Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Abstract

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. 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_WBC) 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_WBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10^-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 there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Fig. 1. Overview of the study populations and analyses.

WBC white blood cell, BM bone marrow, ANC absolute neutrophil count, ICD International Classification of Disease code.

Fig. 2. PGS associations with measured WBC counts among 11,694 BioVU participants.

a Ranges of observed median WBC counts by PGS_WBC value. Ranges summarize WBC counts within sequential windows (±0.2 s.d.) across the range of the PGS_WBC. The dark line is the median value, and the gray ribbon represents the 5th–95th percentiles of the range. The dashed red lines denote the upper and lower clinical reference ranges for the clinical assay used to measure the WBC count. b Predicted probability (with standard errors) of having a WBC count that falls below the lower clinical reference value across a range of PGS_WBC values (n = 623 events). Probabilities are based on a logistic regression model adjusted for age and sex. The dashed red line is the average probability for the entire population.

Fig. 3. PGS associations with bone marrow biopsy outcomes.

a Distribution of the PGS_WBC values among 117 BioVU participants who underwent a bone marrow biopsy for a clinical indication that included a low WBC count. Results are stratified by whether the biopsy identified pathology (abnormal, n = 35) or not (normal, n = 82). Box plots show the median value, interquartile range (gray region), and maximum and minimum values (whiskers) for each stratum. The dashed red line indicates the median PGS_WBC value for the overall BioVU population. b Predicted probabilities (with standard errors) of a normal biopsy finding. Results are stratified by whether the indication for the biopsy included other hematological abnormalities (labeled as present or absent) in addition to a low WBC count. Probabilities are based on a multivariable logistic regression model, adjusted for age, sex, and presence of a hematological abnormality. c, d Scatterplots showing the WBC count at the time of biopsy versus the PGS_WBC values for participants with a c normal or d abnormal biopsy result. Points are colored to denote whether the observed WBC count fell within the range (i.e. above the 2.5th percentile of the distribution) of WBC counts observed among individuals in the WBC cohort whose PGS_WBC value was within 0.2 standard deviations. The dashed red line denotes the lower bound of the clinical reference ranges.

Fig. 4. PGS associations with pharmacogenomic outcomes.

a Odds-ratio and 95% confidence interval of having an ICD code for toxicity from an antineoplastic or immunosuppressive medication with (n = 985) or without (n = 2273) a clinical concern for a low WBC count among 71,078 BioVU participants. Odds-ratios are from a logistic regression model, adjusted for age, sex, and principal components. b Kaplan–Meier plot for a WBC count < 3000 cells/µL (leukopenia) (n = 266 events) after initiating treatment with taxanes among 1724 BioVU participants with cancer. The PGS_WBC strata are Low (<1 s.d. below the mean), Middle (≥−1 s.d. and ≤1 s.d.), High (>1 s.d.).

Fig. 5. Azathioprine discontinuation.

Kaplan–Meier plot for discontinuation of azathioprine due to clinical concern of a low WBC count related to medication toxicity (n = 34 events) among 1180 BioVU participants with autoimmune disease. The PGS_WBC strata are Low (<1 s.d. below the mean), Middle (≥−1 s.d. and ≤1 s.d.), High (>1 s.d.).