Faculty Bibliography

BACKGROUND:Ischemic stroke in Saudi Arabia arises in a highly consanguineous population with a distinctive genetic architecture, likely enriching rare coding variants that influence stroke risk. Yet the contribution of these variants to stroke susceptibility, age at onset, and subtype patterns in this setting remains incompletely defined. METHODS:We analyzed whole-exome sequencing data from 514 stroke patients in a case only study design. Gene-based rare variant burden analyses was performed using SAIGE-GENE+ burden and SKAT-O tests across predefined phenotype contrasts within the cohort, stroke severity (modified Rankin Scale, mild < 3 vs. severe ≥ 3 ,), age at onset (early-onset < 25 years vs. late-onset > 45 years; mid-life onset < 45 vs. > 45), etiological subtypes (TOAST classification), and vascular imaging patterns (intracranial vs. extracranial).Post-association functional annotations included GTEx expression, gnomAD constraint metrics, and draggability insights. RESULTS:Gene-level associations at a suggestive threshold (p < 0.005) identified several candidates including HSP90AB1, PRR23A, and LRRC42 (severity and age-at-onset); POGZ and SMIM34 (age-at-onset); and COL9A3, DCP1B, and ADGRV1 (imaging and etiology subtypes). The highlighted genes showed varying expression across brain and vascular tissues and intolerance to loss-of-function variation. Notably, HSP90AB1, a molecular chaperone highly expressed in the brain and vasculature, has small-molecule inhibitors, supporting its potential relevance to stroke biology. CONCLUSIONS:Our findings identify exploratory candidate gene-level signals across clinically defined ischemic stroke phenotypes based on case-only within-cohort comparisons, in underrepresented population. These results should be considered hypothesis-generating and require replication and functional validation before biological or clinical inferences can be made.

Plasma circular RNAs (circRNAs) are stable RNA molecules found in blood, which makes them potential noninvasive biomarkers for acute myocardial infarction (MI). The aim of this study was to describe the plasma circRNA profile in patients with acute MI and to identify circRNA markers that may help detect heart injury and reflect the biological processes involved. We compared plasma samples from patients with acute MI and healthy controls using total RNA sequencing with unique molecular identifiers (UMIs). After sequencing, reads were processed through quality control, alignment, duplicate removal, and circRNA detection. Differential expression was analyzed after adjusting for age, sex, smoking, and technical factors. Several circRNAs were significantly different between MI cases and controls and were able to separate the two groups in principal component and receiver operating characteristic analyses. Among the most increased circRNAs were hsa-PASK_0004, hsa-STXBP3_0002, hsa-RCAN3_0002, and hsa-RANBP9_0044, while hsa-HIF1A_0002, hsa-SUZ12_0049, hsa-PNRC1_0001, and hsa-RAB2A_0002 were decreased. Several candidates showed AUC values above 0.7. Pathway analysis linked the host genes of these circRNAs to inflammation, platelet activation, coagulation, and cardiomyocyte stress responses. Overall, these findings suggest that circulating circRNAs may serve as useful blood-based markers of MI and provide insight into the molecular changes that accompany acute MI.

The inaugural Richard Slayman Clinical Xenotransplantation Workshop convened >140 participants from North America, Europe, and Asia to discuss emerging advances and challenges in translating xenotransplantation from bench to bedside. This report summarized key discussions spanning kidney, heart, and liver xenotransplantation, with an emphasis on clinical readiness and future directions. Core themes included the importance of patient selection, the role of genetic editing to reduce immune incompatibility, adaptive immunosuppressive strategies, novel molecular tools for immune and infectious surveillance, and the growing recognition of innate immune activation as a barrier to long-term graft survival. The workshop highlighted decedent models as a translational bridge, the use of machine perfusion in liver xenograft applications, and progress in living recipients. Notably, 1 patient achieved 9 mo of kidney xenograft function, underscoring the feasibility of extended survival in carefully selected candidates. Perspectives from patients and families, including a reflection honoring Richard Slayman, the first living recipient of a genetically edited pig kidney, framed the scientific dialogue within the broader human impact of this emerging field. The workshop marked a pivotal moment in aligning scientific, ethical, and regulatory efforts to advance safe and equitable access to xenotransplantation.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution^1-3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure⁴. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A6⁵, SPP1⁶ (Osteopontin), and COLEC11⁷, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

Circular RNAs (circRNAs) have emerged as crucial cardiovascular regulators through gene expression modulation, microRNA sponging, and protein interactions. Their covalently closed structure confers exceptional stability, making them detectable in blood and tissues as potential biomarkers. This review explores current research examining circRNAs across cardiovascular diseases, including atherosclerosis, myocardial infarction, and heart failure. We highlight the control that circRNA exerts over endothelial function, smooth muscle switching, inflammatory recruitment, and cardiomyocyte survival. Key findings distinguish frequently disease-promoting circRNAs (circANRIL, circHIPK3) from context-dependent regulators (circFOXO3). Compartment-specific controllers include endothelial stabilizers (circGNAQ), smooth muscle modulators (circLRP6, circROBO2), and macrophage regulators (circZNF609), functioning as tunable rheostats across vascular compartments. Overall, the literature suggests that circRNAs represent promising tools in two translational avenues: (i) blood-based multimarker panels for precision diagnosis and (ii) targeted modulation of pathogenic circuits. Clinical translation will require precise cell-type targeting, efficient delivery to cardiovascular tissues, and rigorous mitigation of off-target effects.

Human leukocyte antigen-level matching in US kidney allocation has been deemphasized due to its role in elevating racial disparities. Molecular matching based on eplets might improve risk stratification compared to antigen matching, but the magnitude of racial disparities in molecular matching is not known. To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high-resolution allele-level human leukocyte antigen genotypes from the National Kidney Registry. Using repeated random sampling to simulate donor-recipient genotype pairings based on the ethnic composition of the historical US deceased-donor pool, we profiled the percentage of well-matched donors available for candidates by ethnicity. The prevalence of well-matched donors with 0-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates and 2-fold less for Latino candidates compared to 0-ABDR antigen mismatches. Compared to 0-DR antigen mismatch, 0-DR eplet mismatch was 1.33-fold more racially disparate for Asian and 1.28-fold more for Latino, with similar disparity for Black candidates, whereas 0-DQ eplet mismatch reduced disparities, showing 1.26-fold less disparity for Black, 1.14-fold less for Latino, but 1.26-fold higher for Asian candidates. The prevalence of well-matched donors for candidates of different ethnicities varied according to which molecules were chosen to define a low-risk match.

BACKGROUND:The genetic architecture of chronic kidney disease (CKD) is complex, including monogenic and polygenic contributions. CKD progression to kidney failure is influenced by factors including male sex, baseline estimated glomerular filtration rate (eGFR), hypertension, diabetes, proteinuria, and the underlying kidney disease. These traits all have strong genetic components, which can be partially quantified using polygenic risk scores. This paper examines the association between polygenic risk scores for CKD-related traits and age at kidney failure development. METHODS:Genome-wide genotype data from 10,586 patients with kidney failure were compiled from 12 cohorts. Polygenic risk scores for hypertension, albuminuria, rapid decline in eGFR, decreased total kidney volume, and decreased eGFR were calculated using weights from published independent population-scale genome-wide association studies. The association between each polygenic risk score and age at kidney failure was investigated using logistic regression models. The association between polygenic risk score and age at kidney failure was also investigated separately for each primary kidney disease. RESULTS:Individuals in the highest 10% of polygenic risk score for decreased eGFR developed kidney failure 2 years earlier than those in the bottom 90% (49.9 years and 47.9 years, P = 5e-5). A standard deviation increase in decreased eGFR polygenic risk score was associated with increased odds of developing kidney failure before the age of 60 years (Odds ratio (OR) = 1.05; 95% CI 1.01-1.10; P = 0.01), as was high decreased eGFR polygenic risk score (OR = 1.26; 95% CI 1.08-1.46; P = 0.003). CONCLUSIONS:We conclude that decreased eGFR polygenic risk score explains a portion of the variation in age at development of kidney failure.