Imperial College London

DrDipenderGill

Faculty of MedicineSchool of Public Health

Honorary Clinical Research Fellow
 
 
 
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Contact

 

+44 (0)7904 843 810dipender.gill

 
 
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Location

 

School of a Public HealthMedical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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139 results found

Rahman RP, McEwan L, Ryan DK, Gill Det al., 2021, Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines., Br J Clin Pharmacol

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.

Journal article

Karhunen V, Daghlas I, Zuber V, Vujkovic M, Olsen AK, Knudsen LB, Haynes WG, Howson JMM, Gill Det al., 2021, Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling., Diabetologia

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 .

Journal article

Higgins H, Mason AM, Larsson SC, Gill D, Langenberg C, Burgess Set al., 2021, Estimating the Population Benefits of Blood Pressure Lowering: A Wide-Angled Mendelian Randomization Study in UK Biobank., J Am Heart Assoc, Vol: 10

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 (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). 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.

Journal article

Jones DP, Wootton RE, Gill D, Carter AR, Gunnell D, Munafò MR, Sallis HMet al., 2021, Mental Health as a Mediator of the Association Between Educational Inequality and Cardiovascular Disease: A Mendelian Randomization Study., J Am Heart Assoc, Vol: 10

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.

Journal article

Sidebottom DB, Gill D, 2021, Ronapreve for prophylaxis and treatment of covid-19, BMJ-BRITISH MEDICAL JOURNAL, Vol: 374, ISSN: 1756-1833

Journal article

Georgakis MK, Gill D, 2021, Mendelian Randomization Studies in Stroke Exploration of Risk Factors and Drug Targets With Human Genetic Data, STROKE, Vol: 52, Pages: 2992-3003, ISSN: 0039-2499

Journal article

Levin MG, Zuber V, Walker VM, Klarin D, Lynch J, Malik R, Aday AW, Bottolo L, Pradhan AD, Dichgans M, Chang K-M, Rader DJ, Tsao PS, Voight BF, Gill D, Burgess S, Damrauer SMet al., 2021, Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease, CIRCULATION, Vol: 144, Pages: 353-364, ISSN: 0009-7322

Journal article

Fatumo S, Karhunen V, Chikowore T, Sounkou T, Udosen B, Ezenwa C, Nakabuye M, Soremekun O, Daghlas I, Ryan DK, Taylor A, Mason AM, Damrauer SM, Vujkovic M, Keene KL, Fornage M, Jarvelin M-R, Burgess S, Gill Det al., 2021, Metabolic traits and stroke risk in individuals of African ancestry: Mendelian randomization analysis, Stroke, Vol: 52, Pages: 2680-2684, ISSN: 0039-2499

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

Journal article

Rogne T, Liyanarachi KV, Rasheed H, Thomas LF, Flatby HM, Stenvik J, Løset M, Gill D, Burgess S, Willer CJ, Hveem K, Åsvold BO, Brumpton BM, DeWan AT, Solligård E, Damås JKet al., 2021, GWAS Identifies LINC01184/SLC12A2 as a Risk Locus for Skin and Soft Tissue Infections., J Invest Dermatol, Vol: 141, Pages: 2083-2086.e8

Journal article

Carter AR, Gill D, Davey Smith G, Taylor AE, Davies NM, Howe LDet al., 2021, Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank., Heart

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.

Journal article

Larsson SC, Gill D, 2021, Association of Serum Magnesium Levels With Risk of Intracranial Aneurysm A Mendelian Randomization Study, NEUROLOGY, Vol: 97, Pages: E341-E344, ISSN: 0028-3878

Journal article

Giontella A, Lotta LA, Overton JD, Baras A, Minuz P, Melander O, Gill D, Fava Cet al., 2021, Causal Effect of Adiposity Measures on Blood Pressure Traits in 2 Urban Swedish Cohorts: A Mendelian Randomization Study, JOURNAL OF THE AMERICAN HEART ASSOCIATION, Vol: 10

Journal article

Auvinen J, Tapio J, Karhunen V, Kettunen J, Serpi R, Dimova EY, Gill D, Soininen P, Tammelin T, Mykkanen J, Puukka K, Kahonen M, Raitoharju E, Lehtimaki T, Ala-Korpela M, Raitakari OT, Keinanen-Kiukaanniemi S, Jarvelin M-R, Koivunen Pet al., 2021, Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia, SCIENCE ADVANCES, Vol: 7, ISSN: 2375-2548

Journal article

Carcel-Marquez J, Cullell N, Muino E, Gallego-Fabrega C, Lledos M, Ibanez L, Krupinski J, Montaner J, Cruchaga C, Lee J-M, Gill D, Pare G, Mola-Caminal M, Roquer J, Jimenez-Conde J, Marti-Fabregas J, Fernandez-Cadenas Iet al., 2021, Causal Effect of MMP-1 (Matrix Metalloproteinase-1), MMP-8, and MMP-12 Levels on Ischemic Stroke A Mendelian Randomization Study, STROKE, Vol: 52, Pages: E316-E320, ISSN: 0039-2499

Journal article

Gill D, Zuber V, Dawson J, Pearson-Stuttard J, Carter AR, Sanderson E, Karhunen V, Levin MG, Wootton RE, Klarin D, Tsao PS, Tsilidis KK, Damrauer SM, Burgess S, Elliott Pet al., 2021, Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis, International Journal of Obesity, Vol: 45, Pages: 1428-1438, ISSN: 0307-0565

BackgroundHigher 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.MethodsUsing 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.ResultsThe 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.ConclusionsMeasures 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.

Journal article

Gill D, 2021, Genetic evidence for repurposing of glucagon-like peptide-1 receptor agonists to prevent heart failure, Journal of the American Heart Association, Vol: 10, ISSN: 2047-9980

Background: To investigate the genetic evidence for repurposing of glucagon-like peptide-1 receptor (GLP1R) 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 two-sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction (LVEF) as the secondary outcome. The associations were compared to those of general glycemic control on the same outcomes. Genetic associations were obtained from genome-wide association study summary statistics of type 2 diabetes (228,499 cases and 1,178,783 controls), glycated hemoglobin (n=344,182), HF (47,309 cases and 930,014 controls), and LVEF (n=16,923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1mmol/mol decrease in glycated hemoglobin 0.75, 95% confidence interval 0.64-0.87, P=1.69x10-4), and higher LVEF (standard deviation change in LVEF per 1mmol/mol decrease in glycated hemoglobin 0.22, 95% confidence interval 0.03-0.42, P=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 re-purposing of GLP1R agonists for preventing HF.

Journal article

Bonanni P, Cantón R, Gill D, Halfon P, Liebert UG, Crespo KAN, Martín JJP, Trombetta CMet al., 2021, The Role of Serology Testing to Strengthen Vaccination Initiatives and Policies for COVID-19 in Europe, COVID, Vol: 1, Pages: 20-38

<jats:p>This review explores and positions the value of serology testing to support current immunization policies and the broader policy response to the coronavirus disease 2019 (COVID-19) crisis in Europe. We applied an exploratory approach to analysing existing evidence, international recommendations, and national policies using desk research from secondary sources, document analysis, and expert information. Regional and country-level resources from five focus countries were included: France, Germany, Italy, Spain, and the United Kingdom. Seven experts in the fields of COVID-19 immunization, serology testing, seroepidemiology, and vaccine safety and effectiveness studies contributed to the review and convened in two online panel sessions. The paper includes an overview of (1) the impact of the pandemic to date, (2) testing strategies, (3) COVID-19 vaccination policies, (4) lessons on using serology testing to support immunization, (5) current policies and recommendations on the use of a serology testing strategy, and (6) implementation barriers and challenges. Finally, this paper also provides a set of knowledge-based recommendations to advance the effective and timely inclusion of serology testing and resolve impeding knowledge gaps. The recommendations herein are intended to support timely decision-making, raise awareness, guide advocacy initiatives, and inspire future studies.</jats:p>

Journal article

Tsilidis KK, Papadimitriou N, Dimou N, Gill D, Lewis SJ, Martin RM, Murphy N, Markozannes G, Zuber V, Cross AJ, Burrows K, Lopez DS, Key TJ, Travis RC, Perez-Cornago A, Hunter DJ, van Duijnhoven FJB, Albanes D, Arndt V, Berndt SI, Bézieau S, Bishop DT, Boehm J, Brenner H, Burnett-Hartman A, Campbell PT, Casey G, Castellví-Bel S, Chan AT, Chang-Claude J, de la Chapelle A, Figueiredo JC, Gallinger SJ, Giles GG, Goodman PJ, Gsur A, Hampe J, Hampel H, Hoffmeister M, Jenkins MA, Keku TO, Kweon S-S, Larsson SC, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, Milne RL, Moreno V, Nan H, Nassir R, Newcomb PA, Offit K, Pharoah PDP, Platz EA, Potter JD, Qi L, Rennert G, Sakoda LC, Schafmayer C, Slattery ML, Snetselaar L, Schenk J, Thibodeau SN, Ulrich CM, Van Guelpen B, Harlid S, Visvanathan K, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Zheng W, Bueno-de-Mesquita B, Boutron-Ruault M-C, Hughes DJ, Jakszyn P, Kühn T, Palli D, Riboli E, Giovannucci EL, Banbury BL, Gruber SB, Peters U, Gunter MJet al., 2021, Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study, American Journal of Clinical Nutrition, Vol: 113, Pages: 1490-1502, ISSN: 0002-9165

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. Genetica

Journal article

Levin MG, Klarin D, Walker VM, Gill D, Lynch J, Hellwege JN, Keaton JM, Lee KM, Assimes TL, Natarajan P, Hung AM, Edwards TL, Rader DJ, Gaziano JM, Davies NM, Tsao PS, Chang K-M, Voight BF, Damrauer SMet al., 2021, Association Between Genetic Variation in Blood Pressure and Increased Lifetime Risk of Peripheral Artery Disease, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 41, Pages: 2027-2034, ISSN: 1079-5642

Journal article

Pearson-Stuttard J, Papadimitriou N, Markozannes G, Cividini S, Kakourou A, Gill D, Rizos EC, Monori G, Ward HA, Kyrgiou M, Gunter MJ, Tsilidis KKet al., 2021, Type 2 diabetes and cancer: an umbrella review of observational and Mendelian randomisation studies, Cancer Epidemiology, Biomarkers and Prevention, Vol: 30, Pages: 1218-1228, ISSN: 1055-9965

Background Type 2 diabetes(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 summarise the evidence on T2DM and cancer and evaluate the validity of associations from both observational and Mendelian randomisation(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 cancer. Impact Potential causal associations were identified for genetically predicted T2DM and fasting insulin concentrations and risk of endometrial, pancreas, kidney, breast, lung and cervical cancer.

Journal article

Zuber V, Gill D, Ala-Korpela M, Langenberg C, Butterworth A, Bottolo L, Burgess Set al., 2021, High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 50, Pages: 893-901, ISSN: 0300-5771

Journal article

Malik R, Georgakis MK, Vujkovic M, Damrauer SM, Elliott P, Karhunen V, Giontella A, Fava C, Hellwege JN, Shuey MM, Edwards TL, Rogne T, Åsvold BO, Brumpton BM, Burgess S, Dichgans M, Gill Det al., 2021, Relationship between blood pressure and incident cardiovascular disease. Linear and non-linear Mendelian randomization analyses, Hypertension, Vol: 77, Pages: 2004-2013, ISSN: 0194-911X

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.

Journal article

Larsson SC, Gill D, 2021, Genetic predisposition to allergic diseases is inversely associated with risk of COVID-19, Allergy, Vol: 76, Pages: 1911-1913, ISSN: 0105-4538

Journal article

Malik R, Georgakis MK, Vujkovic M, Damrauer SM, Elliott P, Karhunen V, Giontella A, Fava C, Hellwege JN, Shuey MM, Edwards TL, Rogne T, Åsvold BO, Brumpton BM, Burgess S, Dichgans M, Gill Det al., 2021, Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses, Hypertension, Vol: 77, Pages: 2004-2013, ISSN: 0194-911X

<jats:p>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.</jats:p>

Journal article

Walker V, Harrison S, Carter A, Gill D, Tzoulaki I, Davies Net al., 2021, The consequences of adjustment, correction and selection in genome-wide association studies used for two-sample Mendelian randomization, Wellcome Open Research, Vol: 6, Pages: 103-103

<ns4:p><ns4:bold>Introduction</ns4:bold>: Genome-wide association studies (GWASs) often adjust for covariates, correct for medication use, or select on medication users. If these summary statistics are used in two-sample Mendelian randomization analyses, estimates may be biased. We used simulations to investigate how GWAS adjustment, correction and selection affects these estimates and performed an analysis in UK Biobank to provide an empirical example.</ns4:p><ns4:p> <ns4:bold>Methods</ns4:bold>: We simulated six GWASs: no adjustment for a covariate, correction for medication use, or selection on medication users; adjustment only; selection only; correction only; both adjustment and selection; and both adjustment and correction. We then ran two-sample Mendelian randomization analyses using these GWASs to evaluate bias. We also performed equivalent GWASs using empirical data from 306,560 participants in UK Biobank with systolic blood pressure as the exposure and body mass index as the covariate and ran two-sample Mendelian randomization with coronary heart disease as the outcome.</ns4:p><ns4:p> <ns4:bold>Results</ns4:bold>: The simulation showed that estimates from GWASs with selection can produce biased two-sample Mendelian randomization estimates. Yet, we observed relatively little difference between empirical estimates of the effect of systolic blood pressure on coronary artery disease across the six scenarios.</ns4:p><ns4:p> <ns4:bold>Conclusions</ns4:bold>: Given the potential for bias from using GWASs with selection on Mendelian randomization estimates demonstrated in our simulation, careful consideration before using this approach is warranted. However, based on our empirical results, using adjusted, corrected or selected GWASs is unlikely to make a large difference to two-sample Mendelian randomization estimates in practice.</ns4:p>

Journal article

Pazoki R, Elliott J, Evangelou E, Gill D, Pinto R, Zuber V, Said S, Dehghan A, Tzoulaki I, Jarvelin MR, Thursz M, Elliott Pet al., 2021, Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes, Nature Communications, Vol: 12, ISSN: 2041-1723

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.

Journal article

Yuan S, Burgess S, Laffan M, Mason AM, Dichgans M, Gill D, Larsson SCet al., 2021, Genetically Proxied Inhibition of Coagulation Factors and Risk of Cardiovascular Disease: A Mendelian Randomization Study, JOURNAL OF THE AMERICAN HEART ASSOCIATION, Vol: 10, ISSN: 2047-9980

Journal article

Daghlas I, Gill D, 2021, Low-density lipoprotein cholesterol and lifespan: A Mendelian randomization study, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, ISSN: 0306-5251

Journal article

Giontella A, Lotta LA, Overton JD, Melander O, Gill D, Fava Cet al., 2021, THE CAUSAL EFFECT OF ADIPOSITY MEASURES ON BLOOD PRESSURE TRAITS IN TWO URBAN SWEDISH COHORTS: A MENDELIAN RANDOMIZATION STUDY, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E267-E267, ISSN: 0263-6352

Conference paper

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