Racial Health Disparities Linked to Epigenetic Elements

When it comes to health, race typically has an impact. Evidence compiled over several decades points out marked differences in morbidity and mortality rates across varying racial and ethnic minority groups. And while these disparities can arise from any number of environmental or social exposures, exactly how they detrimentally affect the human body and why they continue to impact certain minority groups is not entirely understood.

Most findings attribute minority health disparities to inequalities in education, socioeconomic status, access to healthcare, and the stress caused by racism. These groups are also statistically more likely to be exposed to environmental hazards based on where they live and work. Plus, they are often more susceptible to unhealthy behaviors, including smoking and poor diet. As a result, minority groups are disproportionately burdened with more health issues like diabetes, cancer, cardiovascular disease, depression…and the list goes on.

One growing area of research that is being used to explain the impact of such adverse environmental exposures is epigenetics. Epigenetics can be described as the study of how one interacts with their environment can trigger changes that influence the way genes work or function. These changes do not alter the genetic sequence, but rather they enhance the functional complexity of DNA by providing mechanisms for modifying cellular activities (1). To fully understand human health and disease, it’s important to consider epigenetic modulation of gene expression in addition to DNA code.

Over the years, enormous efforts have been invested into studying the possible causes of leading health issues, particularly the inheritable genetic nature of diseases. This is because many diseases are often passed down from one generation to another. Yet even genetically defined disorders have ties to environmental influence.

We know from previous studies that epigenetic mechanisms, like DNA methylation, Non-coding RNAs, and histone modifications, are susceptible to the environment and associated with mental and physical health issues. Therefore, investigating these mechanisms and their role in diseases related to environmental and adverse social exposure could be key to potentially reducing health disparities.

DNA Methylation

The most widely studied epigenetic mechanism is DNA methylation, primarily because it is stable and can be feasibly analyzed on a large scale. DNA methylation affects gene expression by adding a methyl group to a segment of DNA, resulting in gene repression or inhibiting the binding of transcription factors to DNA. While this mechanism is an essential part of normal cellular differentiation and gene regulation, abnormalities in DNA methylation are fundamental aspects of several diseases. Research has also found evidence that African-Americans and European-Americans differ in their DNA methylation patterns for certain health issues, like cancer, heart disease, diabetes, etc.

As epigenetics is still a relatively new area of research, few studies have focused specifically on race-related to changes in DNA methylation and health. However, this mechanism has been investigated broadly in connection with various diseases. Below are some findings from studies on two of the top disease categories: cancer and cardiovascular disease.

Cancer

Many types of cancers show health disparities in the context of race and ethnicity. However, despite medical advancements, African Americans still have the highest death rates for most cancers- breast cancer and colon cancer in particular.

Breast cancer is one of the most common female cancers in the US. Although it occurs more in European-American (EA) women, African-American (AA) women are more likely to die of it. Previous studies have shown that distinct DNA methylation marks are associated with breast cancer susceptibility. Wang et al. showed that hypermethylation of the tumor suppressor gene, CDH13, was linked to early-onset breast cancer with a significant difference in methylation status between EA and AA patients (2). In addition, Song et al. studied the methylation patterns of known promotor-related CpGs of cancer-related genes in healthy breast tissue (3). They found that over half (52%) were hyper-methylated in white women compared to 27% in black women. These studies and others support the hypothesis that epigenetic factors play a role in AA women’s increased risk of breast cancer.

African-Americans also have the highest prevalence and mortality rates for colorectal cancer (CRC) than any other ethnic group in the US. As the third most common cancer, CRC disproportionately burdens black men and women over whites at 20% more for incidence and 40% more for mortality (4). Studies evaluating CRC tumors have found that certain genes are particularly hypermethylated in AAs. Amongst them is tumor suppressor gene CHD5, which, when downregulated, is believed to be an early indicator of tumor progression in AAs. Other genes epigenetically silenced include ICAM5 and GPNM–both of which play in the high incidence and aggressiveness of CRC in the AA population. More recently, Devall, et al. found that epigenetic age acceleration (a unique pattern of hypermethylation) affects the right side of the colon in most AAs (5). In contrast, EAs have remarkable age deceleration on the right side. The fact that colon biology differs in such a way between races highlights the importance of studying people of African descent to adequately reduce this deadly disease.

Cardiovascular Disease

In the United States, cardiovascular disease (CVD), including heart disease and stroke, is the leading cause of death. Although the risks differ by race and ethnicity, black Americans are 30% more likely to die from heart disease than whites (6). The reasons for the disparity have been debated over the years. But accumulating evidence shows that the risk for heart disease is highly influenced by family history and environmental factors such as stress, early life care, diet, and smoking.

Prior findings show that CVD is associated with alterations in DNA methylation. Movassagh et al.’s study on human cardiac tissue revealed that differential DNA methylation occurs in human heart failure and may be responsible for integrating environmental/dietary signals and inherited traits to influence the pathogenesis and progression of this disease (7). In addition, DNA methylation has been linked to several cardiovascular-related biomarkers, including homocysteine15 and C-reactive protein. In fact, 34 distinct DNA methylation marks were identified by Fernández-Sanlés et al. These marks proved to be consistently related to the prevalence and incidence of cardiovascular events (8).

Furthermore, research utilizing epigenetic clock analysis based on DNA methylation levels has demonstrated that aging rates vary between different racial/ethnic groups (9). One study found that extrinsic aging caused by the environment had significant (though weak) associations with several pro-inflammatory risk factors for coronary heart disease.

To better understand the racial discrepancies in DNA methylation of heart tissue, Pepin et al. performed a differential methylation analysis that compared site-specific methylation of cardiac samples from both AA and EA (9). Their analysis revealed a significant difference between the races, with promotor methylation disproportionately affecting AA patients with end-stage heart failure. The basis for this racial disparity was also shown to correlate with socioeconomic inequity. Although this was an introductory study, it emphasizes the need to examine racial differences in CVD, especially to find ways to treat patients robustly affected by heart disease.

Although the studies mentioned here evaluate DNA methylation and health outcomes, other studies show that differential exposures, like air pollution, psychosocial stress, and poor diet, also influence DNA methylation changes. Because many minority groups are disproportionately affected by these elements, further epigenetic research evaluating human responses to harmful exposures is essential to preventing disparities in morbidity and mortality.

The profound racial and ethnic disparities in health and well-being have been the norm in the US for too long. African-Americans, in particular, are more likely to die from diseases, even treatable ones, on average than white people. And the trend has not changed much over the years despite advancements in health care and technology. We’re seeing that play out right now during the COVID-19 pandemic, as African-Americans and other people of color are three times more likely to be hospitalized after being infected (10).

Today, the NIH and other organizations have boosted their research efforts into health disparities, perhaps spurred on by the pandemic’s huge impact. In consideration, epigenetic research may help validate the science underlying disparities in health that arise from more than just lifestyle choices and acknowledge that society as a whole is at least partly responsible for the current state of health disparities.

References: