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

Abstract

Introduction Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating, fatal disease caused by mutations in the transthyretin (TTR) gene that lead to amyloid deposition in multiple tissues, including peripheral nerves and heart. Historically, patients were identified by their predominant phenotype (polyneuropathy or cardiomyopathy), 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 found in individuals of West African descent, and is thought to be predominantly associated with cardiomyopathy. This analysis characterizes the association between V122I genotype and ICD10 diagnosis codes in the black subpopulation of UK Biobank (UKBB) with replication in the Penn Medicine Biobank (PMBB). 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 Individuals heterozygous or homozygous for V122I (n=387) were identified and were primarily of African or Caribbean descent (minor allele frequency in black subpopulation = 2%; baseline age: 40-70 years). This analysis revealed a significant association between the V122I genotype and a clinical diagnosis of polyneuropathy (OR = 11.2; 95% CI: 3.7-26.6; p=1.1 × 10-6). Of note, these V122I carriers were not diagnosed with diabetic neuropathy. 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 (OR = 1.6; 95% CI: 1.2-2.4; p=0.006). In addition, there was nominally significant evidence that V122I carriers are at increased risk of other symptoms of hATTR amyloidosis, including carpal tunnel syndrome (OR = 2.0; p=0.02) and urinary retention (OR = 2.1; p=0.05) within the UKBB. Conclusion 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 both cardiomyopathy and polyneuropathy.