The V122I Mutation in Hereditary Transthyretin-Mediated Amyloidosis is Significantly Associated with Polyneuropathy (736)

Objective: To characterize the association of the V122I genotype and International Classification of Diseases, 10th revision (ICD10) diagnosis codes in the UK Biobank black subpopulation with replication in the Penn Medicine Biobank. Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a debilitating, fatal disease caused by mutations in the transthyretin (TTR) gene. Historically, patients were identified by their predominant phenotype, however, evidence now suggests that a majority develop a mixed phenotype with both polyneuropathy and cardiomyopathy. The V122I (Val122Ile; p.V142I) variant is the most common pathogenic TTR mutation in the US, primarily in individuals of West African descent, and is thought to be predominantly associated with cardiomyopathy. Design/Methods: The UKBB is a prospective cohort study with genetic, physical, and health data on ~500,000 individuals across the United Kingdom. A phenome wide association study was performed to test for association between the V122I genotype and 1,229 clinical diagnoses in the black subpopulation of UKBB (n=6,063). Results: 387 individuals heterozygous or homozygous for V122I were identified (primarily of African or Caribbean descent). This analysis revealed a significant association between the V122I genotype and a clinical diagnosis of polyneuropathy. Replication analysis was performed in 5,737 black participants of the PMBB, of whom 190 individuals carried the V122I variant. The association of V122I with polyneuropathy was replicated. In addition, there was significant evidence that V122I carriers are at increased risk of other symptoms of hATTR amyloidosis, including carpal tunnel syndrome and urinary retention within the UKBB. Conclusions: These data indicate that carriers of the V122I mutation, historically associated with a predominantly cardiac phenotype, have a significantly increased risk of a clinical diagnosis of polyneuropathy. Additional manifestations were identified, highlighting that V122I causes a mixed phenotype. It is crucial that physicians have a clinical suspicion for the multisystem manifestations of hATTR amyloidosis, which includes cardiomyopathy and polyneuropathy. Disclosure: Dr. Nioi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam Pharmaceuticals. Dr. Nioi holds stock and/or stock options in Alnylam and Amgen.Dr. Parker has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Parker has received research support from Alnylam. Dr. Damrauer has received research support from Renalytix AI. Dr. Rader has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam, Novartis, Pfizer, Verve. Dr. Rader has received personal compensation in an editorial capacity for ATVB senior editor. Dr. Rader holds stock and/or stock options in VascularStrategies, Staten Biotechnology. Dr. Rader has received research support from Novartis, Regeneron. Dr. Ticau has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Ticau holds stock and/or stock options in Alnylam which sponsored research in which Dr. Ticau was involved as an investigator. Dr. Ticau has received research support from Alnylam. Dr. Erbe has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Erbe has received research support from Alnylam. Dr. Hinkle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam.