Abstract: TH-PO0853
Discovery of a Novel IL1R1 Pharmacogenomic Interaction Shaping Frailty in Kidney Transplant Recipients
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1900 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Agarwal, Neel, The Ohio State University College of Medicine, Columbus, Ohio, United States
- Nori, Uday S., The Ohio State University Wexner Medical Center Department of Internal Medicine, Columbus, Ohio, United States
Background
Frailty is a primary driver of morbidity, mortality, and allograft failure following kidney transplantation. While maintenance immunosuppression is mandatory, its contribution to physiological decline and frailty is multifaceted and largely unknown. This study analyzes the interaction between genomic variation within inflammatory pathways with standard calcineurin inhibitors and corticosteroids to modulate host vulnerability to frailty.
Methods
A sex-stratified pharmacogenomic genome-wide association study with gene-environment interaction analyses in 1,722 kidney transplant recipients (852 males, 870 females; age 51±12; 58% non-European; 36% diabetes; BMI 30±6) from the NIH “All of Us” cohort was performed. Frailty was evaluated 1-year post-transplant using a metric incorporating serum albumin, hemoglobin, age, and BMI. Analyses tested interactions between variants and tacrolimus/corticosteroid use, adjusting for genetic ancestry, induction, diabetes, baseline frailty, and 1-year allograft failure.
Results
Analyses uncovered a significant, novel pharmacogenomic interaction governing frailty risk at the IL1R1(Interleukin 1 Receptor Type 1) locus in male recipients (Posterior Inclusion Probability = 0.13). Variants within IL1R1 conferred high frailty risk (Main Effect β = 0.87, P = 5.4×10-8). This observed effect was attenuated by tacrolimus (Interaction β = -0.74, P = 0.0088). A parallel interaction interaction at IL1R1 was observed with corticosteroids (Interaction β = -0.70, P = 0.020; Main Effect β = 0.82). Female frailty exhibited divergent trends, with independent modulation by PPFIBP1 (Interaction β = -1.05, P = 0.0082).
Conclusion
Post-transplant frailty is a genetically determined vulnerability mediated by sex-specific pharmacogenomic interactions between maintenance immunosuppression and host pathways such as IL1R1. Pre-transplant genotyping could serve as a biomarker to individualize immunosuppression—identifying patients requiring immunosuppression minimization protocols to prevent decline—providing a rationale for targeted IL-1R antagonists to mitigate frailty and extend allograft longetivity.
Acknowledgment
We would like to thank Dr. Joseph McElroy for his statistics expertise and consultation.