Abstract
Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3–4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6–15.6, p = 4.2 × 10−5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2–2.4, p = 6.0 × 10–3) and Million Veteran Program (OR = 1.5, 95% CI 1.2–1.8, p = 1.8 × 10−4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7–4.5, p = 2.6 × 10−5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.
Highlights
Hereditary transthyretin-mediated amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR)gene
Baseline characteristics of V122I carriers and non-carriers from the Penn Medicine Biobank and Million Veteran Program are presented in Tables S1 and S2 in the “Supplementary Information”
16.7% of the risk of a polyneuropathy diagnosis, 4.1% of the risk of a CTS diagnosis, 2.4% of the risk of a cardiomyopathy diagnosis, and 6.5% of the risk of an heart failure (HF) diagnosis were attributable to the V122I variant (Table 3). In this analysis of three large biobanks (UK Biobank, Penn Medicine Biobank, and Million Veteran Program) including 2739 carriers, the V122I variant was significantly associated with a polyneuropathy diagnosis
Summary
Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR)gene. Hereditary transthyretin-mediated (hATTR) amyloidosis, known as ATTRv (v for variant) amyloidosis, is an underdiagnosed, progressively debilitating, and fatal disease caused by mutations in the transthyretin (TTR)gene. These pathogenic variants result in misfolding of TTR proteins, which accumulate as amyloid deposits in multiple tissues throughout the body, including the heart, nerves, and gastrointestinal tract[1,2,3]. Organ involvement and symptoms of hATTR amyloidosis can vary by patient and mutation, but carriers of pathogenic variants have an increased risk of developing life-impacting polyneuropathy, cardiomyopathy, and other symptoms (e.g., carpal tunnel syndrome [CTS])[4,5]. Significant associations were assessed for replication in the Penn Medicine Biobank and Million Veteran Program
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