Stable methylation loci are associated with systolic blood pressure in a Croatian island population

Abstract

Background: The objective was to identify stable and dynamic DNA methylation loci associated with cardiometabolic traits among an adult population from the Croatian island of Hvar. Materials & methods: An epigenome-wide association study was conducted using peripheral blood longitudinally collected at two time points 10 years apart via Infinium MethylationEPIC beadarray (n = 112). Stable and dynamic loci were identified using linear mixed models. Associations between cardiometabolic traits and loci were assessed using linear models. Results: 22 CpG loci were significantly associated with systolic blood pressure. Twenty were stable and two were dynamic. Conclusion: Multiple genes may be involved in the determination of systolic blood pressure level via stable epigenetic programming, potentially established earlier in life.

Plain language summary

Cardiovascular disease is the leading cause of death worldwide. Previous studies have found that genetics incompletely explain susceptibility to cardiovascular disease. To find new potential risk factors, the authors investigated the possible contribution of DNA methylation (modifications to DNA that can affect gene expression but do not alter the underlying genetic code) in an adult population on the Croatian island of Hvar, which has a high number of people with cardiovascular and metabolic disease. By examining DNA methylation in blood collected at two time points, 10 years apart, the authors were able to identify DNA methylation that either stayed the same over time (stable) or changed the most over time (dynamic). These were then compared with clinical test results related to cardiovascular or metabolic diseases to determine if they are associated. Twenty-two methylation sites were found to be associated with systolic blood pressure. Of those, 20 were considered stable and two were dynamic. Additionally, there was one stable methylation site associated with serum calcium and one with C-reactive protein. These findings suggest that systolic blood pressure may be regulated through stable DNA methylation that is potentially established earlier in life.

Tweetable abstract

New research from @UC_CoMResearch describes an epigenome-wide association study that suggests an association between stable methylation at multiple loci and adult systolic blood pressure levels.

Graphical abstract

Keywords::

• 850K
• blood
• cardiometabolic
• epigenetics
• epigenome-wide
• epigenomics
• EWAS
• pressure
• SBP
• systolic

Author contributions

The study was conceived and designed by P Rudan, S Missoni and R Deka. Recruitment of subjects, data and sample collection and data cleaning were conducted by M Čoklo, S Missoni and P Rudan. Data processing was performed by L Niu, R Jandarov, X Zhang and G Zhang. Statistical analysis was conducted by AC Sprague, L Niu and SM Langevin. The draft manuscript was prepared by AC Sprague and S Missoni. All authors read and approved the manuscript.

Financial & competing interests disclosure

This study was supported by grants from the National Institutes of Health, USA (R01DK069845, R56HL128493) and from the Croatian Ministry of Science, Education and Sports (196-1962766-2751). The sponsors had no role in the study design or data collection, analysis and interpretation; the writing of this article; or the decision to submit this article for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that the institutional review board at the University of Cincinnati approved the study, which was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). All participants provided written informed consent.

Data sharing statement

The dataset supporting the results of this article is publicly available the Gene Expression Omnibus (GEO) at www.ncbi.nlm.nih.gov/geo/ under accession number GSE207927.

Additional information

Funding

This study was supported by grants from the National Institutes of Health, USA (R01DK069845, R56HL128493) and from the Croatian Ministry of Science, Education and Sports (196-1962766-2751). The sponsors had no role in the study design or data collection, analysis and interpretation; the writing of this article; or the decision to submit this article for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.