Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry.

Autor: Parker MM; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Damrauer SM; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, USA., Tcheandjieu C; 12 VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94304, USA., Erbe D; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Aldinc E; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Hawkins PN; Centre for Amyloidosis & Acute Phase Proteins, Division of Medicine UCL (Royal Free Campus), London, NW3 2PF, UK., Gillmore JD; Centre for Amyloidosis & Acute Phase Proteins, Division of Medicine UCL (Royal Free Campus), London, NW3 2PF, UK., Hull LE; Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.; Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, 01730, USA., Lynch JA; School of Nursing & Health Sciences, University of Massachusetts, Boston, MA, 02125, USA.; VA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, 84148, USA., Joseph J; Department of Medicine, Veterans Affairs Boston Healthcare System, Boston, MA, 02130, USA.; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Ticau S; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Flynn-Carroll AO; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Deaton AM; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Ward LD; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Assimes TL; 12 VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94304, USA., Tsao PS; 12 VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94304, USA., Chang KM; The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, USA.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Rader DJ; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Fitzgerald K; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Vaishnaw AK; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Hinkle G; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA., Nioi P; Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA. pnioi@alnylam.com.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Jun 02; Vol. 11 (1), pp. 11645. Date of Electronic Publication: 2021 Jun 02.
DOI: 10.1038/s41598-021-91113-6
Abstrakt: 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.
Databáze: MEDLINE