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

BACKGROUND Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating disease caused by transthyretin (TTR) gene mutations. The V122I variant, a common pathogenic TTR mutation found primarily in individuals of West African descent, is frequently associated with cardiomyopathy. METHODS The association between the V122I variant and ICD10 diagnosis codes was assessed in the UK Biobank black subpopulation (N=6062); whether significant associations could be replicated in the Penn Medicine Biobank (N=5737) and Million Veteran Program (N=82,382) was then investigated. Cumulative incidence of common hATTR amyloidosis manifestations (polyneuropathy, carpal tunnel syndrome, cardiomyopathy, and heart failure) was estimated by V122I genotype in the UK Biobank using Cox regression controlling for age, sex, and genetic ancestry. RESULTS Phenome-wide analysis identified a significant association between V122I genotype and polyneuropathy diagnosis (odds ratio [OR]=6.4, 95% confidence interval [CI]=2.6-15.6, P=4.2x10-5) in the UK Biobank. A significant association was also observed in the Penn Medicine Biobank (OR=1.6, 95% CI=1.2-2.4, P=6.0x10-3) and the Million Veteran Program (OR=1.5, 95% CI=1.2-1.8, P=1.8x10-4). Prevalence of a polyneuropathy diagnosis among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. In the UK Biobank, common hATTR amyloidosis manifestations were significantly enriched in V122I carriers compared with non-carriers (HR=2.8; 95% CI=1.7-4.5; P=2.6x10-5). By age 75, 37.4% of V122I carriers had a diagnosis of any one of the common manifestations, including polyneuropathy (7.9%). CONCLUSIONS V122I carriers, historically associated with a predominantly cardiac phenotype of hATTR amyloidosis, have a significantly increased risk of polyneuropathy.