المؤلفون: Parker, Margaret M., Damrauer, Scott M., Tcheandjieu, Catherine, Erbe, David, Aldinc, Emre, Hawkins, Philip N., Gillmore, Julian, Hull, Leland E., Lynch, Julie A., Joseph, Jacob, Ticau, Simina, Flynn-Carroll, Alexander O., Deaton, Aimee M., Ward, Lucas D., Assimes, Themistocles L., Tsao, Philip S., Chang, Kyong-Mi, Rader, Daniel J., Fitzgerald, Kevin, Vaishnaw, Akshay K.

المصدر: Journal of Cardiac Failure; 2020 Supplement, Vol. 26 Issue 10, pS96-S96, 1p

مستخلص: Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. The V122I variant, a common pathogenic TTR mutation found primarily in individuals of West African descent, is frequently associated with cardiomyopathy. Other hATTR amyloidosis manifestations have been reported in some carriers of the V122I variant, yet the association remains unclear. The V122I variant may be associated with common hATTR amyloidosis manifestations beyond cardiomyopathy. The association between the V122I variant and ICD10 diagnosis codes was assessed in the UK Biobank (UKBB) black subpopulation (n = 6,062) with replication of significant associations in the Penn Medicine Biobank (PMBB) (n = 5,737) and the VA Million Veteran Program (MVP) (n = 82,382). The cumulative incidence of common hATTR amyloidosis manifestations (polyneuropathy, carpal tunnel syndrome, cardiomyopathy, and heart failure) was estimated by V122I genotype in the UKBB using Cox regression controlling for age, sex and genetic ancestry. Of the 6,062 participants in the UKBB, 243 were V122I carriers. Common hATTR amyloidosis manifestations in the UKBB were significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, P = 2.6 × 10⁻⁵). Phenome-wide analysis identified a significant association between the V122I genotype and polyneuropathy diagnosis (OR = 6.4, P = 4.24 × 10⁻⁵) in the UKBB, which was replicated in both the PMBB (OR = 1.6, P = 6.0 × 10⁻³) and the MVP (OR = 1.48, P = 1.8 × 10⁻⁴). Prevalence of a polyneuropathy diagnosis among V122I carriers was 2.1%, 9.0%, and 4.8% in the UKBB, PMBB, and MVP, respectively. By age 75, 37.4% of V122I carriers in the UKBB had a diagnosis of at least one of the common manifestations, including 7.9% with polyneuropathy. Yet, only 0.8% of carriers had a formal diagnosis of hATTR amyloidosis. The V122I variant, historically associated with cardiomyopathy, is also significantly associated with an increased risk of polyneuropathy. [ABSTRACT FROM AUTHOR]

: Copyright of Journal of Cardiac Failure is the property of W B Saunders and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Parker, Margaret M., Damrauer, Scott M., Rader, Daniel J., Ticau, Simina, Erbe, David, Hinkle, Gregory, Nioi, Paul

المصدر: Journal of Cardiac Failure; 2019 Supplement, Vol. 25 Issue 8, pS110-S110, 1p

مستخلص: Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating, fatal disease caused by mutations in the transthyretin (TTR) gene that lead to amyloid deposition in multiple tissues, including peripheral nerves and heart. Historically, patients were identified by their predominant phenotype (polyneuropathy or cardiomyopathy), however, evidence now suggests that a majority develop a mixed phenotype with both polyneuropathy and cardiomyopathy. The V122I (Val122Ile; p.V142I) variant is the most common pathogenic TTR mutation in the US, primarily found in individuals of West African descent, and is thought to be predominantly associated with cardiomyopathy. This analysis characterizes the association between V122I genotype and ICD10 diagnosis codes in the black subpopulation of UK Biobank (UKBB) with replication in the Penn Medicine Biobank (PMBB). The UKBB is a prospective cohort study with genetic, physical and health data on ∼500,000 individuals across the United Kingdom. A phenome wide association study was performed to test for association between the V122I genotype and 1,229 clinical diagnoses in the black subpopulation of UKBB (n=6,063). Individuals heterozygous or homozygous for V122I (n=387) were identified and were primarily of African or Caribbean descent (minor allele frequency in black subpopulation = 2%; baseline age: 40-70 years). This analysis revealed a significant association between the V122I genotype and a clinical diagnosis of polyneuropathy (OR = 11.2; 95% CI: 3.7-26.6; p=1.1 × 10-6). Of note, these V122I carriers were not diagnosed with diabetic neuropathy. Replication analysis was performed in 5,737 black participants of the PMBB, of whom 190 individuals carried the V122I variant. The association of V122I with polyneuropathy was replicated (OR = 1.6; 95% CI: 1.2-2.4; p=0.006). In addition, there was nominally significant evidence that V122I carriers are at increased risk of other symptoms of hATTR amyloidosis, including carpal tunnel syndrome (OR = 2.0; p=0.02) and urinary retention (OR = 2.1; p=0.05) within the UKBB. These data indicate that carriers of the V122I mutation, historically associated with a predominantly cardiac phenotype, have a significantly increased risk of a clinical diagnosis of polyneuropathy. Additional manifestations were identified, highlighting that V122I causes a mixed phenotype. It is crucial that physicians have a clinical suspicion for the multisystem manifestations of hATTR amyloidosis, which includes both cardiomyopathy and polyneuropathy. [ABSTRACT FROM AUTHOR]

: Copyright of Journal of Cardiac Failure is the property of W B Saunders and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Yun, Jeong H., Lamb, Andrew, Chase, Robert, Singh, Dave, Parker, Margaret M., Saferali, Aabida, Vestbo, Jørgen, Tal-Singer, Ruth, Castaldi, Peter J., Silverman, Edwin K., Hersh, Craig P.

المصدر: Journal of Allergy & Clinical Immunology; Jun2018, Vol. 141 Issue 6, p2037-2047.e10, 1p

مستخلص: Background Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. Objective We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. Methods Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n = 1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n = 1,895). A subset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. Results COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300 cells/μL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300 cells/μL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06-1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300 cells/μL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. Conclusions Patients with moderate-to-severe COPD and blood eosinophil counts of 300 cells/μL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study. [ABSTRACT FROM AUTHOR]

: Copyright of Journal of Allergy & Clinical Immunology is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)