Clinical consequences of a polygenic predisposition to benign lower white blood cell counts
Mosley, J. D.; Shelley, J.; Dickson, A. L.; Zanussi, J.; Daniel, L.; Zheng, N. S.; Bastarache, L.; Wei, W.-Q.; Shi, M.; Jarvik, G. P.; Rosenthal, E. A.; Khan, A.; Sherafati, A.; Kullo, I.; Walunas, T.; Glessner, J.; Hakonarson, H.; Cox, N. J.; Roden, D. M.; Frangakis, S. G.; Vanderwerff, B.; Stein, C. M.; Van Driest, S. L.; Borinstein, S. C.; Zawistowski, M.; Shu, X.-O.; Chung, C.; Kawai, V. K.
Show 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 (PGSWBC) 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 PGSWBC [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=4.0x10-5) 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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