Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry
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...
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2021
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oai:doaj.org-article:5c5a6c2a17f74f718458b7ee194eb2f42021-12-02T15:56:57ZAssociation of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry10.1038/s41598-021-91113-62045-2322https://doaj.org/article/5c5a6c2a17f74f718458b7ee194eb2f42021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91113-6https://doaj.org/toc/2045-2322Abstract 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.Margaret M. ParkerScott M. DamrauerCatherine TcheandjieuDavid ErbeEmre AldincPhilip N. HawkinsJulian D. GillmoreLeland E. HullJulie A. LynchJacob JosephSimina TicauAlexander O. Flynn-CarrollAimee M. DeatonLucas D. WardThemistocles L. AssimesPhilip S. TsaoKyong-Mi ChangDaniel J. RaderKevin FitzgeraldAkshay K. VaishnawGregory HinklePaul NioiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021) |
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Medicine R Science Q Margaret M. Parker Scott M. Damrauer Catherine Tcheandjieu David Erbe Emre Aldinc Philip N. Hawkins Julian D. Gillmore Leland E. Hull Julie A. Lynch Jacob Joseph Simina Ticau Alexander O. Flynn-Carroll Aimee M. Deaton Lucas D. Ward Themistocles L. Assimes Philip S. Tsao Kyong-Mi Chang Daniel J. Rader Kevin Fitzgerald Akshay K. Vaishnaw Gregory Hinkle Paul Nioi Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry |
| description |
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. |
| format |
article |
| author |
Margaret M. Parker Scott M. Damrauer Catherine Tcheandjieu David Erbe Emre Aldinc Philip N. Hawkins Julian D. Gillmore Leland E. Hull Julie A. Lynch Jacob Joseph Simina Ticau Alexander O. Flynn-Carroll Aimee M. Deaton Lucas D. Ward Themistocles L. Assimes Philip S. Tsao Kyong-Mi Chang Daniel J. Rader Kevin Fitzgerald Akshay K. Vaishnaw Gregory Hinkle Paul Nioi |
| author_facet |
Margaret M. Parker Scott M. Damrauer Catherine Tcheandjieu David Erbe Emre Aldinc Philip N. Hawkins Julian D. Gillmore Leland E. Hull Julie A. Lynch Jacob Joseph Simina Ticau Alexander O. Flynn-Carroll Aimee M. Deaton Lucas D. Ward Themistocles L. Assimes Philip S. Tsao Kyong-Mi Chang Daniel J. Rader Kevin Fitzgerald Akshay K. Vaishnaw Gregory Hinkle Paul Nioi |
| author_sort |
Margaret M. Parker |
| title |
Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry |
| title_short |
Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry |
| title_full |
Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry |
| title_fullStr |
Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry |
| title_full_unstemmed |
Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry |
| title_sort |
association of the transthyretin variant v122i with polyneuropathy among individuals of african ancestry |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/5c5a6c2a17f74f718458b7ee194eb2f4 |
| work_keys_str_mv |
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