By Gabrielle Usvyat
The leading cause of death in the United States is heart disease with a toll of around 700,000 people every year. Coronary heart disease (CHD) is a complex cardiovascular disorder that affects the arteries and causes a lack of oxygen-rich blood to the heart. It is the leading cause of mortality in congenital malformation. Congenital heart disease is present at birth and affects about 6-13 in 1,000 newborn babies. Scientists have developed whole-exome sequencing (WES) analysis to identify the genes that are damaged that cause CHD. Over the years through different studies, key evidence has been discovered that suggests that 90% of CHD includes a genetic contribution. However, in many people, the causative genetic mechanism behind CDH is poorly understood which means that about 55% of patients with CHD do not have a genetic diagnosis. Researchers have developed various techniques such as karyotyping, WES, and PRS to try to analyze CHD from a genetic perspective.
Through karyotyping, a process in which chromosomes are paired and organized in order to reveal characteristic structural features for each chromosome, scientists were able to discover the first aneuploidies that are associated with CHD. This includes trisomy 13, Turner syndrome, Klinefelter syndrome, trisomy 18 and so on. Aneuploidies is when there are one or more missing or extra chromosomes which leads to a disbalance in alignment.
With the analysis of WES of numerous samples from patients with CHD, scientists were able to identify 18 genes that have a causal association with CHD. Some of these are ADNP, TAB2, DDX3X, CHD7, CHD4, NSD1, PACS1 and PRKD1. However, WES predicts that there are about 400 genes that contribute to CHD, which is a lot more than scientists have discovered nowadays. Some of those genes probably have damaging variants in patients with CHD. Although this is true, using WES to identify monogenic causes for CHD has only led to about 20% to 30% of diagnoses of CHD patients.
Polygenic risk scores (PRS) is another tool that was developed to quantify genetic risk for common diseases such as coronary artery disease. For CHD which is a developmental disease, the presence or absence can usually be found at birth which is why PRS would not predict genetic risk but potentially offer insight into the genetic etiology of patients whose disease cannot be explained by monogenic causes.
There are still many definitive CHD-associated genes in cardiac development whose role remains unknown. For now, scientists know for sure that CHD is a very complex and heterogeneous disease. There are genetic and environmental factors that affect if a person develops CHD. It is important to note that genetic factors do not act in isolation but interact with environmental factors to influence an individual’s risk of developing CHD. Lifestyle choices such as smoking, diet, physical activity, and exposure to pollutants can modify the effect of genetic variants on CHD risk. Since CHD is a developmental disease there may be a chance that the genetic etiologies may be unique to ancestrally diverse groups. In terms of future research, longitudinal studies and functional analysis of identified genetic variants are crucial for a deeper understanding of disease mechanisms.
References:
Centers for Disease Control and Prevention. (2023, January 17). FASTSTATS - deaths and mortality. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/fastats/deaths.htm#:~:text=Number%20of%20deaths%20for%20leading,Cancer%3A%20605%2C213
N. S., Barish, S., Dong, W., Zhao, S., Allington, G., Yu, X., Kahle, K. T., Brueckner, M., & Jin, S. C. (2021). Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes, 12(7), 1020. https://doi.org/10.3390/genes12071020
Morton, S. U., Quiat, D., Seidman, J. G., & Seidman, C. E. (2022). Genomic frontiers in congenital heart disease. Nature reviews. Cardiology, 19(1), 26–42. https://doi.org/10.1038/s41569-021-00587-4
U.S. Department of Health and Human Services. (n.d.). What is coronary heart disease?. National Heart Lung and Blood Institute. https://www.nhlbi.nih.gov/health/coronary-heart-disease
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