Researchers have validated a genetic scoring tool that may help physicians diagnose idiopathic pulmonary fibrosis and identify which patients are at greatest risk for severe outcomes, including death or the need for a lung transplant. The findings come from a new international study of more than 570,000 people co-led by Mayo Clinic and Brigham and Women's Hospital.
Published in the American Journal of Respiratory and Critical Care Medicine, the study is one of the largest real-world evaluations of a polygenic risk score for idiopathic pulmonary fibrosis. The findings bring this genomic approach one step closer to clinical care.
"Polygenic risk scores add a new layer of biological insight into the prediction of pulmonary fibrosis and mortality outcomes, bringing us closer to a future where diagnosis, prognosis and treatment are informed by each patient's unique molecular signatures."
- Dr. Victor Ortega
Researchers analyzed genomic and electronic health record data from four major biobanks in the U.S. and U.K., including the Mayo Clinic Biobank and Mayo Clinic Tapestry. They calculated a polygenic risk score for each participant by combining the effects of more than 60,000 DNA variants associated with idiopathic pulmonary fibrosis. While each genetic variant contributes only a small amount of risk, together they reveal patterns of inherited susceptibility that would otherwise be difficult to detect.
The researchers then tested whether the score could identify patients with the disease and predict clinical outcomes.
People with high polygenic risk scores were nearly three times more likely to have the disease than those with lower scores. The genetic score became even more predictive as researchers applied increasingly specific definitions of the disease, suggesting the score may one day help distinguish idiopathic pulmonary fibrosis from other forms of interstitial lung disease.
Among patients with the disease, those with high genetic risk were 23% more likely to die or require a lung transplant, indicating the score may also help identify patients at greatest risk of poor outcomes.
"Every patient has a unique genetic blueprint that we can use to estimate risk for the development of disease," says Victor Ortega, M.D., Ph.D., a pulmonologist, associate director of Mayo Clinic's Center for Individualized Medicine in Arizona, and a co-senior author of the study. "Polygenic risk scores add a new layer of biological insight into the prediction of pulmonary fibrosis and mortality outcomes, bringing us closer to a future where diagnosis, prognosis and treatment are informed by each patient's unique molecular signatures."
"Showing that this approach works across more than half a million people receiving routine clinical care is an important step toward understanding how it can ultimately benefit patients."
- Dr. Christopher Grilli
Idiopathic pulmonary fibrosis causes irreversible scarring of the lungs that progressively limits a person's ability to breathe. More than 100,000 Americans are living with the disease, and an estimated 30,000 to 40,000 new cases are diagnosed each year, according to the National Institutes of Health.
Because its symptoms often resemble those of other interstitial lung diseases, diagnosis can be delayed until significant, irreversible lung damage has already occurred. Confirming the diagnosis sometimes requires an invasive lung biopsy to collect lung tissue. Researchers hope a noninvasive genetic test using DNA from a blood or saliva sample may help reduce the need for those procedures in selected patients.
"Most polygenic risk scores are developed in carefully selected research populations," says Christopher Grilli, Pharm.D., a researcher at Mayo Clinic's Center for Individualized Medicine and co-first author of the study. "Showing that this approach also works across more than half a million people receiving routine clinical care is an important step toward understanding how it can ultimately benefit patients."
If further validated, researchers envision genomic risk scores complementing imaging and other diagnostic tools to help physicians diagnose the disease with greater confidence.
This research aligns with Mayo Clinic's Precure Research initiative, which seeks to uncover the earliest biological changes associated with disease and translate those discoveries into clinical tools that improve diagnosis, personalize care and ultimately change the course of disease. As part of that effort, the Precure-Lung study, led by Dr. Ortega, is expanding Mayo Clinic's research into interstitial lung diseases, including idiopathic pulmonary fibrosis.
For a complete list of authors, disclosures and funding, review the study.
