Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis
James YarmolinskyJamie RobinsonDaniela MariosaVille KarhunenJian HuangNiki DimouNeil MurphyKimberley BurrowsEmmanouil BourasKarl Smith‐ByrneSarah J. LewisTessel E. GaleslootLambertus A. KiemeneySita H. VermeulenPaul MartinDemetrius AlbanesLifang HouPolly A. NewcombEmily WhiteAlicja WolkAnna H. WuLoı̈c Le MarchandAmanda I. PhippsDaniel D. BuchananMaria Teresa LandiVictoria L. StevensStephen J. ChanockDemetrius AlbanesNeil E. CaporasoPaul BrennanChristopher I. AmosSanjay SheteRayjean J. HungHeike BickeböllerAngela RischRichard HoulstonStephen LamAdonina TardónChu ChenStig E. BojesenDavid J. HunterH. E. WichmannDavid C. ChristianiGad RennertSusanne M. ArnoldJohn K. FieldLoı̈c Le MarchandOlle MelanderHans BrunnströmGeoffrey LiuAngeline S. AndrewLambertus A. KiemeneyHongbing ShenShanbeh ZienolddinyKjell GrankvistMikael JohanssonM. Dawn TeareYun Chul HongJian‐Min YuanPhilip LazarusMatthew B. SchabathMelinda C. AldrichRosalind A. EelesChristopher A. HaimanZsofia Kote‐JaraiFredrick R. SchumacherSara BenllochAli Amin Al OlamaKenneth MuirSonja I. BerndtDavid V. ContiFredrik WiklundStephen J. ChanockStephen J. ChanockCatherine M. TangenJyotsna BatraJudith A. ClementsHenrik GrönbergNora PashayanJohanna SchleutkerDemetrius AlbanesStephanie J. WeinsteinAlicja WolkCatharine WestLorelei A. MucciGéraldine Cancel‐TassinStella KoutrosKarina D. SørensenEli Marie GrindedalDavid E. NealFreddie C. HamdyJenny DonovanRuth C. TravisRobert J. HamiltonSue A. InglesBarry S. RosensteinYong‐Jie LuGraham G. GilesRobert J. MacInnisAdam S. KibelAna VegaManolis KogevinasKathryn L. PenneyJong Y. ParkJanet L. StanfrodCezary CybulskiBørge G. NordestgaardSune F. NielsenHermann BrennerChristiane MaierChristopher J. LogothetisEsther M. JohnManuel R. TeixeiraSusan L. NeuhausenKim De RuyckAzad RazackLisa F. NewcombDavor LesselRadka KanevaNawaid UsmaniFrank ClaessensPaul A. TownsendJose E. CastelaoMonique J. RoobolF. MénégauxKay-Tee KhawLisa Cannon‐AlbrightHardev PandhaStephen N. ThibodeauDavid J. HunterPeter KraftWilliam J. BlotElio RíboliSizheng Steven ZhaoDipender GillStephen J. ChanockMark P. PurdueGeorge Davey SmithPaul BrennanKarl‐Heinz HerzigMarjo‐Riitta JärvelinChris AmosRayjean J. HungAbbas DehghanDavid J. HunterMarc J. GunterKonstantinos K. TsilidisRichard M. Martin
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Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.Keywords:
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Nutritional epidemiology aims to identify dietary and lifestyle causes for human diseases. Causality inference in nutritional epidemiology is largely based on evidence from studies of observational design, and may be distorted by unmeasured or residual confounding and reverse causation. Mendelian randomization is a recently developed methodology that combines genetic and classical epidemiological analysis to infer causality for environmental exposures, based on the principle of Mendel's law of independent assortment. Mendelian randomization uses genetic variants as proxies for environmental exposures of interest. Associations derived from Mendelian randomization analysis are less likely to be affected by confounding and reverse causation. During the past 5 years, a body of studies examined the causal effects of diet/lifestyle factors and biomarkers on a variety of diseases. The Mendelian randomization approach also holds considerable promise in the study of intrauterine influences on offspring health outcomes. However, the application of Mendelian randomization in nutritional epidemiology has some limitations.
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Lipoproteins are a major risk factor for atherosclerotic cardiovascular diseases (ASCVD). Among the lipoproteins, low-density lipoproteins (LDL) have been shown to be causally associated with ASCVD development. In contrast, triglycerides or triglyceride-rich lipoproteins receive less attention than LDL because there is little definite evidence from randomized controlled trials. A Mendelian randomization study has recently been published in which a causal association could be estimated with observational datasets. Using such Mendelian randomization studies, ranging from common to rare genetic variations, triglycerides seem to be causally associated with ASCVD outcomes independent of LDL. Although the "causal association" of serum triglycerides and ASCVD is difficult to assert, accumulated evidence from clinical and Mendelian randomization studies, using common and rare genetic variations, strongly supports such an association. In this article, we provide a summary of investigations focusing on important causal associations between serum triglycerides and ASCVD from the clinical point of view.
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Observational studies have contributed in a major way to understanding modifiable determinants of cardiovascular disease risk, but several examples exist of factors that were identified in observational studies as potentially protecting against coronary heart disease, that in randomized controlled trials had no such effect. The likely reason for misleading findings from observational epidemiological studies is that associations are influenced by confounding, bias, and reverse causation—where disease influences a risk factor, rather than vice versa. Mendelian randomization utilizes genetic variants that serve as proxy measures for modifiable risk factors to allow estimation of the causal influence of the modifiable risk factor in question. We present examples of the use of the Mendelian randomization approach and discuss both the limitations and potentials of this strategy.
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Preclinical studies have indicated insulin-like growth factor 1 (IGF1) as a novel therapeutic target in the treatment of migraines. We aimed to investigate the causal effect of circulating IGF1 levels on migraine risk using the two-sample Mendelian randomization method.A total of 431 independent variants from 363,228 unrelated individuals in the UK Biobank were used as genetic instruments for circulating IGF1 levels. Summary-level data for migraines were obtained from two independent studies with 10,536 and 28,852 migraine cases, respectively.Mendelian randomization using inverse-variance weighting showed that increased IGF1 levels were significantly associated with decreased risk of migraines in both outcome datasets (odds ratio 0.905, 95% confidence interval 0.842-0.972, p = 0.006; odds ratio 0.929, 95% confidence interval 0.882-0.979, p = 0.006). Although some other robust Mendelian randomization methods did not demonstrate a significant association, no unbalanced horizontal pleiotropy was found by Mendelian randomization-Egger regression (p values for horizontal pleiotropy 0.232 and 0.435). The effect was confirmed in additional analyses including multivariable Mendelian randomization analyses.This two-sample Mendelian randomization study showed that genetically determined increased IGF1 levels are causally associated with decreased migraine risk. Future randomized controlled trials are warranted to confirm the benefits of IGF1 administration on migraines.
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To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease.
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A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This “multivariable Mendelian randomization” approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.
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A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This "multivariable Mendelian randomization" approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.
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Purpose of review Mendelian randomization is a technique for judging the causal impact of a risk factor on an outcome from observational data using genetic variants. Although evidence from Mendelian randomization for the effects of major lipids and lipoproteins on coronary heart disease (CHD) risk has been around for a relatively long time, new data resources and new methodological approaches have given fresh insight into these relationships. The lessons from these analyses are likely to be highly relevant when it comes to lipidomics and the analyses of lipid subspecies whose biology is less well understood. Recent findings Although analyses of low-density lipoprotein cholesterol and lipoprotein(a) are unambiguous as there are genetic variants that associate exclusively with these risk factors and have well understood biology, analyses for triglycerides, and high-density lipoprotein cholesterol (HDL-c) are less clear. For example, a subset of genetic variants having specific associations with HDL-c are not associated with CHD risk, but an allele score including all variants associated with HDL-c does associate with CHD risk. Recently developed methods, such as multivariable Mendelian randomization, Mendelian randomization-Egger, and a weighted median method, suggest that the relationship between HDL-c and CHD risk is null, thus confirming experimental evidence. Summary Robust methods for Mendelian randomization have important utility for understanding the causal relationships between major lipids and CHD risk, and are likely to play an important role in judging the causal relevance of lipid subspecies and other metabolites measured on high-dimensional phenotyping platforms.
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