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A novel genetic marker of decreased inflammation and improved survival after acute myocardial infarction

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Abstract

The CHRNA5 gene encodes a neurotransmitter receptor subunit involved in multiple processes, including cholinergic autonomic nerve activity and inflammation. Common variants in CHRNA5 have been linked with atherosclerotic cardiovascular disease. Association of variation in CHRNA5 and specific haplotypes with cardiovascular outcomes has not been described. The aim of this study was to examine the association of CHRNA5 haplotypes with gene expression and mortality among patients with acute myocardial infarction (AMI) and explore potential mechanisms of this association. Patients (N = 2054) hospitalized with AMI were genotyped for two common variants in CHRNA5. Proportional hazard models were used to estimate independent association of CHRNA5 haplotype with 1-year mortality. Both individual variants were associated with mortality (p = 0.0096 and 0.0004, respectively) and were in tight LD (D′ = 0.99). One haplotype, HAP3, was associated with decreased mortality one year after AMI (adjusted HR = 0.42, 95% CI 0.26, 0.68; p = 0.0004). This association was validated in an independent cohort (N = 637) of post-MI patients (adjusted HR = 0.23, 95% CI 0.07, 0.79; p = 0.019). Differences in CHRNA5 expression by haplotype were investigated in human heart samples (n = 28). Compared with non-carriers, HAP3 carriers had threefold lower cardiac CHRNA5 mRNA expression (p = 0.023). Circulating levels of the inflammatory marker hsCRP were significantly lower in HAP3 carriers versus non-carriers (3.43 ± 4.2 versus 3.91 ± 5.1; p = 0.0379). Activation of the inflammasome, an important inflammatory complex involved in cardiovascular disease that is necessary for release of the pro-inflammatory cytokine IL-1 β, was assessed in bone marrow-derived macrophages (BMDM) from CHRNA5 knockout mice and wild-type controls. In BMDM from CHRNA5 knockout mice, IL-1β secretion was reduced by 50% compared to wild-type controls (p = 0.004). Therefore, a common haplotype of CHRNA5 that results in reduced cardiac expression of CHRNA5 and attenuated macrophage inflammasome activation is associated with lower mortality after AMI. These results implicate CHRNA5 and the cholinergic anti-inflammatory pathway in survival following AMI.

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Abbreviations

AMI:

Acute myocardial infarction

BMDM:

Bone marrow-derived macrophages

CAD:

Coronary artery disease

GWAS:

Genome-wide association study

HWE:

Hardy–Weinberg equilibrium

PVD:

Peripheral vascular disease

LD:

Linkage disequilibrium

MACE:

Major adverse cardiac events

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Funding

This work and Dr. Cresci’s effort are supported in part by the National Institutes of Health (Cresci R01 NR013396). TRIUMPH was sponsored by the National Institutes of Health: Washington University School of Medicine SCCOR Grant P50 HL077113. Dr. Coverstone’s effort is supported in part by the National Institutes of Health: National Research Service Award 5-T32-HL07081-38 from the National Heart, Lung, and Blood Institute (NHLBI) and Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. Dr. Bierut’s effort is supported in part by the National Institutes of Health (R01 DA025888 and R01 DA036583). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. Dr. Sucharov's effort is supported in part by the National Institutes of Health R01 HL107715 and American Heart Association  13GRNT16950045.

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Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Campus, Box 8086, Saint Louis, MO, 63110, USA

    Edward D. Coverstone, Richard G. Bach, Allie Y. Li, Joel D. Schilling & Sharon Cresci

  2. Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA

    Sharon Cresci

  3. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

    LiShiun Chen & Laura J. Bierut

  4. Statistical Genomics Division, Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA

    Petra A. Lenzini

  5. Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City, Kansas City, MO, USA

    John A. Spertus

  6. Cardiology Division, Department of Medicine, University of Colorado Denver, Aurora, USA

    Carmen C. Sucharov

  7. Institute for Behavioral Genetics, University of Colorado, Boulder, USA

    Heidi C. O’Neill & Jerry A. Stitzel

  8. Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA

    Joel D. Schilling

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  1. Edward D. Coverstone
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  11. Joel D. Schilling
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  12. Sharon Cresci
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Corresponding author

Correspondence to Sharon Cresci.

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Conflict of interest

Edward Coverstone: None. Richard G. Bach: Research Grants: Novartis, MyoKardia. Consultant (Clinical Event Committee activity only): Novo Nordisk, Pharmacosmos NA. LiShiun Chen: None. Laura J. Bierut: Copyrights/Patents: Listed as an inventor on Issued U.S. Patent 8080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Allie Y. Li: None. Petra A. Lenzini: None. Heidi C. O'Neill: None. John A. Spertus: Research Grants: Eli Lilly, EveHeart, Genentech, Gilead. Consultant: St. Jude Medical, United Healthcare, Amgen, Genentech, Janssen. Copyrights/Patents: Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, Peripheral Artery Questionnaire, US Patents: 7643,969; 7,853,456; 12/965,656; 13/615,401. Carmen Sucharov: Scientific founder and shareholder, CoramiR Inc. and miRagen Inc. Jerry Stitzel: Research grants: Pfizer. Joel Schilling: None. Sharon Cresci: None.

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Coverstone, E.D., Bach, R.G., Chen, L. et al. A novel genetic marker of decreased inflammation and improved survival after acute myocardial infarction. Basic Res Cardiol 113, 38 (2018). https://doi.org/10.1007/s00395-018-0697-7

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