The Cardiovascular Impact and Genetics of Pericardial Adiposity

Joel T Rämö; Shinwan Kany; Cody R Hou; Samuel F Friedman; Carolina Roselli; Victor Nauffal; Satoshi Koyama; Juha Karjalainen; FinnGen; Mahnaz Maddah; Aarno Palotie; Patrick T Ellinor; James P Pirruccello

doi:10.1101/2023.07.16.23292729

The Cardiovascular Impact and Genetics of Pericardial Adiposity

medRxiv [Preprint]. 2023 Jul 18:2023.07.16.23292729. doi: 10.1101/2023.07.16.23292729.

Authors

Joel T Rämö^{1

2

3}, Shinwan Kany^{1

2

4}, Cody R Hou^{1

5}, Samuel F Friedman⁶, Carolina Roselli^{1

7}, Victor Nauffal^{8

1}, Satoshi Koyama¹, Juha Karjalainen^{3

9

10}; FinnGen; Mahnaz Maddah⁶, Aarno Palotie^{3

11

12

9

10}, Patrick T Ellinor^{1

13

14

15}, James P Pirruccello^{16

1

17

18}

Affiliations

¹ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
⁴ Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ University of Minnesota Medical School, Minneapolis, Minnesota, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁸ Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹² Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Harvard Medical School, Boston, MA, USA.
¹⁶ Bakar Computation Health Sciences Institute, University of California San Francisco, San Francisco, CA, USA.
¹⁷ Division of Cardiology, University of California San Francisco, San Francisco, California, USA, San Francisco, CA, USA.
¹⁸ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.

Abstract

Background: While previous studies have reported associations of pericardial adipose tissue (PAT) with cardiovascular diseases such as atrial fibrillation and coronary artery disease, they have been limited in sample size or drawn from selected populations. Additionally, the genetic determinants of PAT remain largely unknown. We aimed to evaluate the association of PAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of PAT in a large population cohort.

Methods: A deep learning model was trained to quantify PAT area from four-chamber magnetic resonance images in the UK Biobank using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. A genome-wide association study was performed, and a polygenic score (PGS) for PAT was examined in 453,733 independent FinnGen study participants.

Results: A total of 44,725 UK Biobank participants (51.7% female, mean [SD] age 64.1 [7.7] years) were included. PAT was positively associated with male sex (β = +0.76 SD in PAT), age (r = 0.15), body mass index (BMI; r = 0.47) and waist-to-hip ratio (r = 0.55) (P < 1×10^-230). PAT was more elevated in prevalent heart failure (β = +0.46 SD units) and type 2 diabetes (β = +0.56) than in coronary artery disease (β = +0.22) or AF (β = +0.18). PAT was associated with incident heart failure (HR = 1.29 per +1 SD in PAT [95% CI 1.17-1.43]) and type 2 diabetes (HR = 1.63 [1.51-1.76]) during a mean 3.2 (±1.5) years of follow-up; the associations remained significant when controlling for BMI. We identified 5 novel genetic loci for PAT and implicated transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2 and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The PAT PGS was associated with T2D, heart failure, coronary artery disease and atrial fibrillation in FinnGen (ORs 1.03-1.06 per +1 SD in PGS, P < 2×10^-10).

Conclusions: PAT shares genetic determinants with abdominal adiposity and is an independent predictor of incident type 2 diabetes and heart failure.

Publication types

Preprint

Abstract

Publication types

Grants and funding