Genetics Of Cardiovascular Disease

Cardiovascular disease (CVD), commonly called heart disease, remains one of the leading global causes of mortality and morbidity, particularly in India. In fact, CVDs tend to affect individuals in India almost 10 years earlier compared to other countries. In 2017, CVDs were responsible for 14.7 per cent of disability-adjusted life years (DALYs) and 31.8 per cent of deaths in the country. While there has been a slight decline in the burden of CVD in India, it remains a significant public health concern. Key risk factors include obesity, poor diet, diabetes, high cholesterol, hypertension, and a sedentary lifestyle. Understanding the genetic basis of CVD has become critical in shaping the treatment and prevention of these diseases.

Initially, identifying single-gene mutations was the first step toward understanding the genetics of CVD, laying the foundation for comprehensive genetic investigations. Genome-wide association studies (GWAS) have enabled researchers to analyse common genetic variants across the entire genome, identifying over 50 loci associated with CVD. Many of these loci point to important biological pathways involved in the pathogenesis of CVD. For example, the identification of the 9p21 locus is considered a strong and common genetic risk factor, influencing the expression of nearby genes such as CDKN2A and CDKN2B, which regulate the cell cycle. The PCSK9 gene and LDL receptor, both related to lipid metabolism, highlight the critical role of cholesterol metabolism in CVD development.

Variants in the LPA gene, which codes for lipoprotein(a), also contribute to CVD risk, alongside traditional factors like LDL-C. Elevated levels of lipoprotein(a) are thought to promote CVD through both lipid accumulation and pro-inflammatory mechanisms. Inflammation plays a major role in the development of CVD, with the IL6R gene, coding for the interleukin-6 receptor, paving the way for targeted therapies. Anti-inflammatory drugs, such as canakinumab, which targets the IL-1β pathway, have been shown to reduce cardiovascular events, highlighting the potential of these findings.

One of the most promising aspects of genetic research in CVD is clinical translation. Identifying genetic risk factors is crucial in developing risk prediction tools, allowing for early intervention in individuals with high risk. Polygenic risk scores (PRS), which combine the effects of multiple genetic variants into a single score, can enhance traditional risk assessment models, which typically rely on clinical factors like lipid levels, age, and gender.

Personalised treatment strategies can also be developed based on genetic information. For example, patients with high cholesterol and genetic variants in the PCSK9 gene may benefit more from PCSK9 inhibitors. Similarly, patients with elevated lipoprotein(a) levels due to variants in the LPA gene may benefit from therapies targeting lipoprotein(a), such as antisense oligonucleotides.

Additionally, genetic research has accelerated drug development. The identification of new molecular targets is a key focus, helping to develop novel therapies that can prevent or treat CVD more effectively. The success of PCSK9 inhibitors is a prime example of how genetic discoveries are being translated into therapeutics. These inhibitors were developed based on the discovery that rare mutations in the PCSK9 gene, which lower LDL-C levels, are associated with a reduced risk of coronary artery disease (CAD).

The understanding of CVD genetics has evolved significantly over the past few decades. These discoveries have provided valuable insights into the biological mechanisms that drive CVD, particularly in lipid metabolism, inflammation, and vascular biology. Importantly, these findings are being integrated into clinical practice through genetic risk prediction tools, personalised treatment strategies, and new therapeutic targets. With ongoing research, the integration of genetic information into routine clinical care holds the potential to revolutionise cardiovascular medicine, offering more effective prevention and treatment options.

The author is Doctor-in-charge, Medical Genetics, Metropolis Healthcare Limited

Dr. Talat Khan

Guest Author Doctor-in-charge, Medical Genetics, Metropolis Healthcare