Abstract: TH-PO0983
Novel Sex-Specific Genetic Drivers of Frailty in Kidney Transplant Recipients
Session Information
- Transplantation: Basic - Immune Biology, Tissue Injury, and Emerging Technologies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2001 Transplantation: Basic
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 predicts morbidity, mortality, and allograft loss following kidney transplantation. While clinical manifestations are well documented, underlying genetic determinants are unknown, and it is unclear whether biological pathways differ between sexes. This study aimed to elucidate the sex-specific genetic architecture of frailty to identify novel pathways and therapeutic targets.
Methods
A sex-stratified genome-wide association study on 1,722 kidney transplant recipients (852 males, 870 females; age 51±12; 58% non-European; 36% DM; BMI 30±6) using the NIH “All of Us” cohort was performed. Frailty was evaluated 1-year post-transplant using a metric incorporating serum albumin, hemoglobin, age, and body mass index. Analyses were adjusted for genetic ancestry, tacrolimus/steroid use, induction, diabetes, baseline frailty, and 1-year allograft failure.
Results
Male frailty fine-mapping identified a risk-increasing locus linked to TSHZ2 (PIP = 0.27) and a protective locus at OPCML (PIP = 0.47) driven by protein hydroxylation processes (Pbon = 0.022) with support by 3D chromatin analysis. Conversely, females exhibited a diffuse polygenic architecture lacking single dominant loci (top suggestive locus SCD5, PIP = 0.45), with dispersed polygenic burden concentrated within metabolic and stress-response pathways, including the Ragulator complex (Pbon = 0.0017), eicosanoid transport (Pbon = 0.0029), and adaptation to hypoxia (Pbon = 0.038). Tissue-expression analysis in male and females exhibit different features, shown in Figure 1.
Conclusion
The genetic pathophysiology of post-transplant frailty exhibits sexual dimorphism. Male frailty is associated with genes governing hepatic function and protein hydroxylation, whereas female frailty is a diffuse polygenic burden linked to renal tissues and metabolic pathways. These data question frailty as a uniform, sex-neutral aging process. Clinically, findings suggest sex-stratified risk assessments and provide a rationale for investigating sex-specific targeted interventions to mediate decline and prolong allograft survival.
Acknowledgment
We would like to thank Dr. Joseph McElroy for his statistics expertise and consultation.