People whose genetic makeup predisposes them to having low white blood cell levels experience changes in clinical care, a recent study reports. They are more likely to receive a diagnosis of leukopenia (low white blood cell count), undergo a bone marrow biopsy, and have medications discontinued, according to the study published in the journal Nature Communications.
White blood cell (WBC) count is a routinely measured biomarker that guides clinical care. Levels that are too low or too high — based on a reference range determined in a healthy population — may indicate the presence of disease and prompt further diagnostic testing. But genetic variation can affect WBC count, so that in some people a WBC count outside the reference range does not indicate disease or increased risk of infection.
“We know that for most traits or biomarkers we measure in people, there’s a genetic influence,” said Jonathan Mosley, MD, PhD, associate professor of Medicine in the Division of Clinical Pharmacology and corresponding author of the study. “We’re interested in the genetic variation associated with benign differences between us and not related to underlying disease. Our question is: How much are those genetic influences contributing to clinical decisions?”
Mosley and colleagues at Vanderbilt University Medical Center previously showed that a single genetic variant that lowers WBC count and is common in individuals of African ancestry contributes to unnecessary bone marrow biopsies and discontinuation or reduced dosing of the immunosuppressant drug azathioprine.
They were curious if people who have many genetic variants that each exert a small effect on WBC count might also experience similar changes in clinical care. To test this idea, the researchers constructed a polygenic score for WBC count — a tally of the genetic variants associated with WBC count, but not associated with disease. They evaluated the clinical consequences of a genetic predisposition to a lower WBC count among 89,559 BioVU and other biobank participants. BioVU is Vanderbilt’s DNA biobank linked to de-identified electronic health records.
People with a polygenic score that predicted a low WBC count were:
- More likely to receive a diagnostic code noting a WBC count outside the reference range
- More likely to have a bone marrow biopsy because of a low WBC count and less likely to have the biopsy identify disease
- More likely to experience low WBC count when treated with a chemotherapeutic or immunosuppressant drug
- More likely to have the immunosuppressant azathioprine, which is prescribed for a variety of inflammatory conditions, discontinued because of concern about a low WBC count
“Our study shows that people whose white blood cell counts are near the edges of a normal distribution will hit a clinical decision point that has consequences,” Mosley said. “Something that’s not problematic for them — a genetic predisposition to low white blood cell count — becomes problematic in certain settings…when someone draws their blood.”
While personalized reference ranges for WBC count and other biomarkers based on genotype may be developed in the future, the WBC polygenic score can be used now to inform decisions about diagnostic investigations or changes to medication treatment, Mosley noted. In cases where a bone marrow biopsy for low WBC count does not identify disease, the polygenic score could offer a possible biological explanation for the low count.
Mosley and his colleagues are also evaluating how genetic variation in other biomarkers, such as prostate specific antigen and children’s height, affects clinical decision-making.
Important VUMC contributors included John Shelley, a student in the Medical Scientist Training Program, Scott Borinstein, MD, PhD, professor of Pediatrics in the Division of Pediatric Hematology and Oncology, and Vivian Kawai, MD, MPH, assistant professor of Medicine in the Division of Clinical Pharmacology.
The research was supported by the National Institutes of Health (grants R01GM130791, R01GM126535, R35GM131770, U01HG011181) and the Ingram Cancer Research Professorship fund.
