A new type of genetic test known as a polygenic risk score could change the way clinicians detect and treat chronic diseases. But to be widely used, genomic results in large populations must first be translated into valid clinical tests for individual patients. Next, physicians need meaningful interpretations of test data to help make clinical decisions about patient care.
In a study published in natural medicine, the researchers report details on how they set up a genetic test for six common diseases and developed explanatory reports to help bridge the gap between science and clinical care.
The test and reports were created for the GenoVA study, a clinical trial to investigate whether polygenic risk scores (PRS), also known as polygenic scores (PGS), could be used effectively in a primary care setting. The randomized trial will enroll 1,000 patients at Boston Veterans Health System and follow them for 2 years.
The authors report the first data from the new laboratory test. Of the 227 participants enrolled to date, 11% were at high risk of atrial fibrillation7% were at risk of coronary artery disease8% for Type 2 diabetes6% for colorectal cancer15% of men had an increase Prostate cancer risk, and 13% of women had an increased risk of breast cancer.
Polygenic scores show promise for informing screening and treatment decisions, with the goal of preventing chronic disease. Jason Vassy, MD, of Brigham and Women’s Hospital and VA Boston, says, “It is important to view PRS as a risk factor for disease, not as a diagnostic test or an indication that an individual will definitely develop disease.
He continues, “Most diseases have complex, multifactorial etiologies, and high SRP is only one piece of the puzzle. PRS does not replace the traditional risk factors we usually think of in clinical medicine, such as diet and exercise to prevent type 2 diabetes and quitting smoking to reduce the risk of cardiovascular disease.”
Currently, clinical genetic testing is usually done when a patient is suspected of having a specific disease or a family history of a disease, such as sickle cell disease or breast cancer. Tests for these types of conditions are often monogenic, detecting only certain mutations.
PRS testing has the potential to inform clinical decisions years before patients become symptomatic. The PRS test in this study combines large amounts of genetic information to assess a patient’s risk for several conditions. The risk of common chronic diseases can involve hundreds to millions of small genetic variations. Alone, these variations have minimal impact on a person’s risk of disease, but together they can lead to an increased risk of specific diseases.
Some PRS tests are currently available from direct-to-consumer laboratories, in oncology, and in some clinical trials, but they are not commonly used in general practice.
Vassy and colleagues developed and validated PRSs for atrial fibrillation, coronary artery disease, type 2 diabetes, breast cancer, colorectal cancer, and prostate cancer at the Mass General Brigham Laboratory for Molecular Medicine.
The team calculated the final PRS based on individual patient genotyping combined with population statistical models.
In the GenoVA study, adults between the ages of 50 and 70 who have no history of disease provide saliva or blood for the PRS test at the Boston VA. Participants are stratified by risk outcome and are randomly assigned to receive test results either immediately or after 24 months.
Enrollees are then followed for 2 years to observe how they and their primary care providers use the risk score information and whether preventive measures or other clinical tests are used. Guidelines are provided to patients and clinicians throughout the study, as well as genetic counseling. Ultimately, the study aims to determine whether implementing PRS improves health outcomes.
Study participants come from a variety of backgrounds; 52% of the first 227 patients report non-white, non-Hispanic ethnicity. To account for the fact that most genomic research to date has been based on European populations, the researchers used statistical methods to calculate scores between racial groups.
Is the PRS test the future of chronic disease prevention?
Genome-wide association studies (GWAS) from more inclusive datasets are needed to improve the relevance of PRS across all ancestry groups, the authors write.
Vassy points out that “GWAS risk estimates are the foundation of polygenic scores, so a score is only as valid as its original.” Fortunately, he adds, “progress is occurring on several fronts, and this will be critical to promoting the equitable implementation of polygenic scores. Larger and more diverse cohorts are being recruited for GWAS studies, and statistical methods More sophisticated, trans-ancestry GWAS are being developed to analyze this more diverse data.
In England, researchers are considering the benefits of using polygenic scores in National Health Service checks for cardiovascular disease, a well-studied area of genetic risk. The new article and the English effort are inspired by the SGP Catalogan open database built by Samuel Lambert, Department of Public Health and Primary Care, University of Cambridge, and colleagues to provide scores and methods that can be reused and adapted for clinical use.
He says he would confidently recommend PRS to his family members – in particular, some extensive cancer testing – “provided [the results] would be interpreted in conjunction with a medical professional who understands genetics (e.g., a genetic counselor) with carefully verified information about the validity and actionability of the test result.”
Lambert believes it is important to understand that PRS tests are not deterministic. “Risk information is inherently probabilistic and relative (e.g. you have a four times higher risk than the average person, but if the disease prevalence is 0.5%, that’s a small absolute difference) “, he says.
“PRS also explains a fraction of the variability in risk in the population and therefore should not be used alone but in combination with other established risk factors and tools to predict future risks when they exist,” says Lambert.
“And third, most current PRSs are less accurate in those of non-European ancestry due to a lack of ancestral diversity in the cohorts and datasets that were used to develop these PRSs; special care should be taken. given to ensure that the results of the PRS are valid for the individual,” he adds.
Funding for the study was provided by the NIH National Human Genome Research Institute and the NIH, American Heart Association, National Heart, Lung and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and Massachusetts General Hospital. Vassy is an employee of the United States Department of Veterans Affairs; the views expressed do not represent those of the VA or the US government. Lambert is an employee of the Cambridge-Baker Systems Genomics Initiative, Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care.
NatMed. Published online April 22, 2022. Full Text
Alyse Gray is an assistant pathologist and writer who has written two books. She holds a bachelor’s degree in psychology from the College of Geneva and a master’s degree in pathology from the University of Maryland, Baltimore.