Genetic technology has the potential to significantly improve human health by improving disease risk prediction and guiding prevention strategies. The development of a new genetic test called a polygenic risk score is a major advance. Still, it may widen health disparities because such scores may not work equally well for different populations. Iftikhar Kullo, M.D., a cardiologist at Mayo Clinic, believes that global collaboration is needed to refine polygenic risk scores so they perform equitably across people from diverse groups.

Dr. Kullo recently authored a perspective piece in Nature Genetics, where he made the case for efforts to bring genomics to low- and middle-income countries. His argument is that the information gleaned from testing could not only benefit local populations but also many other groups around the world, including in the U.S. Here, he elaborates on this.

Q: You've noted that the disease burden worldwide is shifting from communicable diseases such as  hepatitis and influenza to noncommunicable diseases such as heart disease and cancer. How can genetics address this shift?

Dr. Kullo: The shift from infectious disease to noncommunicable disease is part of the "epidemiologic transition." Famines and pandemics were once the leading cause of mortality, but fortunately, these were addressed by antibiotics, vaccinations and adequate food production. Now, we live longer and, as a result, are prone to developing other diseases like heart disease, diabetes or cancer. One of the ways that we can reduce the burden of these noncommunicable diseases is to employ better ways of predicting risk. For many of these conditions, we have existing tools for risk prediction, but they don't always perform as well as we would like them to.

Q: You are referring to a new genetic test called a polygenic risk score. Could you explain what a polygenic risk score is, and how it works?

Dr. Kullo: Genetically, humans are 99.9% similar. Our genome has three billion letters (A, G, T and C), and every 1,000 letters or so, there is a variation or difference between any two people. These differences, or variants, account for how we look or behave, how we might react to drugs, and our predisposition to different diseases. Polygenic risk scores add up information from multiple such genetic variants that affect our risk of developing certain diseases. Each variant is not very useful by itself, but if we combine the information from many — thousands or even millions of variants in some cases — we get useful and actionable information about disease risk.

Q: What is the limitation of polygenic risk scores? How could they widen global health disparities?

Dr. Kullo: Polygenic risk scores don't perform well across different genetic ancestry groups. Because the vast majority of genetic studies are done in people of European genetic ancestry, these scores don't work very well, for example, in people of African genetic ancestry. One way we can address that disparity is to increase diversity in our studies here in the U.S., but an even better approach may be to undertake a global effort, conducting this work in diverse regions across the globe. We know that using diverse sources of data will improve the performance of these scores for everybody.

Q: You wrote that African datasets are still a high priority for genomic studies. Yet, they are the least represented — less than 2% of human genomes analyzed so far are of people with African genetic ancestry. How can studying African genomes help advance our understanding of the genomic basis of common diseases in all people?

Dr. Kullo: Africa contains the greatest genetic diversity among the continents, accumulated over 300,000 years of human evolution. By studying people of African ancestry, we will learn so much more about human origins and genetics because we're all Africans, in a way — that's where Homo sapiens arose. That long evolutionary history means that African populations could yield more information about genetic variants associated with disease. And it's a chance to make up for this big disparity in the number of Africans in genomic studies thus far.

Q: What steps do you believe are necessary to achieve equity in the availability of polygenic risk scores to improve global health?

Dr. Kullo: We certainly need to increase the representation of minorities in genomic studies. Mayo Clinic is part of a large National Institutes of Health (NIH)-funded consortium called eMERGE that is looking at polygenic risk scores for 10 common conditions, including heart disease, diabetes, chronic kidney disease, breast cancer and prostate cancer. The consortium is committed to ensuring that at least half of the 25,000 participants across the country come from diverse groups.

It's important to learn about the spectrum of genetic variation in all of humanity, not just in one group. I believe that means going beyond our borders, helping other countries to set up infrastructure to generate their own genetic data and creating resources for data-sharing across the globe. It's not an easy task, but we have many elements in place, and I think it's doable.

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Iftikhar Kullo, MD., has been invited to serve on the National Advisory Council on Human Genome Research (NACHGR) of the National Institutes of Health (NIH), by the Hon’ble Xavier Becerra, Secretary of the Department of Health and Human Services (DHHS), for a term beginning immediately and ending September 30, 2024. The Council advises the DHHS, the NIH, and the National Human Genome Research Institute (NHGRI), on genetics, genomic research, training and programs related to the human genome initiative.

Dr. Kullo is a professor of medicine at Mayo Clinic College of Medicine and Science, and a consultant in the Department of Cardiovascular Medicine and the Gonda Vascular Center. His research is focused on the genetic basis of coronary heart disease, as well as the implementation of genomic medicine. Dr. Kullo heads the Atherosclerosis and Lipid Genomics Laboratory, chairs the Cardiovascular Genomics Task Force and directs the Early Atherosclerosis and Familial Hypercholesterolemia Clinics at Mayo Clinic. He has been continuously funded by the NIH since 2003 and is a Principal Investigator in the NHGRI’s eMERGE and PRIMED consortia.

“I am honored to serve on the National Advisory Council on Human Genome Research,” Dr. Kullo says. “Genomics is transforming biomedical research and I’m excited to have the opportunity to advise on the discovery and implementation aspects of genomic medicine to improve outcomes for our patients.”

Read more about his research on the genetic basis of high cholesterol in adults and genetic risk of heart disease in diverse populations.

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In a new study published in NPJ Genomic Medicine, Mayo Clinic researchers found that genetic testing may help identify patients with high cholesterol, or hypercholesterolemia. It also may have implications for the clinical management of patients diagnosed with high cholesterol due to a genetic disorder, or familial hypercholesterolemia.

"In our study, we found more than 50% of the people with disease-causing variants did not meet the clinical criteria for familial hypercholesterolemia," says Iftikhar Kullo, M.D, a Mayo Clinic cardiologist. "Increased genetic testing and population-scale genomics may help to identify patients in this category who otherwise would go undetected." Dr. Kullo is the senior author of the study.

Hypercholesterolemia is a disease that affects how the body processes cholesterol, the waxy substance found in the blood. It is a significant risk factor for atherosclerotic cardiovascular disease. Nearly 95 million U.S. adults have an elevated cholesterol level, with only half on a lipid-lowering treatment. Both genetic and lifestyle factors are known to predispose a person to hypercholesterolemia.

Prior studies attempted to uncover the genetic basis of hypercholesterolemia included people clinically diagnosed or referred to lipid clinics due to their raised or abnormal levels of blood fats. The reported prevalence of a single gene (monogenic) or two or more genes (polygenic) causes of the disease was high in these cohorts.

Dr. Kullo says these estimates were affected by the referral bias inherent in these groups, the inclusion of people with secondary forms of the disease, and the variable application of guidelines to find disease-causing variants in familial hypercholesterolemia genes.

"Our goal was to address these limitations by studying a cohort of people from the community who did not have a secondary cause of hypercholesterolemia and use an established framework to identify the disease-causing variants," says Dr. Kullo.

Researchers studied 1,682 people from Southeast Minnesota with primary hypercholesterolemia, including those with familial hypercholesterolemia. Genetic testing was performed to identify a monogenic cause, defined as presence of a disease-causing or likely disease-causing variant. A polygenic risk score for low-density lipoprotein cholesterol was estimated, and a score greater than 90^% was used to define a polygenic cause.

Researchers found a genetic cause of hypercholesterolemia ― either monogenic or polygenic ― was present in 17% of the people studied. There was poor overlap between the presence of a genetic cause and clinically diagnosed familial hypercholesterolemia.

For people who met the clinical criteria for familial hypercholesterolemia, only 26% had an identifiable genetic cause and only 12% had an identifiable genetic cause that met the criteria for familial hypercholesterolemia.

Dr. Kullo says the results suggest that genetic testing could help detect familial hypercholesterolemia cases for those patients who would otherwise go undetected. They also bring to light the differences in the definitions of familial hypercholesterolemia.

"To better manage care for patients, continued research is needed to identify new genetic causes for hypercholesterolemia," says Dr. Kullo.

Funding

This study was funded as part of the National Human Genome Research Institute-supported Electronic Medical Records and Genomics Network (U01HG006379) and Mayo Clinic's Center for Individualized Medicine. The Mayo Clinic Biobank is funded by Mayo Clinic's Center for Individualized Medicine. Dr. Kullo is also funded by National Heart, Lung, and Blood Institute grant K24-HL137010. The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health.

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The work to improve health and health care is ongoing and ever-evolving. It takes many shapes, from streamlining delivery to improving care and pursuing inclusive medical research to help develop precision medicine for all populations.

This was a key element of the Arizona Return of Actionable Variants Empirical, or RAVE, study, which brought genomic medicine to a federally qualified community health center that serves low-income patients in the Phoenix area. Researchers from Arizona State University, Mayo Clinic and Mountain Park Health Center collaborated on this study.

"One of the central aims of our study was to assess the feasibility of offering genomic screening in a nontraditional setting," says Richard Sharp. Ph.D., director of Mayo Clinic's Bioethics program. "In the past, access to genomic medicine has been limited to large academic medical centers like Mayo Clinic and, unfortunately, not all patients have convenient access to those types of facilities." Dr. Sharp is a co-principal investigator for the study.

Specifically, 500 Latino adults consented to have their DNA sequenced for a panel of "medically actionable genes." The panel included genes that predispose people to certain diseases such as heart disease, and breast and colon cancers. Findings in these genes are related to health conditions with established medical recommendations or interventions. Then the results were shared with the participants and their providers for follow-up.

Challenges in returning sequencing results were published in Genetics in Medicine. The study highlights the intersection of medical advances with social determinants of health, including factors such as the unequal distribution of resources, poverty, access to health care and transportation, housing instability, and health literacy. 

The researchers will be able to extend their efforts further with funding from the National Human Genome Research Institute at the National Institutes of Health (NIH). They will work on a five-year project with a handful of other institutions across the U.S. through the Electronic Medical Records and Genomics, or eMERGE, Network, an NIH-organized and funded consortium of U.S. medical research institutions.

"In the next phase of this project, we plan to focus on the genomic risk of common diseases, including coronary heart disease, diabetes, high blood pressure and colon cancer," says Iftikhar Kullo, M.D., a Mayo Clinic cardiologist. "Our goal is to incorporate genomic risk variants in conventional risk stratification algorithms to increase their accuracy and assess outcomes after returning results to participants and providers." Dr. Kullo is a co-principal investigator for the study.

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ANSWER: Familial hypercholesterolemia is not the same as a typical case of high cholesterol. Familial hypercholesterolemia is an inherited condition that affects the way the body processes cholesterol. It results in high cholesterol in the blood and significantly raises the risk of a heart attack or stroke. Familial hypercholesterolemia can be detected with a genetic test. Once it’s identified, it often can be effectively treated.

Cholesterol is a waxy substance that’s found in the fats in blood. While the body needs some cholesterol to build healthy cells, having too much cholesterol can cause health problems. In people who have familial hypercholesterolemia, a defective gene prevents the body from removing from the blood low-density lipoprotein cholesterol — known as LDL (sometimes referred to as the “bad” cholesterol). Because of the extra cholesterol, plaque builds up in the arteries, causing them to narrow and increasing the likelihood of a heart attack or a stroke.

The gene mutation that causes familial hypercholesterolemia is passed from parent to child. Children with familial hypercholesterolemia inherit a defective copy of the gene from one parent. In most cases, they have one affected gene and one normal gene. In rare cases, a person inherits an affected copy of the gene from both parents. That leads to a much more severe form of the disease.

Familial hypercholesterolemia is a relatively common genetic condition. About 5 percent of the general population has high cholesterol as defined by LDL cholesterol greater than 190 milligrams per deciliter of blood. Of that group, about 5 to 7 percent have familial hypercholesterolemia.

Familial hypercholesterolemia can be serious and life-threatening. It typically does not cause any symptoms. If left untreated, it can lead to sudden cardiac death due to a heart attack, often before the age of 50. Because of the potentially devastating nature of this disease, it’s crucial that it is identified and treated early. Unfortunately, many people with familial hypercholesterolemia don’t know they have it. Current estimates are that only about 10 percent of those affected by the disease have been diagnosed.

Identifying who should be tested for familial hypercholesterolemia can be difficult, and there is some disagreement among researchers and physicians regarding screening guidelines. What everyone agrees on, though, is that when a person is diagnosed with familial hypercholesterolemia, all of the members of that individual’s family should be tested for the familial hypercholesterolemia gene mutation, too, particularly first-degree relatives — children, parents and siblings.

Diagnosing familial hypercholesterolemia involves a cholesterol check, called a lipid panel or a lipid profile, as well as a genetic test. As is common at most health care facilities, Mayo Clinic strongly recommends that patients meet with a genetic counselor before undergoing any genetic testing. The counselor can explain what the test involves and what it means, as well as the possible implications of the test results.

Once familial hypercholesterolemia has been diagnosed, treatment typically includes taking medication to lower LDL cholesterol. Adopting positive lifestyle choices, such as eating a low-fat diet, exercising and maintaining a healthy body weight, is always a good way to help ensure heart health and is recommended for people who have familial hypercholesterolemia. In most cases, though, lifestyle changes alone aren’t enough to lower LDL cholesterol to healthy levels in people who have familial hypercholesterolemia.

If you are concerned about the possibility of familial hypercholesterolemia in your family, especially if you have a family member who experienced a heart attack or stroke before age 50, talk to your health care provider about your risk factors for the condition and whether you should be tested for it. — Dr. Iftikhar Kullo, Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota

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Vitamin D is found in many foods, including fish, eggs, fortified milk and cod liver oil. The sun also adds to the body’s daily production of vitamin D, and as little as 10 minutes of exposure is thought to help prevent deficiency. Vitamin D helps the body absorb calcium, which forms and maintains strong bones. On the Mayo Clinic Radio program, preventive medicine specialist Dr. Donald Hensrud covers the latest vitamin D recommendations and discusses the second edition of The Mayo Clinic Diet. Also on the program, Dr. Rekha Mankad, director of Mayo Clinic's Cardio-Rheumatology Clinic, discusses women and heart disease as part of American Heart Month. And cardiologist Dr. Iftikhar Kullo explains a new genetic test being used to detect a cardiovascular condition known as familial hypercholesterolemia.

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In this study, the investigators tested the hypothesis that incorporating genetic risk information into CHD risk estimates would lead to lowering of LDL levels. Participants were randomized to receive a CHD risk estimate that included genetic risk information versus an estimate based on conventional risk factors alone. Conventional risk factors include high blood pressure, diabetes, physical inactivity and a history of smoking. Six months after risk disclosure, the LDL levels were nearly 10 milligrams per deciliter of blood lower in those randomized to receive genetic risk information. The lower LDL levels resulted from a greater proportion of individuals in this group being started on statin medication.

“This study demonstrates for the first time that disclosing genetic risk information for a common disease such as CHD can result in changes in a relevant health outcome, in this case, LDL levels,” says Iftikhar Kullo, M.D., Mayo Clinic cardiologist and lead author. “The study also demonstrates the feasibility of placing genetic risk information into the electronic health record to empower patients and physicians to make decisions related to initiation of a statin medication. This is an important advance in the area of precision medicine for cardiovascular diseases.”

MEDIA CONTACT: Traci Klein, Mayo Clinic Public Affairs, 507-990-1182, Klein.traci@mayo.edu

Journalists: Sound bites with Dr. Kullo are available in the downloads.

The MI-GENES Study included 207 people, ages 45-65, with no known atherosclerotic vascular disease who were not on a statin and were at intermediate risk for CHD. The 10-year probability of heart attack was 5 to 20 percent. They were randomized to receive a 10-year probability of heart disease based on conventional risk factors alone  versus conventional risk factors plus a genetic risk score (GRS). The GRS is derived from 28 genetic variants associated with CHD risk. For both groups, heart disease risk was disclosed by a genetic counselor, followed by a discussion with a physician about statin use. Participants’ LDL levels were checked at three and six months.

LDL cholesterol transports cholesterol particles throughout the body and can build up in the walls of arteries, making them hard and narrow and may cause heart attacks. CHD remains the leading cause of death in the U.S. Often, the first manifestation is sudden death or heart attack.

“Our ability to predict the risk of an individual to suffer such an event is somewhat limited,” Dr. Kullo says. “Incorporating genetic risk information into CHD risk estimates may improve our ability to more precisely identify individuals at risk.”

The study was one of the genomic medicine pilots initiated in the last phase of the Electronic Medical Records and Genomics Network that is funded by the National Human Genome Research Institute.

Co-authors are: Hayan Jouni, M.D.; Iyad Isseh, M.B.B.S.; Erin Austin, Ph.D.; Teresa Kruisselbrink, M.S., C.G.C.; Sherry-Ann Brown, M.D., Ph.D.; Victor Montori, M.D.; Raad Haddad, M.B.B.S.; Daniel Schaid, Ph.D.; and Kent Bailey, Ph.D., all of Mayo Clinic; Ulrich Broeckel, M.D., Medical College of Wisconsin; and Robert Green, M.D., Brigham and Women’s Hospital and Harvard Medical School.

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