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Distinct DNA methylation sites associated with heart disease

A new study, published in JAMA Cardiology, has identified DNA methylation sites associated with heart disease. Most importantly, the study reported that the DNA signatures identified varied greatly between different populations. Their findings highlight the importance of studying disease in racially diverse groups.

DNA methylation and coronary heart disease

The risk of coronary heart disease (CHD) varies between different racial and ethnic populations. For example, American Indian communities in the USA are disproportionately impacted by CHD compared to other groups. Discovering the mechanisms underlying higher CHD risk is crucial in order to develop and implement preventative treatments.

Epigenetic changes to DNA, such as DNA methylation (DNAm), have previously been associated with CHD risk. However, recent studies have been limited due to a lack of replication across populations as well as the uncertainty in identified methylation sites. Now, in a recent study, researchers aimed to overcome these challenges.

Samples from diverse populations

In the study, researchers evaluated blood DNAm from multiple racial groups across the USA. Blood samples were taken from a total of 9,400 people that were involved in four long-term heart health studies. The participants were then split into five cohorts:

  1. The Strong Heart Study (SHS), which studies American Indians
  2. The Women’s Health Initiative (WHI), which studies African-American, Hispanic and White women
  3. Framingham Heart Study (FHS), which studies men and women of any race
  4. Atherosclerosis Risk in Communities Study – Black (ARIC-Black), which studies Black individuals
  5. Atherosclerosis Risk in Communities Study – White (ARIC-White), which studies White individuals

As American Indian communities experience higher incidences of CHD, the team compared the SHS samples to the other four cohorts.

“In this study, we harness the country’s best clinical data on heart disease from diverse populations to begin to unlock the specific epigenetic changes involved in the complex biology that leads to disease,” first author Ana Navas-Acien said.

Methylated sites associated with heart disease

The researchers conducted an epigenome-wide association study (EWAS) of each sample to search for differences in DNAm.

In total, the team identified 505 methylation sites associated with higher risk of CHD in the American Indian population. Of these sites, only four were found in all study groups. A further 29 sites were found in at least three additional cohorts. However, the direction of CHD associations were not consistent across all groups. In fact, some methylation sites were actually associated with lower CHD risk in non-American Indian populations. These results suggest that the same epigenetic change can cause very different effects in different racial groups.

In addition, the researchers carried out a targeted analysis of 248 methylation sites found to be associated with cardiovascular disease in previous studies. They found that only 16 of these sites were associated with CHD in the American Indian cohort. In the remaining four cohorts, the number of these sites associated with CHD ranged from 56 in the WHI and ARIC-Black cohorts to 146 in the ARIC-White cohort. These results imply that CHD risk can be genetically different across populations.

Genes associated with methylation sites

Next, the researchers carried out protein-protein interaction analyses to identify the genes associated with methylation sites. The analyses were carried out on all methylation sites associated with CHD in all five cohorts.

Overall, a distinct set of genes were identified for each group. However, the EGFR gene, which encodes the protein epidermal growth factor receptor, was commonly associated in all cohorts. These results suggest a potential role for EGFR in CHD.

Conclusions and future work

In conclusion, this study has identified the DNAm sites that are associated with heart disease in different populations. The team’s discoveries show that in the future, DNAm may help in the identification of individuals at higher risk of developing CHD.

Importantly, their results also highlight the differences in the genetic basis of CHD across various ethnic groups. In the future, CHD risk in additional subpopulations should also be studied.

Senior author Shelly Cole said: “This [work] underscores the need to tailor indicators of risk and resilience, as well as interventions and treatments, for subpopulations as we move away from a one-size-fits-all approach and towards precision medicine.”

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