Polygenic Risk Scores for Prediction of Immune Checkpoint Inhibitor Thyroid Toxicity in Diverse Populations.

PURPOSE: Immune checkpoint inhibitor (ICI)-induced thyroiditis is a common immune-related adverse event (irAE) linked to improved survival. Polygenic risk scores (PRS) for autoimmune hypothyroidism predict thyroid irAEs in European-ancestry patients; performance in non-European populations is unclear.

EXPERIMENTAL

DESIGN

In the Veterans Affairs Million Veteran Program (MVP; 2011-2023), we identified ICI-treated patients with germline genotyping and a chemotherapy-treated control cohort, excluding those with thyroid disease or prior thyroid-directed treatments. Harmonized ancestry and race/ethnicity (HARE) defined non-Hispanic White (NHW) and non-Hispanic Black (NHB) groups. Thyroid irAEs within 1 year were defined using laboratory criteria capturing both hyperthyroid and hypothyroid phases. We compared two PRSs: a published European-derived PRS and an updated PRS selected across multiple genome-wide association study (GWAS) sources and methods (including the MVP multiancestry GWAS) to maximize discrimination in African-ancestry individuals in a held-out test set. HARE-stratified multivariable Cox models estimated time to thyroiditis; a 6-month landmark analysis assessed overall survival.

RESULTS

The ICI cohort included 4,289 patients (3,473 NHW; 816 NHB). The baseline PRS was associated with thyroiditis in NHW [adjusted hazard ratio (aHR) per standard deviation, 1.33; 95% confidence interval (CI), 1.19-1.50) but not NHB patients or controls. The updated PRS improved risk stratification in NHW (aHR, 1.45; 95% CI, 1.28-1.63) and predicted thyroiditis in NHB patients (aHR, 1.48; 95% CI, 1.11-1.98) but not in controls. Thyroiditis within 6 months was associated with improved survival, but neither PRS was.

CONCLUSIONS

Germline polygenic liability to hypothyroidism predicts ICI-induced thyroiditis in NHW and NHB patients when PRSs are selected via ancestry-stratified validation. Careful exploration of the dataset-method space is critical for equitable PRS development.