Association of <i>PHACTR1</i> with Coronary Artery Calcium Differs by Sex and Cigarette Smoking

Kirsten Voorhies; Kendra Young; Fang-Chi Hsu; Nicholette D. Palmer; Merry-Lynn N. McDonald; Sanghun Lee; Georg Hahn; Julian Hecker; Dmitry Prokopenko; Ann Chen Wu; Elizabeth A. Regan; Dawn DeMeo; Greg L. Kinney; James D. Crapo; Michael H. Cho; Edwin K. Silverman; Christoph Lange; Matthew J. Budoff; John E. Hokanson; Sharon M. Lutz

doi:10.3390/jcdd11070194

Journal of Cardiovascular Development and Disease (Jun 2024)

Association of <i>PHACTR1</i> with Coronary Artery Calcium Differs by Sex and Cigarette Smoking

Kirsten Voorhies,
Kendra Young,
Fang-Chi Hsu,
Nicholette D. Palmer,
Merry-Lynn N. McDonald,
Sanghun Lee,
Georg Hahn,
Julian Hecker,
Dmitry Prokopenko,
Ann Chen Wu,
Elizabeth A. Regan,
Dawn DeMeo,
Greg L. Kinney,
James D. Crapo,
Michael H. Cho,
Edwin K. Silverman,
Christoph Lange,
Matthew J. Budoff,
John E. Hokanson,
Sharon M. Lutz

Affiliations

Kirsten Voorhies: Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02115, USA
Kendra Young: Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Fang-Chi Hsu: Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
Nicholette D. Palmer: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
Merry-Lynn N. McDonald: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35212, USA
Sanghun Lee: Division of Medicine, Department of Medical Consilience, Graduate School, Dankook University, Yongin 16890, Republic of Korea
Georg Hahn: Brigham and Women’s Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics, and Department of Medicine, Harvard Medical School, Boston, MA 02120, USA
Julian Hecker: Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Dmitry Prokopenko: Genetics and Aging Research Unit and the McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
Ann Chen Wu: Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02115, USA
Elizabeth A. Regan: Department of Medicine, National Jewish Health, Denver, CO 80206, USA
Dawn DeMeo: Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Greg L. Kinney: Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
James D. Crapo: Department of Medicine, National Jewish Health, Denver, CO 80206, USA
Michael H. Cho: Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Edwin K. Silverman: Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Christoph Lange: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Matthew J. Budoff: Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
John E. Hokanson: Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Sharon M. Lutz: Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02115, USA

DOI: https://doi.org/10.3390/jcdd11070194
Journal volume & issue: Vol. 11, no. 7
p. 194

Abstract

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Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10−14) and among males (p = 1.0 × 10−9), but the signal was not genome-wide significant among females (p = 6.4 × 10−6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10−8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10−7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10−7) than former smokers (p = 7.5 × 10−3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10−8) and current smokers (p = 1.7 × 10−7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Published in Journal of Cardiovascular Development and Disease

ISSN: 2308-3425 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system
Website: http://www.mdpi.com/journal/jcdd

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