The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers.
We designed a case–control, two-stage, epigenome-wide association study on AMI (ndiscovery = 391, nvalidation = 204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. We performed a fixed-effects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n ~ 1800 and n ~ 2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infinium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic influence and therefore the results were not conclusive.
We have identified 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.
Bibliographical noteFunding Information:
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Carlos III Health Institute–European Regional Development Fund [Grant Numbers FIS PI18/00017, FIS PI15/00051, PI12/00232, CIBERCV, CIBERESP, CIBERONC]; PERIS from Agència de Gestió d’Ajuts Universitaris i de Recerca [Grant Number SLT002/16/00088]; the Government of Catalonia through the Agency for Management of University and Research Grants [Grant Numbers 2014SGR240, 2017SGR946]; the Spanish Ministry of Economy and Competitiveness [Grant Number BES-2014–069718 to AF-S]; and Carlos III Health Institute-FEDER (grant number IFI14/00007 to SS-B). The Framingham Heart Study (FHS) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University [Contract No. N01-HC-25195 and HHSN268201500001I]. The Women’s Health Initiative (WHI) program is funded by the NHLBI [Contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129–32, and 44221]. This manuscript was not prepared in collaboration with investigators of the FHS/ WHI, has not been reviewed and/or approved by the FHS/WHI, and does not necessarily reflect the opinions or views of the FHS and WHI investigators or the NHLBI.
© 2021, The Author(s).
- DNA methylation
- Epigenome-wide association study
- Predictive biomarkers
- Myocardial infarction
- Cardiovascular disease