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Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases : A Mendelian Randomization Study

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Author(s): Michael G. Levin , MD ¹ ^, ² ^, ³ , Derek Klarin , MD ⁴ ^, ⁵ , Themistocles L. Assimes , MD, PhD ⁶ ^, ⁷ ^, ⁸ , Matthew S. Freiberg , MD ⁹ ^, ¹⁰ ^, ¹¹ , Erik Ingelsson , MD, PhD ⁷ ^, ⁸ ^, ¹² ^, ¹³ , Julie Lynch , PhD ¹⁴ ^, ¹⁵ , Pradeep Natarajan , MD ¹⁶ ^, ¹⁷ ^, ¹⁸ ^, ¹⁹ , Christopher O’Donnell , MD ¹⁹ , Daniel J. Rader , MD ² ^, ²⁰ ^, ²¹ , Philip S. Tsao , PhD ⁶ ^, ²² , Kyong-Mi Chang , MD ² ^, ³ , Benjamin F. Voight , PhD ³ ^, ²⁰ ^, ²¹ ^, ²³ , Scott M. Damrauer , MD ³ ^, ²⁴ ^,

Publication date (Electronic): 19 January 2021

Journal: JAMA Network Open

Publisher: American Medical Association

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Key Points

Question

Are there differential associations between genetic liability to smoking and atherosclerotic cardiovascular disease (ASCVD) outcomes (coronary artery disease, peripheral artery disease, and ischemic stroke)?

Findings

In this mendelian randomization study including summary data for more than 1 million individuals, genetic liability to smoking was associated with increased risk of ASCVD, with the largest association with peripheral artery disease, independent from other cardiovascular risk factors.

Meaning

Findings of this study indicate that genetic liability to smoking has a strong, independent effect on ASCVD but is most strongly associated with peripheral artery disease; further studies of the differential effects of other ASCVD risk factors may improve risk stratification and treatment.

Abstract

Importance

Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood.

Objective

To determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke.

Design, Setting, and Participants

Mendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462 690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60 801 cases, 123 504 controls), PAD (VA Million Veteran Program; up to 24 009 cases, 150 983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406 111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020.

Exposures

Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index).

Main Outcomes and Measures

Risk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke.

Results

Genetic liability to smoking was associated with increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56; P = 3.6 × 10 ⁻¹⁶), CAD (OR, 1.48; 95% CI, 1.25-1.75; P = 4.4 × 10 ⁻⁶), and stroke (OR, 1.40; 95% CI, 1.02-1.92; P = .04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19; P = .02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84; P = .004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors.

Conclusions and Relevance

In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.

Abstract

This mendelian randomization study evaluates summary statistics from genome-wide associations involving more than 1 million individuals to assess whether there are differential associations between genetic liability to smoking and risk of coronary artery disease, peripheral artery disease, and large-artery stroke.

Related collections

Most cited references 60

Record: found
Abstract: found
Article: found

Is Open Access

Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator

Jack Bowden, George Davey Smith, Philip C. Haycock … (2017)

ABSTRACT Developments in genome‐wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse‐variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite‐sample Type 1 error rates than the inverse‐variance weighted method, and is complementary to the recently proposed MR‐Egger (Mendelian randomization‐Egger) regression method. In analyses of the causal effects of low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol on coronary artery disease risk, the inverse‐variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR‐Egger regression methods suggest a null effect of high‐density lipoprotein cholesterol that corresponds with the experimental evidence. Both median‐based and MR‐Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants.

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Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases

Marie Verbanck, Chia-Yen Chen, Benjamin M. Neale … (2018)

Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the ‘no horizontal pleiotropy’ assumption can cause severe bias in MR. We developed the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that MR-PRESSO is best suited when horizontal pleiotropy occurs in <50% of instruments. Next, we applied MR-PRESSO, along with several other MR tests to complex traits and diseases, and found that horizontal pleiotropy: (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from −131% to 201%; (iii) induced false positive causal relationships in up to 10% of relationships; and (iv) can be corrected in some but not all instances.

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Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.

Paul M Ridker, Brendan M. Everett, Tom Thuren … (2017)

Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.

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Author and article information

Journal

Journal ID (nlm-ta): JAMA Netw Open

Journal ID (iso-abbrev): JAMA Netw Open

Journal ID (pmc): JAMA Netw Open

Title: JAMA Network Open

Publisher: American Medical Association

ISSN (Electronic): 2574-3805

Publication date (Electronic): 19 January 2021

Publication date Collection: January 2021

Publication date PMC-release: 19 January 2021

Volume: 4

Issue: 1

Electronic Location Identifier: e2034461

Affiliations

[1 ]Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia

[2 ]Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia

[3 ]Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania

[4 ]Malcolm Randall VA Medical Center, Gainesville, Florida

[5 ]Department of Surgery, University of Florida, Gainesville

[6 ]Palo Alto VA Healthcare System, Palo Alto, California

[7 ]Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California

[8 ]Stanford Cardiovascular Institute, Stanford University, Stanford, California

[9 ]Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

[10 ]Geriatric Research Education and Clinical Centers, Veterans Affairs Tennessee Valley Healthcare System, Nashville

[11 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

[12 ]Stanford Diabetes Research Center, Stanford University, Stanford, California

[13 ]Now with GlaxoSmithKline, San Francisco, California

[14 ]Edith Nourse VA Medical Center, Bedford, Massachusetts

[15 ]VA Informatics and Computing Infrastructure, Salt Lake City, Utah

[16 ]Cardiovascular Research Center, Massachusetts General Hospital, Boston

[17 ]Broad Institute of Harvard and MIT, Cambridge, Massachusetts

[18 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts

[19 ]VA Boston Healthcare System, Boston, Massachusetts

[20 ]Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia

[21 ]Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia

[22 ]Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Palo Alto, California

[23 ]Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia

[24 ]Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia

Author notes

Article Information

Accepted for Publication: November 11, 2020.

Published: January 19, 2021. doi:10.1001/jamanetworkopen.2020.34461

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Levin MG et al. JAMA Network Open.

Corresponding Author: Scott M. Damrauer, MD, Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Ave, Philadelphia, PA 19104 ( scott.damrauer@ 123456va.gov ; damrauer@ 123456upenn.edu ).

Author Contributions: Dr Levin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Levin, Ingelsson, O’Donnell, Chang, Damrauer.

Acquisition, analysis, or interpretation of data: Levin, Klarin, Assimes, Freiberg, Ingelsson, Lynch, Natarajan, Rader, Tsao, Voight, Damrauer.

Drafting of the manuscript: Levin, Klarin, Lynch, Chang.

Critical revision of the manuscript for important intellectual content: Levin, Klarin, Assimes, Freiberg, Ingelsson, Lynch, Natarajan, O’Donnell, Rader, Tsao, Voight, Damrauer.

Statistical analysis: Levin, Klarin, Lynch, Voight, Damrauer.

Obtained funding: Assimes, Lynch, Rader, Tsao, Chang, Damrauer.

Administrative, technical, or material support: Klarin, Assimes, Lynch, Chang, Voight, Damrauer.

Supervision: Klarin, Assimes, Natarajan, Rader, Tsao, Damrauer.

Conflict of Interest Disclosures: Dr Klarin reported receiving personal fees from Regeneron Pharmaceuticals outside the submitted work. Dr Natarajan reported receiving grants from Amgen, Apple, AstraZeneca, and Boston Scientific outside the submitted work; receiving personal fees from Blackstone Life Sciences, Novartis, Apple, Genetech/Roche; and having equity in and a spousal employment at Vertex Pharmaceuticals. Dr Tsao reported receiving grants from the VA Office of Research and Development during the conduct of the study. Dr Voight reported receiving personal fees from JAMA as a statistical reviewer for JAMA Network Open and receiving personal fees from the American Heart Association as an Associate Editor outside the submitted work. Dr Damrauer reported receiving grants from the US Department of Veterans Affairs during the conduct of the study and receiving grants from RenalytixAI and personal fees from Calico Labs outside the submitted work. No other disclosures were reported.

Funding/Support: This research was supported by award MVP003 from the VA Million Veteran Program; grants IK2-CX001780 (to Dr Damrauer) and I01-BX003362 (to Drs Tsao and Chang) from the US Department of Veterans Affairs; award 18SFRN33960373 (to Dr Freiberg) from the American Heart Association Strategically Focused Research Network in Vascular Disease; grants HL125032 (to Dr Freiberg) and R01HL142711 (to Dr Natarajan) from the National Heart, Lung, and Blood Institute; grants DK101478 and HG010067 (to Dr Voight) from the National Institute of Diabetes and Digestive and Kidney Diseases; and a Linda Pechenik Montague Investigator Award (to Dr Voight).

Role of the Funder/Sponsor: The funders had no role in design and conduct of the study; in collection, management, analysis, and interpretation of the data; and in the decision to submit the manuscript for publication. The MVP Publications committee was involved in preparation, review, or approval of the manuscript.

Group Information: The VA Million Veteran Program (MVP) contributors include the following: MVP Executive Committee: J. Michael Gaziano, MD, MPH, co-chair, VA Boston Healthcare System; Sumitra Muralidhar, PhD, co-chair, US Department of Veterans Affairs; Rachel Ramoni, DMD, ScD, US Department of Veterans Affairs; Jean Beckham, PhD, Durham VA Medical Center; Kyong-Mi Chang, MD, Philadelphia VA Medical Center; Christopher J. O’Donnell, MD, MPH, VA Boston Healthcare System; Philip S. Tsao, PhD, VA Palo Alto Health Care System; James Breeling, MD, Ex-Officio, US Department of Veterans Affairs; Grant Huang, PhD, Ex-Officio, US Department of Veterans Affairs; and J.P. Casas Romero, MD, PhD, Ex-Officio, VA Boston Healthcare System. MVP Program Office: Sumitra Muralidhar, PhD, and Jennifer Moser, PhD, both of US Department of Veterans Affairs. MVP Recruitment/Enrollment: Recruitment/Enrollment Director/Deputy Director, Boston—Stacey B. Whitbourne, PhD; Jessica V. Brewer, MPH, VA Boston Healthcare System; MVP Coordinating Centers: Clinical Epidemiology Research Center (CERC), West Haven—Mihaela Aslan, PhD, West Haven VA Medical Center; Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque—Todd Connor, PharmD; Dean P Argyres, BS, MS, New Mexico VA Health Care System; Genomics Coordinating Center, Palo Alto—Philip S. Tsao, PhD, VA Palo Alto Health Care System; MVP Boston Coordinating Center, Boston—J. Michael Gaziano, MD, MPH, VA Boston Healthcare System; MVP Information Center, Canandaigua—Brady Stephens, MS, Canandaigua VA Medical Center; VA Central Biorepository, Boston—Mary T Brophy MD, MPH; Donald E Humphries, PhD; Luis E Selva, PhD, VA Boston Healthcare System; MVP Informatics, Boston—Nhan Do, MD; Shahpoor Shayan, VA Boston Healthcare System; MVP Data Operations/Analytics, Boston—Kelly Cho, PhD, VA Boston Healthcare System. MVP Science: Science Operations—Christopher J. O’Donnell, MD, MPH, VA Boston Healthcare System; Genomics Core—Christopher J. O’Donnell, MD, MPH; Saiju Pyarajan PhD, VA Boston Healthcare System; Philip S. Tsao, PhD, VA Palo Alto Health Care System; Phenomics Core—Kelly Cho, MPH, PhD, VA Boston Healthcare System; Data and Computational Sciences—Saiju Pyarajan, PhD, VA Boston Healthcare System; Statistical Genetics—Elizabeth Hauser, PhD, Durham VA Medical Center; Yan Sun, PhD, Atlanta VA Medical Center; Hongyu Zhao, PhD, West Haven VA Medical Center. Current MVP Local Site Investigators: Atlanta VA Medical Center, Peter Wilson, MD; Bay Pines VA Healthcare System, Rachel McArdle, PhD; Birmingham VA Medical Center, Louis Dellitalia, MD; Central Western Massachusetts Healthcare System, Kristin Mattocks, PhD, MPH; Cincinnati VA Medical Center, John Harley, MD, PhD; Clement J. Zablocki VA Medical Center, Jeffrey Whittle, MD, MPH; VA Northeast Ohio Healthcare System, Frank Jacono, MD; Durham VA Medical Center, Jean Beckham, PhD; Edith Nourse Rogers Memorial Veterans Hospital; Edward Hines, Jr VA Medical Center, Salvador Gutierrez, MD; Veterans Health Care System of the Ozarks, Gretchen Gibson, DDS, MPH; Fargo VA Health Care System, Kimberly Hammer, PhD; VA Health Care Upstate New York, Laurence Kaminsky, PhD; New Mexico VA Health Care System, Gerardo Villareal, MD; VA Boston Healthcare System, Scott Kinlay, MBBS, PhD; VA Western New York Healthcare System, Junzhe Xu, MD; Ralph H Johnson VA Medical Center, Mark Hamner, MD; Columbia VA Health Care System, Roy Mathew, MD; VA North Texas Health Care System, Sujata Bhushan, MD; Hampton VA Medical Center, Pran Iruvanti, DO, PhD; Richmond VA Medical Center, Michael Godschalk, MD; Iowa City VA Health Care System, Zuhair Ballas, MD; Eastern Oklahoma VA Health Care System, Douglas Ivins, MD; James A. Haley Veterans’ Hospital, Stephen Mastorides, MD; James H. Quillen VA Medical Center, Jonathan Moorman, MD, PhD; John D Dingell VA Medical Center, Saib Gappy, MD; Louisville VA Medical Center, Jon Klein, MD, PhD; Manchester VA Medical Center, Nora Ratcliffe, MD; Miami VA Health Care System, Hermes Florez, MD, PhD; Michael E. DeBakey VA Medical Center, Olaoluwa Okusaga, MD; Minneapolis VA Health Care System, Maureen Murdoch, MD, MPH; N FL/S GA Veterans Health System, Peruvemba Sriram, MD; Northport VA Medical Center, Shing Shing Yeh, PhD, MD; Overton Brooks VA Medical Center, Neeraj Tandon, MD; Philadelphia VA Medical Center, Darshana Jhala, MD; Phoenix VA Health Care System, Samuel Aguayo, MD; Portland VA Medical Center, David Cohen, MD; Providence VA Medical Center, Satish Sharma, MD; Richard Roudebush VA Medical Center, Suthat Liangpunsakul, MD, MPH; Salem VA Medical Center, Kris Ann Oursler, MD; San Francisco VA Health Care System, Mary Whooley, MD; South Texas Veterans Health Care System, Sunil Ahuja, MD; Southeast Louisiana Veterans Health Care System, Joseph Constans, PhD; Southern Arizona VA Health Care System, Paul Meyer, MD, PhD; Sioux Falls VA Health Care System, Jennifer Greco, MD; St Louis VA Health Care System, Michael Rauchman, MD; Syracuse VA Medical Center, Richard Servatius, PhD; VA Eastern Kansas Health Care System, Melinda Gaddy, PhD; VA Greater Los Angeles Health Care System, Agnes Wallbom, MD, MS, 11301 Wilshire Blvd, Los Angeles, CA 90073; VA Long Beach Healthcare System, Timothy Morgan, MD; VA Maine Healthcare System, Todd Stapley, DO; VA New York Harbor Healthcare System, Scott Sherman, MD, MPH; VA Pacific Islands Health Care System, George Ross, MD; VA Palo Alto Health Care System, Philip Tsao, PhD; VA Pittsburgh Health Care System, Patrick Strollo, Jr, MD; VA Puget Sound Health Care System, Edward Boyko, MD; VA Salt Lake City Health Care System, Laurence Meyer, MD, PhD; VA San Diego Healthcare System, Samir Gupta, MD, MSCS; VA Sierra Nevada Health Care System, Mostaqul Huq, PharmD, PhD; VA Southern Nevada Healthcare System, Joseph Fayad, MD; VA Tennessee Valley Healthcare System, Adriana Hung, MD, MPH; Washington DC VA Medical Center, Jack Lichy, MD, PhD; W.G., Bill Hefner VA Medical Center, Robin Hurley, MD; White River Junction VA Medical Center, Brooks Robey, MD; William S. Middleton Memorial Veterans Hospital, Robert Striker, MD, PhD.

Disclaimer: This publication does not represent the views of the Department of Veterans Affairs or the United States government.

Additional Contributions: The CARDIoGRAMplusC4D and UK Biobank CardioMetabolic Consortium CHD working group used the UK Biobank Resource (application number 9922) to contribute data on coronary artery disease; data were downloaded from http://www.CARDIOGRAMPLUSC4D.ORG. The MEGASTROKE investigators contributed the GWAS summary statistics for ischemic stroke.

Additional Information: The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgements.html. The data that support the findings of this study are available from the corresponding author on reasonable request.

Article

Publisher ID: zoi201044

DOI: 10.1001/jamanetworkopen.2020.34461

PMC ID: 7816104

PubMed ID: 33464320

SO-VID: 28ffa9bc-9929-4272-9b76-a5860783ce23

Copyright © Copyright 2021 Levin MG et al. JAMA Network Open.

License:

This is an open access article distributed under the terms of the CC-BY License.

History

Date received : 30 June 2020

Date accepted : 11 November 2020

Funding

Funded by: VA Million Veteran Program

Funded by: US Department of Veterans Affairs

Funded by: American Heart Association Strategically Focused Research Network in Vascular Disease

Funded by: National Heart, Lung, and Blood Institute

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases

Funded by: Linda Pechenik Montague

Categories

Subject: Research

Subject: Original Investigation

Subject: Online Only

Subject: Cardiology

Data availability:

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