Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation.
Ontology highlight
ABSTRACT:
SUBMITTER: Schooling CM
PROVIDER: S-EPMC7449694 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation.
Schooling C M CM Zhao J V JV Au Yeung S L SL Leung G M GM
eLife 20200825
We examined whether specifically statins, of the major lipid modifiers (statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) have pleiotropic effects on ischemic heart disease (IHD) via testosterone in men or women. As a validation, we similarly assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. Using previously published genetic instruments we conducted a sex-specific univariable and multivariable Mendelian randomiz ...[more]
Similar Datasets
Project description:Despite effective lipid reduction and corresponding benefits for cardiovascular disease prevention and treatment, statins have pleiotropic effects potentially increasing the risk of ischemic heart disease (IHD), particularly by increasing body mass index (BMI). We assessed whether the effects of genetically mimicked statins on IHD were strengthened by adjusting for BMI in men and women. We also assessed if increasing BMI was specific to statins in comparison to other major lipid-lowering treatments in current use, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe. Using univariable and multivariable Mendelian randomization (MR) we found genetically mimicked effects of statins increased BMI (0.33, 95% confidence interval (CI) 0.28 to 0.38), but genetically mimicked PCSK9 inhibitors and ezetimibe did not. Genetically mimicked effects of statins on IHD reduction in both sexes (odds ratio (OR) 0.55 per unit decrease in effect size of low-density lipoprotein cholesterol (LDL-c), 95% confidence interval (CI) 0.40 to 0.76), was largely similar after adjusting for BMI, in both men (OR 0.48, 95% CI 0.38 to 0.61) and women (OR 0.66, 95% CI 0.53 to 0.82). Compared with variations in PCSK9 and NPC1L1, only variation in HMGCR was associated with higher BMI. The effects on IHD of mimicking statins were similar after adjusting for BMI in both men and women. The BMI increase due to statins does not seem to be a concern as regards the protective effects of statins on IHD, however other factors driving BMI and the protective effects of statins could be.
| S-EPMC8894423 | biostudies-literature
Project description:BackgroundMuscle weakness, which increases in prevalence with age, is a major public health concern. Grip strength is commonly used to identify weakness and an improved understanding of its determinants is required. We aimed to investigate if total and central adiposity are causally associated with grip strength.MethodsUp to 470,786 UK Biobank participants, aged 38-73 years, with baseline data on four adiposity indicators (body mass index (BMI), body fat percentage (BF%), waist circumference (WC) and waist-hip-ratio (WHR)) and maximum grip strength were included. We examined sex-specific associations between each adiposity indicator and grip strength. We explored whether associations varied by age, by examining age-stratified associations (< 50 years, 50-59 years, 60-64 years,65 years +). Using Mendelian randomisation (MR), we estimated the strength of the adiposity-grip strength associations using genetic instruments for each adiposity trait as our exposure.ResultsIn males, observed and MR associations were generally consistent: higher BMI and WC were associated with stronger grip; higher BF% and WHR were associated with weaker grip: 1-SD higher BMI was associated with 0.49 kg (95% CI: 0.45 kg, 0.53 kg) stronger grip; 1-SD higher WHR was associated with 0.45 kg (95% CI:0.41 kg, 0.48 kg) weaker grip (covariate adjusted observational analyses). Associations of BMI and WC with grip strength were weaker at older ages: in males aged < 50 years and 65 years + , 1-SD higher BMI was associated with 0.93 kg (95% CI: 0.84 kg, 1.01 kg) and 0.13 kg (95% CI: 0.05 kg, 0.21 kg) stronger grip, respectively. In females, higher BF% was associated with weaker grip and higher WC was associated with stronger grip; other associations were inconsistent.ConclusionsUsing different methods to triangulate evidence, our findings suggest causal links between adiposity and grip strength. Specifically, higher BF% (in both sexes) and WHR (males only) were associated with weaker grip strength.
| S-EPMC9161610 | biostudies-literature
Project description:ObjectiveTo determine whether body mass index, body fat percentage, and waist circumference influence smoking status and intensity.DesignMendelian randomisation study.SettingUK Biobank, with replication of results from the Tobacco and Genetics (TAG) consortium.ParticipantsEuropean descent participants from the UK Biobank cohort (n=372 791) and the TAG consortium (n=74 035).Main outcome measuresRisk of current and past smoking, number of cigarettes smoked per day, age of smoking initiation.ResultsThe Mendelian randomisation analysis indicated that each standard deviation increment in body mass index (4.6) increased the risk of being a smoker (odds ratio 1.18 (95% confidence interval 1.13 to 1.23), P<0.001). This association was replicated in the TAG consortium data (1.19 (1.06 to 1.33), P=0.003). Furthermore, each standard deviation increment in body mass index was estimated to increase smoking intensity by 0.88 cigarettes per day (95% confidence interval 0.50 to 1.26, P<0.001) in UK Biobank and 1.27 cigarettes per day in the TAG consortium (0.46 to 2.07, P=0.002). Similar results were also seen for body fat percentage and waist circumference in both UK Biobank and the TAG consortium data.ConclusionsThese results strongly suggest that higher adiposity influences smoking behaviour and could have implications for the implementation of public health interventions aiming to reduce the prevalence of these important risk factors.
| S-EPMC5953237 | biostudies-literature
Project description:ObjectiveTo determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction.DesignTwo sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence.SettingReduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study.Participants3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation.Main outcome measuresThromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death.ResultsOf the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.ConclusionsEndogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.
| S-EPMC6402044 | biostudies-literature
Project description:ObjectiveTo determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status.DesignMendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non-genetic factors.SettingUK Biobank.Participants119,669 men and women of British ancestry, aged between 37 and 73 years.Main outcome measuresAge completed full time education, degree level education, job class, annual household income, and Townsend deprivation index.ResultsIn the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a £210 (€276; $300; 95% confidence interval £84 to £420; P=6 × 10(-3)) lower annual household income in men and a £1890 (£1680 to £2100; P=6 × 10(-15)) lower annual household income in women. Genetic analysis provided evidence that these associations were partly causal. A genetically determined 1 SD (6.3 cm) taller stature caused a 0.06 (0.02 to 0.09) year older age of completing full time education (P=0.01), a 1.12 (1.07 to 1.18) times higher odds of working in a skilled profession (P=6 × 10(-7)), and a £1130 (£680 to £1580) higher annual household income (P=4 × 10(-8)). Associations were stronger in men. A genetically determined 1 SD higher BMI (4.6 kg/m(2)) caused a £2940 (£1680 to £4200; P=1 × 10(-5)) lower annual household income and a 0.10 (0.04 to 0.16) SD (P=0.001) higher level of deprivation in women only.ConclusionsThese data support evidence that height and BMI play an important partial role in determining several aspects of a person's socioeconomic status, especially women's BMI for income and deprivation and men's height for education, income, and job class. These findings have important social and health implications, supporting evidence that overweight people, especially women, are at a disadvantage and that taller people, especially men, are at an advantage.
| S-EPMC4783516 | biostudies-literature
Project description:Alcohol consumption is associated with the development of cardiovascular diseases, cancer, and liver disease. The biological mechanisms are still largely unclear. Here, we aimed to use an agnostic approach to identify phenotypes mediating the effect of alcohol on various diseases.MethodsWe performed an agnostic association analysis between alcohol consumption (red and white wine, beer/cider, fortified wine, and spirits) with over 7800 phenotypes from the UK biobank comprising 223,728 participants. We performed Mendelian randomisation analysis to infer causality. We additionally performed a Phenome-wide association analysis and a mediation analysis between alcohol consumption as exposure, phenotypes in a causal relationship with alcohol consumption as mediators, and various diseases as the outcome.ResultsOf 45 phenotypes in association with alcohol consumption, 20 were in a causal relationship with alcohol consumption. Gamma glutamyltransferase (GGT; β = 9.44; 95% CI = 5.94, 12.93; Pfdr = 9.04 × 10-7), mean sphered cell volume (β = 0.189; 95% CI = 0.11, 0.27; Pfdr = 1.00 × 10-4), mean corpuscular volume (β = 0.271; 95% CI = 0.19, 0.35; Pfdr = 7.09 × 10-10) and mean corpuscular haemoglobin (β = 0.278; 95% CI = 0.19, 0.36; Pfdr = 1.60 × 10-6) demonstrated the strongest causal relationships. We also identified GGT and physical inactivity as mediators in the pathway between alcohol consumption, liver cirrhosis and alcohol dependence.ConclusionOur study provides evidence of causality between alcohol consumption and 20 phenotypes and a mediation effect for physical activity on health consequences of alcohol consumption.
| S-EPMC9317105 | biostudies-literature
Project description:BackgroundMultimorbidity, typically defined as having two or more long-term health conditions, is associated with reduced wellbeing and life expectancy. Understanding the determinants of multimorbidity, including whether they are causal, may help with the design and prioritisation of prevention interventions. This study seeks to assess the causality of education, BMI, smoking and alcohol as determinants of multimorbidity, and the degree to which BMI, smoking and alcohol mediate differences in multimorbidity by level of education.MethodsParticipants were 181,214 females and 155,677 males, mean ages 56.7 and 57.1 years respectively, from UK Biobank. We used a Mendelian randomization design; an approach that uses genetic variants as instrumental variables to interrogate causality.ResultsThe prevalence of multimorbidity was 55.1%. Mendelian randomization suggests that lower education, higher BMI and higher levels of smoking causally increase the risk of multimorbidity. For example, one standard deviation (equivalent to 5.1 years) increase in genetically-predicted years of education decreases the risk of multimorbidity by 9.0% (95% CI: 6.5 to 11.4%). A 5 kg/m2 increase in genetically-predicted BMI increases the risk of multimorbidity by 9.2% (95% CI: 8.1 to 10.3%) and a one SD higher lifetime smoking index increases the risk of multimorbidity by 6.8% (95% CI: 3.3 to 10.4%). Evidence for a causal effect of genetically-predicted alcohol consumption on multimorbidity was less strong; an increase of 5 units of alcohol per week increases the risk of multimorbidity by 1.3% (95% CI: 0.2 to 2.5%). The proportions of the association between education and multimorbidity explained by BMI and smoking are 20.4% and 17.6% respectively. Collectively, BMI and smoking account for 31.8% of the educational inequality in multimorbidity.ConclusionsEducation, BMI, smoking and alcohol consumption are intervenable causal risk factors for multimorbidity. Furthermore, BMI and lifetime smoking make a considerable contribution to the generation of educational inequalities in multimorbidity. Public health interventions that improve population-wide levels of these risk factors are likely to reduce multimorbidity and inequalities in its occurrence.
| S-EPMC10463319 | biostudies-literature
Project description:Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N?=?10,674) and replication (N?=?11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (?: 0.125 to 0.868, pFDR?<?0.043). Several behavioural traits are also associated with depression-PRS (?: 0.014 to 0.180, pFDR: 0.049 to 1.28?×?10-14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.
| S-EPMC7210889 | biostudies-literature
Project description:BackgroundConflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity.MethodsWe undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase).ResultsThere were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1-9/day: OR 2.14, 95% CI 0.87 to 5.24; 10-19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72).InterpretationCongruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.
| S-EPMC8483921 | biostudies-literature
Project description:A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55-1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55-0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42-0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66-0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.
| S-EPMC8440633 | biostudies-literature