Publications by authors named "Dipender Gill"

115 Publications

Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines.

Br J Clin Pharmacol 2021 Sep 10. Epub 2021 Sep 10.

Clinical Pharmacology and Therapeutics Section, Institute for Infection and Immunity, St George's, University of London, London, UK.

Interleukin 6 (IL-6) is a circulating cytokine implicated in inflammatory processes. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines, and growth factors. The significant results include IL-10 (Mendelian randomization estimate: -0.306, standard error, SE: 0.093), IL-4 (estimate: -0.393, SE: 0.1007), eotaxin (estimate: -0.510, SE: 0.1213) and FGF (estimate: -0.334, SE: 0.1005). The findings from this study support feedback effects of IL-6R signalling on reducing levels of some circulating cytokines and identify compensatory mechanisms that maybe modulating its inflammatory effects. These results provide insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.
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http://dx.doi.org/10.1111/bcp.15079DOI Listing
September 2021

Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling.

Diabetologia 2021 Sep 9. Epub 2021 Sep 9.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

Aims/hypothesis: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling.

Methods: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome.

Results: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome.

Conclusions/interpretation: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted.

Data Availability: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP .
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http://dx.doi.org/10.1007/s00125-021-05564-7DOI Listing
September 2021

Ronapreve for prophylaxis and treatment of covid-19.

BMJ 2021 09 2;374:n2136. Epub 2021 Sep 2.

Imperial College London, London, UK

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http://dx.doi.org/10.1136/bmj.n2136DOI Listing
September 2021

Mental Health as a Mediator of the Association Between Educational Inequality and Cardiovascular Disease: A Mendelian Randomization Study.

J Am Heart Assoc 2021 Sep 2;10(17):e019340. Epub 2021 Sep 2.

Department of Population Health Sciences Bristol Medical School University of Bristol UK.

Background Education is inversely associated with cardiovascular disease (CVD). Several mediators of this have been established; however, a proportion of the protective effect remains unaccounted for. Mental health is a proposed mediator, but current evidence is mixed and subject to bias from confounding factors and reverse causation. Mendelian randomization is an instrumental variable technique that uses genetic proxies for exposures and mediators to reduce such bias. Methods and Results We performed logistic regression and 2-step Mendelian randomization analyses using UK Biobank data and genetic summary statistics to investigate whether educational attainment affects risk of mental health disorders. We then performed mediation analyses to explore whether mental health disorders mediate the association between educational attainment and cardiovascular risk. Higher levels of educational attainment were associated with reduced depression, anxiety, and CVD in observational analyses (odds ratio [OR], 0.79 [95% CI, 0.77-0.81], 0.76 [95% CI, 0.73-0.79], and 0.75 [95% CI, 0.74-0.76], respectively), and Mendelian randomization analyses provided evidence of causality (OR, 0.72 [95% CI, 0.67-0.77], 0.50 [95% CI, 0.42-0.59], and 0.62 [95% CI, 0.58-0.66], respectively). Both anxiety and depression were associated with CVD in observational analyses (OR, 1.63 [95% CI, 1.49-1.79] and 1.70 [95% CI, 1.59-1.82], respectively) but only depression showed evidence of causality in the Mendelian randomization analyses (OR, 1.09; 95% CI, 1.03-1.15). An estimated 2% of the total protective effect of education on CVD was mediated by depression. Conclusions Higher levels of educational attainment protect against mental health disorders, and reduced depression accounts for a small proportion of the total protective effect of education on CVD.
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http://dx.doi.org/10.1161/JAHA.120.019340DOI Listing
September 2021

Estimating the Population Benefits of Blood Pressure Lowering: A Wide-Angled Mendelian Randomization Study in UK Biobank.

J Am Heart Assoc 2021 Sep 28;10(17):e021098. Epub 2021 Aug 28.

Department of Public Health and Primary Care University of Cambridge United Kingdom.

Background The 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 Results We 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 (<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). Conclusions Risk 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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http://dx.doi.org/10.1161/JAHA.121.021098DOI Listing
September 2021

Mendelian Randomization Studies in Stroke: Exploration of Risk Factors and Drug Targets With Human Genetic Data.

Stroke 2021 Aug 17;52(9):2992-3003. Epub 2021 Aug 17.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (D.G.).

Elucidating the causes of stroke is key to developing effective preventive strategies. The Mendelian randomization approach leverages genetic variants related to an exposure of interest to investigate the effects of varying that exposure on disease risk. The random allocation of genetic variants at conception reduces confounding from environmental factors and thus strengthens causal inference, analogous to treatment allocation in a randomized controlled trial. With the recent explosion in the availability of human genetic data, Mendelian randomization has proven a valuable tool for studying risk factors for stroke. In this review, we provide an overview of recent developments in the application of Mendelian randomization to unravel the pathophysiology of stroke subtypes and identify therapeutic targets for clinical translation. The approach has offered novel insight into the differential effects of risk factors and antihypertensive, lipid-lowering, and anticoagulant drug classes on risk of stroke subtypes. Analyses have further facilitated the prioritization of novel drug targets, such as for inflammatory pathways underlying large artery atherosclerotic stroke and for the coagulation cascade that contributes to cardioembolic stroke. With continued methodological advances coupled with the rapidly increasing availability of genetic data related to a broad range of stroke phenotypes, the potential for Mendelian randomization in this context is expanding exponentially.
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http://dx.doi.org/10.1161/STROKEAHA.120.032617DOI Listing
August 2021

Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank.

Heart 2021 Jul 27. Epub 2021 Jul 27.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Objective: Identify whether participants with lower education are less likely to report taking statins for primary cardiovascular prevention than those with higher education, but an equivalent increase in underlying cardiovascular risk.

Methods: Using data from a large prospective cohort study, UK Biobank, we calculated a QRISK3 cardiovascular risk score for 472 097 eligible participants with complete data on self-reported educational attainment and statin use (55% female participants; mean age 56 years). We used logistic regression to explore the association between (i) QRISK3 score and (ii) educational attainment on self-reported statin use. We then stratified the association between QRISK3 score and statin use, by educational attainment to test for interactions.

Results: There was evidence of an interaction between QRISK3 score and educational attainment. Per unit increase in QRISK3 score, more educated individuals were more likely to report taking statins. In women with ≤7 years of schooling, a one unit increase in QRISK3 score was associated with a 7% higher odds of statin use (OR 1.07, 95% CI 1.07 to 1.07). In women with ≥20 years of schooling, a one unit increase in QRISK3 score was associated with an 14% higher odds of statin use (OR 1.14, 95% CI 1.14 to 1.15). Comparable ORs in men were 1.04 (95% CI 1.04 to 1.05) for ≤7 years of schooling and 1.08 (95% CI 1.08, 1.08) for ≥20 years of schooling.

Conclusion: Per unit increase in QRISK3 score, individuals with lower educational attainment were less likely to report using statins, likely contributing to health inequalities.
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http://dx.doi.org/10.1136/heartjnl-2021-319238DOI Listing
July 2021

Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia.

Sci Adv 2021 Jul 14;7(29). Epub 2021 Jul 14.

Biocenter Oulu, 90014 Oulu, Finland.

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans ( = 7175) and used Mendelian randomization (MR) to evaluate potential causality ( = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes and in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.
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http://dx.doi.org/10.1126/sciadv.abi4822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279517PMC
July 2021

Genetic Evidence for Repurposing of GLP1R (Glucagon-Like Peptide-1 Receptor) Agonists to Prevent Heart Failure.

J Am Heart Assoc 2021 Jul 29;10(13):e020331. Epub 2021 Jun 29.

Department of Epidemiology and Biostatistics School of Public HealthImperial College London London UK.

Background This study was designed to investigate the genetic evidence for repurposing of GLP1R (glucagon-like peptide-1 receptor) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results We applied 2-sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction as the secondary outcome. The associations were compared with those of general glycemic control on the same outcomes. Genetic associations were obtained from genome-wide association study summary statistics of type 2 diabetes mellitus (228 499 cases and 1 178 783 controls), glycated hemoglobin (n=344 182), HF (47,309 cases and 930 014 controls), and left ventricular ejection fraction (n=16 923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1 mmol/mol decrease in glycated hemoglobin 0.75; 95% CI, 0.64-0.87; =1.69×10), and higher left ventricular ejection fraction (SD change in left ventricular ejection fraction per 1 mmol/mol decrease in glycated hemoglobin 0.22%; 95% CI, 0.03-0.42; =0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions This genetic evidence supports the repurposing of GLP1R agonists for preventing HF.
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http://dx.doi.org/10.1161/JAHA.120.020331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403330PMC
July 2021

Association of Serum Magnesium Levels With Risk of Intracranial Aneurysm: A Mendelian Randomization Study.

Neurology 2021 07 22;97(4):e341-e344. Epub 2021 Jun 22.

From the Unit of Cardiovascular and Nutritional Epidemiology (S.C.L.), Institute of Environmental Medicine, Karolinska Institutet, Stockholm; Unit of Medical Epidemiology (S.C.L.), Department of Surgical Sciences, Uppsala University, Sweden; Department of Epidemiology and Biostatistics (D.G.), School of Public Health, St Mary's Hospital, Imperial College London; Clinical Pharmacology and Therapeutics Section (D.G.), Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London; Clinical Pharmacology Group (D.G.), Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London; and Novo Nordisk Research Centre Oxford (D.G.), UK.

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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http://dx.doi.org/10.1212/WNL.0000000000012244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362358PMC
July 2021

Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease.

Circulation 2021 Aug 18;144(5):353-364. Epub 2021 Jun 18.

Department of Surgery (V.M.W., S.M.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.

Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.

Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.

Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; =0.003) and CAD (marginal inclusion probability, 0.92; =0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84-0.91]; =9×10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; =4×10), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; <1×10). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; =2.3×10), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; =0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03-1.04]; =1.0×10).

Conclusions: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323712PMC
August 2021

Causal Effect of Adiposity Measures on Blood Pressure Traits in 2 Urban Swedish Cohorts: A Mendelian Randomization Study.

J Am Heart Assoc 2021 Jul 14;10(13):e020405. Epub 2021 Jun 14.

Department of Medicine University of Verona Verona Italy.

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, GRS-WHR, GRS-VAT, GRS-BF) 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 795Projects 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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http://dx.doi.org/10.1161/JAHA.120.020405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403279PMC
July 2021

Metabolic Traits and Stroke Risk in Individuals of African Ancestry: Mendelian Randomization Analysis.

Stroke 2021 Aug 3;52(8):2680-2684. Epub 2021 Jun 3.

Department of Epidemiology and Biostatistics, Medical School Building, St Mary's Hospital, Imperial College London, United Kingdom (V.K., M.-R.J., D.G.).

Background And Purpose: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals.

Methods: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy.

Results: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07-1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04-1.21]; total cholesterol: 1.23 [1.06-1.43]; HDL-C, 0.93 [0.89-0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals.

Conclusions: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.
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http://dx.doi.org/10.1161/STROKEAHA.121.034747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312569PMC
August 2021

Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis.

Int J Obes (Lond) 2021 07 17;45(7):1428-1438. Epub 2021 May 17.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Background: Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood.

Methods: Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke.

Results: The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% -23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI -20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome.

Conclusions: Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.
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http://dx.doi.org/10.1038/s41366-021-00807-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236409PMC
July 2021

Antivirals against SARS-CoV-2 by autumn?

BMJ 2021 05 17;373:n1215. Epub 2021 May 17.

St George's, University of London, London, UK

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http://dx.doi.org/10.1136/bmj.n1215DOI Listing
May 2021

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.

Nat Commun 2021 05 10;12(1):2579. Epub 2021 May 10.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-021-22338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110798PMC
May 2021

Genetic Evidence Supporting Fibroblast Growth Factor 21 Signalling as a Pharmacological Target for Cardiometabolic Outcomes and Alzheimer's Disease.

Nutrients 2021 Apr 29;13(5). Epub 2021 Apr 29.

Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Hospital, Imperial College London, London W2 1PG, UK.

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 gene region was leveraged to investigate the potential clinical effects of targeting FGF21. The 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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http://dx.doi.org/10.3390/nu13051504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146158PMC
April 2021

We need clinical guidelines fit for a pandemic.

BMJ 2021 04 29;373:n1093. Epub 2021 Apr 29.

St George's, University of London, London, UK.

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http://dx.doi.org/10.1136/bmj.n1093DOI Listing
April 2021

Genetically Proxied Inhibition of Coagulation Factors and Risk of Cardiovascular Disease: A Mendelian Randomization Study.

J Am Heart Assoc 2021 04 9;10(8):e019644. Epub 2021 Apr 9.

Unit of Cardiovascular and Nutritional Epidemiology Institute of Environmental MedicineKarolinska Institutet Stockholm Sweden.

Background We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases. Methods and Results Genetic instruments proxying coagulation factor inhibition were identified from genome-wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age- and sex-adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large-artery stroke risk (=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage. Conclusions This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.
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http://dx.doi.org/10.1161/JAHA.120.019644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174173PMC
April 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

Type 2 Diabetes and Cancer: An Umbrella Review of Observational and Mendelian Randomization Studies.

Cancer Epidemiol Biomarkers Prev 2021 06 18;30(6):1218-1228. Epub 2021 Mar 18.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Background: Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of developing several common cancers, but it is unclear whether this association is causal. We aimed to summarize the evidence on T2DM and cancer and evaluate the validity of associations from both observational and Mendelian randomization (MR) studies.

Methods: We performed an umbrella review of the evidence across meta-analyses of observational studies that examined associations of T2DM with risk of developing or dying from site-specific cancers, and MR studies that explored the potential causal association of T2DM and associated biomarkers with cancer risk.

Results: We identified eligible observational meta-analyses that assessed associations between T2DM and cancer incidence for 18 cancer sites, cancer mortality for seven sites, and cancer incidence or mortality for four sites. Positive associations between T2DM and six cancers reached strong or highly suggestive evidence. We found eight MR studies assessing the association of genetically predicted T2DM and seven and eight studies assessing the association of genetically predicted fasting insulin or fasting glucose concentrations, respectively, upon site-specific cancers. Positive associations were found between genetically predicted T2DM and fasting insulin and risk of six cancers. There was no association between genetically predicted fasting plasma glucose and cancer except for squamous cell lung carcinoma.

Conclusions: We found robust observational evidence for the association between T2DM and colorectal, hepatocellular, gallbladder, breast, endometrial, and pancreatic cancers.

Impact: Potential causal associations were identified for genetically predicted T2DM and fasting insulin concentrations and risk of endometrial, pancreas, kidney, breast, lung, and cervical cancers.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1245DOI Listing
June 2021

Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic Profile: A Phenome-Wide Association Study.

Circulation 2021 Mar 15;143(11):1177-1180. Epub 2021 Mar 15.

Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany (M.K.G., R.M., M.D.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052604DOI Listing
March 2021

Low-density lipoprotein cholesterol and lifespan: A Mendelian randomization study.

Br J Clin Pharmacol 2021 Oct 4;87(10):3916-3924. Epub 2021 Apr 4.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Aims: It is unknown whether long-term low-density lipoprotein cholesterol (LDL-c) lowering increases lifespan and longevity in a general population not selected for elevated cardiovascular risk. The present study aimed to investigate the overall and gene-specific effect of circulating LDL-c levels on lifespan and longevity in a general population.

Methods: Leveraging data from the Global Lipids Genetics Consortium (n = 173 082), we identified genetic variants to proxy LDL-c levels generally, and also through perturbation of particular drug targets (HMGCR, NPC1L1 and PCSK9). We investigated their association with lifespan (n = 1 012 240) using Mendelian randomization, and replicated results using the outcome of longevity to the 90th vs. 60th percentile age (11 262 cases/25 483 controls).

Results: A 1-standard deviation increase in genetically proxied LDL-c was associated with 1.2 years lower lifespan (95% confidence interval [CI] -1.55, -0.87; P = 3.83 × 10 ). Findings were consistent in statistical sensitivity analyses, and when considering the outcome of longevity (odds ratio for survival to the 90th vs 60th percentile age 0.72, 95% CI 0.64, 0.81, P = 7.83 × 10 ). Gene-specific Mendelian randomization analyses showed a significant effect of LDL-c modification through PCSK9 on lifespan (-0.99 years, 95% CI -1.43, 0.55, P = 6.80 × 10 ); however, estimates for HMGCR and NPC1L1 were underpowered.

Conclusions: This genetic evidence supports that higher LDL-c levels reduce lifespan and longevity. In a general population that is not selected for increased cardiovascular risk, there is likely to be a net lifespan benefit of LDL-c lowering therapies, particularly for PCSK9 inhibitors, although randomized controlled trials are necessary before modification of clinical practice.
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http://dx.doi.org/10.1111/bcp.14811DOI Listing
October 2021

Leveraging genetic data to elucidate the relationship between Covid-19 and ischemic stroke.

medRxiv 2021 Mar 1. Epub 2021 Mar 1.

Background: The relationship between coronavirus disease 2019 (Covid-19) and ischemic stroke is poorly defined. We aimed to leverage genetic data to investigate reported associations.

Methods: Genetic association estimates for liability to Covid-19 and cardiovascular traits were obtained from large-scale consortia. Analyses primarily focused on critical Covid-19, defined as hospitalization with Covid-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical Covid-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both Covid-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical Covid-19 was associated with increased risk of any of the cardiovascular outcomes for which genetic correlation was identified.

Results: There was evidence of genetic correlation between critical Covid-19 and ischemic stroke (r =0.29, FDR -value=4.65×10 ), body mass index (r =0.21, FDR- -value 6.26×10 ) and C-reactive protein (r =0.20, FDR- -value=1.35×10 ), but none of the other considered traits. In Mendelian randomization analysis, liability to critical Covid-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical Covid-19 liability 1.03, 95% confidence interval 1.00-1.06, -value=0.03). Similar estimates were obtained when considering ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical Covid-19.

Conclusions: These data support that liability to critical Covid-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe Covid-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.
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http://dx.doi.org/10.1101/2021.02.25.21252441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941632PMC
March 2021

Genetically proxied growth-differentiation factor 15 levels and body mass index.

Br J Clin Pharmacol 2021 Oct 19;87(10):4036-4039. Epub 2021 Mar 19.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

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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http://dx.doi.org/10.1111/bcp.14808DOI Listing
October 2021

GWAS Identifies LINC01184/SLC12A2 as a Risk Locus for Skin and Soft Tissue Infections.

J Invest Dermatol 2021 Aug 1;141(8):2083-2086.e8. Epub 2021 Mar 1.

Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU Norwegian University of Science and Technology, Trondheim, Norway; Department of Infectious Diseases, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, NTNU Norwegian University of Science and Technology, Trondheim, Norway.

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http://dx.doi.org/10.1016/j.jid.2021.01.020DOI Listing
August 2021

Mendelian randomization for studying the effects of perturbing drug targets.

Wellcome Open Res 2021 10;6:16. Epub 2021 Feb 10.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.
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http://dx.doi.org/10.12688/wellcomeopenres.16544.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903200PMC
February 2021
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