◽  
Hao Wu ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Blood Lipids ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Outcome Data ◽  
Causal Effects ◽  
Lipoprotein Cholesterol ◽  
Global Pandemic ◽  
The Uk

Objective: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2. It has been reported that dyslipidemia is correlated with COVID-19, and blood lipids levels, including total cholesterol, HDL-C (high-density lipoprotein cholesterol), and LDL-C (low-density lipoprotein cholesterol) levels, were significantly associated with disease severity. However, the causalities of blood lipids on COVID-19 are not clear. Approach and Results: We performed 2-sample Mendelian randomization (MR) analyses to explore the causal effects of blood lipids on COVID-19 susceptibility and severity. Using the outcome data from the UK Biobank (1221 cases and 4117 controls), we observed potential positive causal effects of dyslipidemia (odds ratio [OR], 1.27 [95% CI, 1.08–1.49], P =3.18×10 −3 ), total cholesterol (OR, 1.19 [95% CI, 1.07–1.32], P =8.54×10 −4 ), and ApoB (apolipoprotein B; OR, 1.18 [95% CI, 1.07–1.29], P =1.01×10 −3 ) on COVID-19 susceptibility after Bonferroni correction. In addition, the effects of total cholesterol (OR, 1.01 [95% CI, 1.00–1.02], P =2.29×10 −2 ) and ApoB (OR, 1.01 [95% CI, 1.00–1.02], P =2.22×10 −2 ) on COVID-19 susceptibility were also identified using outcome data from the host genetics initiative (14 134 cases and 1 284 876 controls). Conclusions: In conclusion, we found that higher total cholesterol and ApoB levels might increase the risk of COVID-19 infection.

Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

2021 ◽  
Author(s):  
Christa Meisinger ◽  
Dennis Freuer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Atopic Dermatitis ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
The Other ◽  
Uk Biobank ◽  
Inflammatory Bowel ◽  
The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

LPA and APOE are associated with statin selection in the UK Biobank

2020 ◽  
Author(s):  
Adam Lavertu ◽  
Gregory McInnes ◽  
Yosuke Tanigawa ◽  
Russ B Altman ◽  
Manuel A. Rivas
Keyword(s):  
Statin Therapy ◽  
High Intensity ◽  
Drug Response ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Treatment Decisions ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
The Uk

AbstractGenetics plays a key role in drug response, affecting efficacy and toxicity. Pharmacogenomics aims to understand how genetic variation influences drug response and develop clinical guidelines to aid clinicians in personalized treatment decisions informed by genetics. Although pharmacogenomics has not been broadly adopted into clinical practice, genetics influences treatment decisions regardless. Physicians adjust patient care based on observed response to medication, which may occur as a result of genetic variants harbored by the patient. Here we seek to understand the genetics of drug selection in statin therapy, a class of drugs widely used for high cholesterol treatment. Genetics are known to play an important role in statin efficacy and toxicity, leading to significant changes in patient outcome. We performed genome-wide association studies (GWAS) on statin selection among 59,198 participants in the UK Biobank and found that variants known to influence statin efficacy are significantly associated with statin selection. Specifically, we find that carriers of variants in APOE and LPA that are known to decrease efficacy of treatment are more likely to be on atorvastatin, a stronger statin. Additionally, carriers of the APOE and LPA variants are more likely to be on a higher intensity dose (a dose that reduces low-density lipoprotein cholesterol by greater than 40%) of atorvastatin than non-carriers (APOE: p(high intensity) = 0.16, OR = 1.7, P = 1.64 × 10−4, LPA: p(high intensity) = 0.17, OR = 1.4, P = 1.14 × 10−2). These findings represent the largest genetic association study of statin selection and statin dose association to date and provide evidence for the role of LPA and APOE in statin response, furthering the possibility of personalized statin therapy.

scholarly journals A novel Mendelian randomization method identifies causal relationships between gene expression and low-density lipoprotein cholesterol levels

2019 ◽  
Author(s):  
Adriaan van der Graaf ◽  
Annique Claringbould ◽  
Antoine Rimbert ◽  
Harm-Jan Westra ◽  
Yang Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Causal Relationships ◽  
Low Density Lipoprotein Cholesterol ◽  
Individual Level

AbstractRobust inference of causal relationships between gene expression and complex traits using Mendelian Randomization (MR) approaches is confounded by pleiotropy and linkage disequilibrium (LD) between gene expression quantitative loci (eQTLs). Here we propose a new MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data. In simulations, MR-link shows false positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other MR methods we tested, even when only one eQTL variant is present. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals and eQTLs summary statistics from whole blood and liver identified 19 genes causally linked to LDL-C. These include the previously functionally validatedSORT1gene, and thePVRL2gene, located in theAPOElocus, for which a causal role in liver was yet unknown. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.

scholarly journals Causal effect of atrial fibrillation/flutter on chronic kidney disease: A bidirectional two-sample Mendelian randomization study

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261020
Author(s):  
Masahiro Yoshikawa ◽  
Kensuke Asaba ◽  
Tomohiro Nakayama
Keyword(s):  
Atrial Fibrillation ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
European Population ◽  
Genome Wide Association Studies ◽  
The Uk

Chronic kidney disease (CKD) and atrial fibrillation are both major burdens on the health care system worldwide. Several observational studies have reported clinical associations between CKD and atrial fibrillation; however, causal relationships between these conditions remain to be elucidated due to possible bias by confounders and reverse causations. Here, we conducted bidirectional two-sample Mendelian randomization analyses using publicly available summary statistics of genome-wide association studies (the CKDGen consortium and the UK Biobank) to investigate causal associations between CKD and atrial fibrillation/flutter in the European population. Our study suggested a causal effect of the risk of atrial fibrillation/flutter on the decrease in serum creatinine-based estimated glomerular filtration rate (eGFR) and revealed a causal effect of the risk of atrial fibrillation/flutter on the risk of CKD (odds ratio, 9.39 per doubling odds ratio of atrial fibrillation/flutter; 95% coefficient interval, 2.39–37.0; P = 0.001), while the causal effect of the decrease in eGFR on the risk of atrial fibrillation/flutter was unlikely. However, careful interpretation and further studies are warranted, as the underlying mechanisms remain unknown. Further, our sample size was relatively small and selection bias was possible.

scholarly journals Pleiotropic effects of statins on ischemic heart disease: a Mendelian Randomization study in the UK Biobank

2020 ◽  
Author(s):  
CM Schooling ◽  
JV Zhao ◽  
SL Au Yeung ◽  
GM Leung
Keyword(s):  
Heart Disease ◽  
Effect Size ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pleiotropic Effects ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
The Uk ◽  
Statin Use

AbstractObjectivesStatins appear to have pleiotropic effects. We examined whether specifically statins, of the major lipid modifiers, operate on ischemic heart disease (IHD) via testosterone. As a validation, we assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone.DesignA sex-specific univariable and multivariable Mendelian randomization studySettingA large, population-based cohort study recruited in the UK from 2006-10, the UK BiobankParticipants179918 men with 25410 IHD cases and 212080 women with 12511 IHD casesMain Outcome measuresTestosterone and IHDResultsOf the three lipid modulations considered, statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe, only genetically predicted statin use in men affected testosterone (−0.15 effect size testosterone per effect size lower (of low-density lipoprotein cholesterol), 95% confidence interval (CI) −0.23 to −0.06). The genetically predicted effect of statin use on IHD in specifically men was partially mediated by testosterone (odds ratio (OR) 0.55 per effect size lower (low-density lipoprotein cholesterol), 95% CI 0.38 to 0.79, compared to OR 0.73, 95% CI 0.46 to 1.11 after allowing for testosterone). The estimate for the effect of genetically predicted statin use, independent of testosterone, was very similar in women, giving overall meta-analyzed OR 0.72, 95% CI 0.57 to 0.90 per effect size lower of low-density lipoprotein cholesterol. The genetically predicted effect of anakinra use also affected testosterone (0.022 per effect size (of IL-1Ra), 95% CI 0.01 to 0.04), and increased IHD in men.ConclusionsStatins may partially operate via testosterone in men, which may contribute to sex-specific pleiotropic effects. Anakinra operating by testosterone may also explain its unexpected effects. Our findings could facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific investigations and possibly treatments.Section 1: What is already known on this topicStatins appear to have pleiotropic effects on cardiovascular disease. Whether such effects exist and why they should occur is unclear, but could be highly relevant to the prevention and treatment of the leading cause of death.Section 2: What this study addsOur study shows that statins have similar protective effects on ischemic heart disease via low-density lipoprotein cholesterol in men and women, but unlike other major lipid modifiers statins have an additional effect specific to men via testosterone, while any harms of anakinra in men may operate by a similar mechanism. Our findings highlighting the possibility of sex-specific causes of cardiovascular disease and the need for sex-specific investigations, prevention and treatment.

scholarly journals Causal Effect of the Triglyceride-Glucose Index and the Joint Exposure of Higher Glucose and Triglyceride With Extensive Cardio-Cerebrovascular Metabolic Outcomes in the UK Biobank: A Mendelian Randomization Study

2021 ◽  
Vol 7 ◽  
Author(s):  
Shucheng Si ◽  
Jiqing Li ◽  
Yunxia Li ◽  
Wenchao Li ◽  
Xiaolu Chen ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect ◽  
Heart Diseases ◽  
Cerebrovascular Diseases ◽  
European Ancestry ◽  
Uk Biobank ◽  
Tyg Index ◽  
Metabolic Outcomes ◽  
Meta Regression ◽  
The Uk

Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.

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