The Role of Genetics in Cholesterol and Heart Disease Risk

At the Family Heart Global Summit 2024, Helen Hobbs, MD, Howard Hughes Medical Institute investigator and professor of internal medicine and molecular genetics at the University of Texas Southwestern Medical Center, shared groundbreaking insights into the genetic roots of high cholesterol and offered a detailed look at how genetic discoveries are reshaping the landscape of cardiovascular disease prevention and treatment.

His presentation focused on decades of research on familial hypercholesterolemia (FH) and cholesterol regulation, and highlighted key topics such as the French-Canadian deletion, the low-density lipoprotein receptor (LDLR) mutations and the implications of low LDL cholesterol levels throughout life on coronary heart disease (CHD).

The French-Canadian deletion: a historical genetic anomaly

Hobbs began by recounting one of his most compelling discoveries: the French-Canadian deletion. This mutation, which affects the LDLR The gene has a particularly high prevalence among French Canadians, with 63% of FH heterozygous individuals in Quebec, Canada, carrying this specific deletion.¹

This mutation is the result of genetic isolation. Between 1608 and 1763, approximately 8,000 settlers from France settled in what is now Quebec. Because of their linguistic and geographic distance from the surrounding populations, these settlers formed a genetically isolated group. Over time, the mutation that disrupts the LDL receptor, which is essential for removing LDL cholesterol from the blood, became common among this population.

“We found that part of the gene was missing, the part that goes to the promoter that turns the gene on in the very first part of the gene, so no protein was being produced,” Hobbs explained.

She identified this specific mutation during her early research by examining the genetic profiles of people with FH, after noticing that almost all of the people in the sample with this deletion had French ancestry. This mutation provided a key piece of the puzzle for understanding how FH manifests itself at the population level and highlighted the role of genetic bottlenecks in amplifying certain mutations.

The Power of Low LDL: Lifelong Protection Against Heart Disease

A central theme of Hobbs’ presentation was the protective effect of low LDL levels throughout life on coronary heart disease. Drawing on data from the Dallas Heart Study, she presented compelling evidence that people with naturally low LDL levels due to genetic mutations are much less likely to develop coronary heart disease.

In his presentation, Hobbs highlighted an important discovery related to genetic mutations in the PCSK9 gene that plays a crucial role in regulating cholesterol. She explained that 2% of black or African-American people in the Dallas Heart Study carried mutations in PCSK9—a gene that promotes the breakdown of the LDL receptor—and had 40% lower LDL cholesterol levels than people without the mutation.² These participants with the PCSK9 Patients with the mutation also saw a 28% reduction in average LDL cholesterol levels after statin use, leading to a staggering 88% reduction in coronary heart disease risk. A similar sequence variation was seen in 3% of white participants, although the effect on LDL reduction was more modest. Patients with the mutation who used statins saw a 15% reduction in LDL cholesterol levels and a 46% reduction in coronary heart disease risk, a smaller but still significant result.

The results from both groups reinforced a central question in Hobbs’ research: What is the long-term effect of low LDL cholesterol from birth on the risk of coronary heart disease? By identifying these genetic mutations and their effects, his team was able to establish a direct link between low LDL cholesterol levels throughout life and a dramatic reduction in coronary heart disease.

Genetic discoveries pave the way for future therapies

PCSK9 has also become a focal point in cholesterol management research, as mutations in PCSK9 can either increase or decrease its activity. In individuals carrying loss-of-function mutations, PCSK9 is unable to effectively degrade LDL receptors, resulting in significant lowering of LDL levels. PCSK9 inhibitor therapies, first approved in 2015, have been shown to reduce LDL levels by up to 60% and significantly decrease the risk of coronary events.³ More recent developments, such as the siRNA-based drug inclisiran, offer a more convenient dosing regimen, requiring only 2 injections per year. However, Hobbs acknowledged the challenges patients face in accessing these therapies due to cost and availability.

Hobbs concluded his presentation by reflecting on how genetics has transformed our understanding of cholesterol metabolism and its link to heart disease. His research has not only identified key mutations, but also paved the way for innovative therapies that could change the trajectory of heart disease for millions of people. Given his seminal discoveries in the field of cholesterol management throughout his career, it is no surprise that Hobbs received the Family Heart Pioneer Award at the summit.

Although she emphasized that there is still much to learn, her presentation left the audience with a sense of optimism about the future of cholesterol management. In closing, Hobbs offered a message of perseverance, especially to women in science and medicine. Reflecting on the challenges and rewards of her own journey, she emphasized the importance of remaining committed to discovery, no matter the obstacles.

“Stay in the game,” Hobbs told women around the world, encouraging them to continue pushing boundaries and contributing to advancements that will shape the future of health care.

References

1. Hobbs HH, Brown MS, Russell DW, Davignon J, Goldstein JL. Low-density lipoprotein receptor gene deletion in a majority of French Canadians with familial hypercholesterolemia. N Engl J Med. 1987;317(12):734-737. doi:10.1056/NEJM198709173171204
2. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013

3. Lepor NE, Kereiakes DJ. PCSK9 inhibitors: a new therapeutic target enters clinical practice. Am Health Drug Benefits. 2015;8(9):483-489.