The Role of Genetics in Cholesterol, Heart Disease Risk

At the 2024 Family Heart Global Summit, Helen Hobbs, MD, investigator for the Howard Hughes Medical Institute 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.

Her presentation centered on decades of research into familial hypercholesterolemia (FH) and cholesterol regulation, and highlighted key topics like the French Canadian deletion, low-density lipoprotein receptor (LDLR) mutations, and the implications of lifelong low LDL cholesterol levels on coronary heart disease (CHD).

Helen Hobbs, MD | Image credit: Harvard University

The French Canadian Deletion: A Historical Genetic Anomaly

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

This mutation is a product of genetic isolation. Between 1608 and 1763, around 8000 settlers from France established themselves in what is now Quebec. Due to linguistic and geographical separation from surrounding populations, these settlers formed a genetically isolated group. Over time, the mutation that disrupts the LDL receptor—essential for clearing LDL cholesterol from the blood—became common among this population.

“We figured out that they were missing part of the gene, 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 made,” Hobbs explained.

She identified this specific mutation during her early research while examining the genetic profiles of people with FH, after she noticed that almost everyone in the sample with this deletion had French ancestry. This mutation provided a critical piece of the puzzle in understanding how FH manifests at a population level and underscored 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 lifelong low LDL levels on coronary heart disease (CHD). Drawing on data from the Dallas Heart Study, she presented compelling evidence that individuals with naturally low LDL levels due to genetic mutations are significantly less likely to develop CHD.

In her presentation, Hobbs highlighted a significant discovery related to genetic mutations in the PCSK9 gene, which plays a crucial role in cholesterol regulation. She explained that 2% of Black or African American individuals in the Dallas Heart Study carried mutations in PCSK9—a gene that promotes LDL receptor degradation—and that they had 40% lower LDL cholesterol levels compared with those without the mutation.² These participants with the PCSK9 mutation also saw a 28% reduction in mean LDL cholesterol after using statins, leading to an astounding 88% reduction in CHD risk. A similar sequence variation was found in 3% of White participants, though the effect on LDL reduction was more modest. patients with the mutations who used statins saw a 15% reduction in LDL cholesterol and a 46% reduction in CHD risk—a smaller but still significant result.

The findings from both groups reinforced a central question in Hobbs’ research: what is the long-term effect of having low LDL cholesterol from birth on CHD risk? By identifying these genetic mutations and their effects, her team was able to draw a direct link between lifelong low LDL levels and a dramatic reduction in CHD.

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 with loss-of-function mutations, PCSK9 is unable to degrade LDL receptors effectively, leading to significantly lower LDL levels. PCSK9 inhibitor therapies, first approved in 2015, have been shown to reduce LDL levels by as much as 60% and significantly lower the risk of CHD events.³ More recent developments, such as the siRNA-based drug inclisiran, offer a more convenient dosing schedule, requiring only 2 injections per year. However, Hobbs acknowledged the challenges patients face in accessing these therapies due to cost and availability.

Hobbs concluded her presentation by reflecting on how genetics has transformed our understanding of cholesterol metabolism and its connection to heart disease. Her 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. Looking at her major discoveries in the space of cholesterol management throughout her career, it is no surprise that Hobbs was honored with the Family Heart Pioneer Award during the summit.

While 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, particularly to women in science and medicine. Reflecting on the challenges and rewards of her own journey, she emphasized the importance of staying committed to discovery, no matter the obstacles.

“Stay in the game,” Hobbs told women everywhere, encouraging them to keep pushing boundaries and contributing to advances that will shape the future of health care.

References

1. Hobbs HH, Brown MS, Russell DW, Davignon J, Goldstein JL. Deletion in the gene for the low-density-lipoprotein receptor 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. The PCSK9 inhibitors: a novel therapeutic target enters clinical practice. Am Health Drug Benefits. 2015;8(9):483-489.