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Master of Public Health

Clinical consequences of a polygenic predisposition to benign lower white blood cell counts

AUTHORS

Mosley JD , Shelley JP , Dickson AL , Zanussi J , Daniel LL , Zheng NS , Bastarache L , Wei WQ , Shi M , Jarvik GP , Rosenthal EA , Khan A , Sherafati A , Kullo IJ , Walunas TL , Glessner J , Hakonarson H , Cox NJ , Roden DM , Frangakis SG , Vanderwerff B , Stein CM , Van Driest SL , Borinstein SC , Shu XO , Zawistowski M , Chung CP , Kawai VK , . medRxiv : the preprint server for health sciences. 2023 8 21; ().

ABSTRACT

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is undefined. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGS ) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio=0.55 per standard deviation increase in PGS [95%CI, 0.30 – 0.94], p=0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n=1,724, hazard ratio [HR]=0.78 [0.69 – 0.88], p=4.0×10 ) or immunosuppressant (n=354, HR=0.61 [0.38 – 0.99], p=0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n=1,466, HR=0.62 [0.44 – 0.87], p=0.006). Collectively, these findings suggest that a WBC count polygenic score identifies individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

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