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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 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.

SUBMITTER: Parker MM

PROVIDER: S-EPMC8172853 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Parker Margaret M MM Damrauer Scott M SM Tcheandjieu Catherine C Erbe David D Aldinc Emre E Hawkins Philip N PN Gillmore Julian D JD Hull Leland E LE Lynch Julie A JA Joseph Jacob J Ticau Simina S Flynn-Carroll Alexander O AO Deaton Aimee M AM Ward Lucas D LD Assimes Themistocles L TL Tsao Philip S PS Chang Kyong-Mi KM Rader Daniel J DJ Fitzgerald Kevin K Vaishnaw Akshay K AK Hinkle Gregory G Nioi Paul P

Scientific reports 20210602 1

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 Bioban ...[more]

PMID: 34079032

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Project description:ImportanceHereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown.ObjectiveTo assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure.Design, setting, and participantsCross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018.ExposuresTTR V122I carrier status.Main outcomes and measuresThe primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured.ResultsThe cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years.Conclusions and relevanceAmong individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.

Project description:BackgroundLong-term data on cardiovascular disease (CVD) and mortality in female carriers of the transthyretin (TTR) V122I (pV142I) variant, one of the most common variants of hereditary transthyretin cardiac amyloidosis, are sparse and the effects of blood pressure, heart rate, body mass index, and physical activity on CVD outcomes remain largely unknown.ObjectivesThe aim was to first examine the relationship of TTR V122I (pV142I) carrier status with CVD and mortality and second to investigate the effects of blood pressure, heart rate, body mass index, and physical activity in a large cohort of postmenopausal women.MethodsThe study population consisted of 9,862 non-Hispanic Black/African American women, 9,529 noncarriers and 333 TTR V122I carriers, enrolled in the Women's Health Initiative at 40 centers in the United States. Women were generally healthy and postmenopausal at the time of enrollment (1993-1998). CVD was defined as a composite endpoint consisting of coronary heart disease, stroke, acute heart failure or CVD death, and all-cause mortality. CVD cases were based on self-reported annual mailed health updates. All information was centrally adjudicated by trained physicians. HRs and 95% CIs were obtained from adjusted Cox proportional hazards models.ResultsAmong 9,862 Black female participants (mean age: 62 years [IQR: 56-67 years]), the population frequency of the TTR V122I variant was 3.4% (333 variant carriers and 9,529 noncarriers). During a mean follow-up of 16.1 years (IQR: 9.7-22.2 years), incident CVD occurred in 2,229 noncarriers and 96 carriers, whereas 2,689 noncarriers and 108 carriers died. In adjusted models including demographic, lifestyle, and medical history covariates, TTR V122I carriers were at higher risk of the composite endpoint CVD (HR: 1.52; 95% CI: 1.22-1.88), acute heart failure (HR: 2.21; 95% CI: 1.53-3.18), coronary heart disease (HR: 1.80; 95% CI: 1.30-2.47), CVD death (HR: 1.70; 95% CI: 1.26-2.30), and all-cause mortality (HR: 1.28; 95% CI: 1.04-1.56). The authors found a significant interaction by age but not by blood pressure, heart rate, body mass index, or physical activity.ConclusionsBlack female TTR V122I (pV142I) carriers have a higher CVD and all-cause mortality risk compared to noncarriers. In case of clinical suspicion of amyloidosis, they should be screened for TTR V122I (pV142I) carrier status to ensure early treatment onset.

Project description:ImportanceA genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis.ObjectiveTo estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals.Design, setting, and participantsRetrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020.ExposuresTTR Val122Ile (rs76992529) genotype.Main outcome and measuresThe primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors.ResultsAmong 7514 Black participants (median age, 64 years [IQR, 57-70 years]; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio [HR], 2.43 [95% CI, 1.71-3.46]; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 [95% CI, 2.33-7.54]; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 [95% CI, 1.19-2.39]; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 [95% CI, 1.19-1.78]; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes.Conclusions and relevanceAmong a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.

Dataset Information

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

Publications

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

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