Association of the Transthyretin Variant V122I With Polyneuropathy Among Individuals of African Descent

Abstract

IntroductionHereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. The V122I variant, one of the most common pathogenic TTR mutations, is found in 3-4% of Black individuals, and has been associated with cardiomyopathy. MethodsTo better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes for association with this variant in Black participants of the UK Biobank (n= 6,062). Significant associations were tested for replication in the Penn Medicine Biobank (n= 5,737) and the Million Veteran Program (n= 82,382). ResultsOur analyses discovered a significant association between V122I and polyneuropathy diagnosis (odds ratio = 6.4, 95% confidence interval [CI] = 2.6 to 15.6, P = 4.2 x 10-5) in the UK Biobank,which was replicated in the Penn Medicine Biobank (p=6.0x10-3)) and Million Veteran Program (P= 1.8x10-4)). Polyneuropathy prevalence among V122I carriers was 2.1-9.0% across biobanks. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers versus non-carriers (hazard ratio = 2.8, 95% CI = 1.7-4.5, P = 2.6 x 10-5) in the UK Biobank;37.4% of V122I carriers having a diagnosis of any one of these manifestations by age 75. ConclusionsOur findings show that, although the V122I variant is known to be associated with cardiomyopathy, carriers are also at significantly increased risk of developing polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.