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Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With
Tessa Schillemans1, Vinicius Tragante2, Buamina Maitusong1
1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Insights
Polymorphisms in the PPARGC1A gene do not appear to increase the risk of subsequent coronary heart disease (CHD) events in patients with established CHD. Further research is needed to clarify potential associations in specific subgroups.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Metabolic Disease Research
Background:
- Factors influencing disease progression in established coronary heart disease (CHD) require further elucidation.
- Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a key regulator of energy metabolism, may influence cardiac function and CHD outcomes.
- The association between PPARGC1A gene single nucleotide polymorphisms (SNPs) and subsequent CHD events in patients with pre-existing CHD is not well understood.
Purpose of the Study:
- To investigate the impact of three specific PPARGC1A gene SNPs (rs8192678, rs7672915, rs3755863) on the risk of subsequent CHD events.
- To analyze these associations in a large cohort of patients with established CHD.
- To explore potential associations with secondary cardiovascular outcomes and all-cause mortality.
Main Methods:
- An individual-level meta-analysis was conducted using data from 23 studies within the GENIUS-CHD consortium (n=80,900).
- Participants had established CHD (acute coronary syndrome, stable CHD, or mixed).
- Cox proportional hazards models were used to assess the association between three PPARGC1A SNPs and the primary outcome (CHD death/myocardial infarction), adjusted for age and sex.
Main Results:
- No significant association was found between any of the three PPARGC1A variants (rs8192678, rs7672915, rs3755863) and the primary outcome of CHD death or myocardial infarction.
- Secondary outcomes and all-cause mortality also showed no significant associations with these SNPs.
- Stratified analyses revealed a significant inverse association between rs7672915 and the primary outcome in specific subgroups: individuals aged ≥65, those with renal impairment, and antiplatelet users.
Conclusions:
- The study found no clear link between the investigated PPARGC1A gene polymorphisms and subsequent CHD events in patients with established CHD.
- Limited inverse associations for rs7672915 were observed in specific subgroups, warranting further investigation.
- These findings contribute to understanding the genetic factors influencing CHD progression.
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, 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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