Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease: An Individual-Level Meta-Analysis
Schillemans, Tessa; Tragante, Vinicius; Maitusong, Buamina; Gigante, Bruna; Cresci, Sharon; Laguzzi, Federica; Vikström, Max; Richards, Mark; Pilbrow, Anna; Cameron, Vicky; Foco, Luisa; Doughty, Robert N; Kuukasjärvi, Pekka; Allayee, Hooman; Hartiala, Jaana A; Tang, W H Wilson; Lyytikäinen, Leo-Pekka; Nikus, Kjell; Laurikka, Jari O; Srinivasan, Sundararajan; Mordi, Ify R; Trompet, Stella; Kraaijeveld, Adriaan; van Setten, Jessica; Gijsberts, Crystel M; Maitland-van der Zee, Anke H; Saely, Christoph H; Gong, Yan; Johnson, Julie A; Cooper-DeHoff, Rhonda M; Pepine, Carl J; Casu, Gavino; Leiherer, Andreas; Drexel, Heinz; Horne, Benjamin D; van der Laan, Sander W; Marziliano, Nicola; Hazen, Stanley L; Sinisalo, Juha; Kähönen, Mika; Lehtimäki, Terho; Lang, Chim C; Burkhardt, Ralph; Scholz, Markus; Jukema, J Wouter; Eriksson, Niclas; Åkerblom, Axel; James, Stefan; Held, Claes; Hagström, Emil; Spertus, John A; Algra, Ale; de Faire, Ulf; Åkesson, Agneta; Asselbergs, Folkert W; Patel, Riyaz S; Leander, Karin
(2022) Frontiers in Physiology, volume 13
(Article)
Abstract
Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus,
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its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants ( n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged ≥65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.
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Keywords: PPARGC1A, SNPs, cohort studies, coronary heart disease, meta-analysis, polymorphisms, Physiology, Physiology (medical)
ISSN: 1664-042X
Publisher: Frontiers Research Foundation
Note: Funding Information: The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Within GENIUS-CHD, all participating investigators and sponsors who contributed to data and analyses are acknowledged irrespective of academic or industry affiliations. The GENIUS-CHD was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The UCORBIO are thankful for the support of the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation [CVON 2011/B019 and CVON 2017–20: Generating the best evidence-based pharmaceutical targets for atherosclerosis (GENIUS I&II)], the ERA-CVD program “druggable-MI-targets” (grant number: 01 KL 1802), and the Leducq Fondation “PlaqOmics.” The CDCS and PMI studies were funded by the Health Research Council and Heart Foundation of New Zealand; the AGNES study was supported by research grants from the Netherlands Heart Foundation [2001D019, 2003T302, and 2007B202 and the PREDICT project (CVON 2012–10)], the Leducq Foundation (grant 05-CVD) and the Center for Translational Molecular Medicine (CTMM COHFAR); the Cleveland Clinic Genebank Study was supported in part by NIH grants R01HL103866, R01DK106000, P01HL147823, P01HL098055, P01HL076491, R01HL133169, and R01HL148110; the Corogene study was supported by grants from the Aarno Koskelo Foundation, Helsinki University Central Hospital special government funds (EVO #TYH7215, #TKK2012005, #TYH2012209, and #TYH2014312), and the Finnish Foundation for Cardiovascular research; the Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, and 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. The IATVB was supported by Epidemiologia e Genetica della Morte Improvvisa in Sardegna; INVEST-GENES was supported by the National Institute of Health Pharmacogenomics Research Network grants U01-GM074492, NIH R01 HL074730, University of Florida Opportunity Fund, BASF Pharma and Abbott Laboratories; LIFE-Heart was funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig and funded by means of the European Union, by the European Regional Development Fund (ERDF) and by funds of the Free State of Saxony within the framework of the excellence initiative; the LURIC study was supported by the Seventh Framework Program (AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union; the OHGS was funded in part by a Heart and Stroke Foundation grant; the PROSPER study was supported by an investigator-initiated grant obtained from Bristol Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050–060-810); the SHEEP study was supported by grants from the Swedish Council for Work Life and Social Research, and the Stockholm County Council; the TRIUMPH study was sponsored by the National Institutes of Health: Washington University School of Medicine SCCOR Grant P50 HL077113; the UCP studies were funded by the Netherlands Heart Foundation and the Dutch Top Institute Pharma Mondriaan Project. RP was funded by a British Heart Foundation Intermediate Fellowship (FS/14/76/30933); FA was supported by UCL Hospitals NIHR Biomedical Research Centre; TS was supported by the Swedish Research Council no 2017-00822; KL was supported, in part, by the Swedish Heart-Lung Foundation (grant number 20180540); SC was supported, in part, by the National Institutes of Health (Cresci R01 NR013396); SL was funded through EU H2020 TO_AITION (grant number: 848146). AP was funded by the Health Research Council of New Zealand and the Christchurch Heart Institute Trust; JJ is an established clinical investigator of the Netherlands Heart Foundation (grant 2001 D 032). Publisher Copyright: Copyright © 2022 Schillemans, Tragante, Maitusong, Gigante, Cresci, Laguzzi, Vikström, Richards, Pilbrow, Cameron, Foco, Doughty, Kuukasjärvi, Allayee, Hartiala, Tang, Lyytikäinen, Nikus, Laurikka, Srinivasan, Mordi, Trompet, Kraaijeveld, van Setten, Gijsberts, Maitland-van der Zee, Saely, Gong, Johnson, Cooper-DeHoff, Pepine, Casu, Leiherer, Drexel, Horne, van der Laan, Marziliano, Hazen, Sinisalo, Kähönen, Lehtimäki, Lang, Burkhardt, Scholz, Jukema, Eriksson, Åkerblom, James, Held, Hagström, Spertus, Algra, de Faire, Åkesson, Asselbergs, Patel and Leander.
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