Kaiser Permanente study suggests that polygenic risk score can improve cholesterol management
It’s widely known that high cholesterol is bad for the heart. That’s because the plaque that builds up in arteries can block blood flow, increasing the risk of a heart attack, stroke, or death.
But there are in fact some people with lower levels of low-density lipoprotein (LDL) cholesterol levels — sometimes called the “bad” cholesterol — who are also at high risk for coronary heart disease. That’s because these people are born with genetic variants that increase this risk.
A new study by Kaiser Permanente researchers found a test that uses saliva to look for these genetic variants could identify the people who, despite their low cholesterol levels, are at increased risk for coronary heart disease. The findings expand upon previous Kaiser Permanente research that showed the polygenic risk score could predict future heart disease risk.
“We always hope that our research will have the potential to improve outcomes for patients,” said first author Carlos Iribarren, MD, MPH, PhD, a research scientist at the Kaiser Permanente Division of Research (DOR). “This study is a beautiful example of that because the findings have important clinical implications.”
The new study, published in JACC Advances, included 47,576 adults enrolled in the Kaiser Permanente Northern California (KPNC) Genetic Epidemiology Resource in Adult Health and Aging (GERA) study affiliated with the KPNC Research Program on Genes, Environment, and Health.
The study participants had previously provided a saliva sample for genomic testing research. None had diabetes or had taken a statin, a medication used to reduce cholesterol.
The saliva was tested for 12 genetic variants — called single nucleotide polymorphisms (SNPs) — that prior studies have suggested increase a person’s risk for coronary heart disease. The test reports a polygenic risk score; the higher the score, the higher the person’s risk.
Medical records showed that over 13 years there were a total of 1,678 heart attacks, instances of heart-related chest pain, surgeries to unblock arteries, or deaths from coronary heart disease among the adults in the study group.
When the researchers looked at each individual’s risk score, they found that those who had a low score were at low risk of developing coronary heart disease until their LDL cholesterol reached 190 mg/dL, a level considered very high. But those with an intermediate score had a risk of coronary heart disease that increased when their LDL cholesterol levels reached 160 mg/dL.
“We’ve long thought that two people who have the same LDL cholesterol level have the same risk of developing coronary heart disease,” said Iribarren. “But this study tells us that if one of those people has a low polygenic score, and the other has a high polygenic score, their risk of developing coronary heart disease is quite different. This is the type of information we can use to improve care.”
The study also showed that adults with a high polygenic risk score had an increased risk of coronary heart disease even when their LDL cholesterol was under 100 mg/dL — a level typically considered healthy, and low risk.
“These are exciting findings,” said senior author Jamal S. Rana, MD, PhD, a cardiologist with The Permanente Medical Group (TPMG) and a DOR adjunct investigator. “This study points to the potential to use genetics to create more personalized, precision medical care to help prevent heart disease.”
Focusing on risk
The new study also found that individuals who had a higher risk score and had LDL cholesterol over 190 mg/dL had 3.5 times the risk of being diagnosed with coronary heart disease.
This is the same high risk seen in people born with an inherited genetic disorder called familial hypercholesterolemia (FH), which causes LDL cholesterol to begin building up in childhood.
KPNC has a program in place to screen for FH and follows children and adults with this condition closely to provide medical interventions. The genomic test used in the new study could potentially help people with a family history of cholesterol who don’t have this inherited condition better understand their risk for coronary heart disease.
“If you want to understand the risk for this type of early heart attack or stroke, this genetic information is helpful,” explained Leslie Manace Brenman, MD, a TPMG medical geneticist. “In general, everyone is at risk of developing high cholesterol, in the same way that everyone living in California is at risk of experiencing an earthquake. But the people who live on a fault line are at higher risk. The genetic test tells us how close you are to that fault line. And if you’re close, and your risk is higher, we would want to intervene early.”
Manace Brenman recently started a small pilot project that will evaluate whether the information the polygenic test provides helps physicians care for people who have a personal and family history of high cholesterol who do not appear to have FH. The pilot project will allow Manace Brenman and her colleagues to see if the test is beneficial for KP members, and, if so, how it might be implemented more widely. “It’s exciting to work in an organization where we can have this handshake between clinically relevant research like this study and daily practice,” Manace Brenman said. “It’s all about moving research into the real world.”
The study was funded by GENinCode, PLC.
Co-authors include Meng Lu, MS, of the Division of Research; Roberto Elosua, MD, PhD, of the Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona, Spain; Martha Gulati, MD, MS, of Cedars-Sinai Medical Center; and Nathan D. Wong, PhD, MPH, of the University of California, Irvine.
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About the Kaiser Permanente Division of Research
The Kaiser Permanente Division of Research conducts, publishes, and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and society at large. KPDOR seeks to understand the determinants of illness and well-being and to improve the quality and cost-effectiveness of health care. Currently, DOR’s 720-plus staff, including 73 research and staff scientists, are working on nearly 630 epidemiological and health services research projects. For more information, visit divisionofresearch.kp.org or follow us @KPDOR.
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