Should We Systematically Screen for the Amyloidogenic V142I Variant?

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Is it time to employ systematic genetic screening for V142I transthyretin cardiac amyloidosis? Strategic research programs are needed to fill evidence gaps before meaningful and equitable implementation can begin to reduce health disparities and improve morbidity and mortality.

Population-based genetic screening for monogenic diseases in asymptomatic individuals remains controversial. Among inherited cardiomyopathies, transthyretin cardiomyopathy (ATTR-CM) is a substantially underdiagnosed disease which, left untreated, carries high morbidity rates (including heart failure [HF], arrhythmias and stroke) and mortality.^1,2 In the United States, V142I (legacy nomenclature V122I) is the most common transthyretin genetic variant underlying ATTR-CM and is present in 3%–4% of self-identified Black individuals.³ Given the high morbidity and mortality rates of V142I-associated ATTR-CM, steep age-dependent penetrance and emergence of disease-modifying therapies, the question of whether we should employ more widespread screening for V142I is both timely and important.

ATTR-CM may be considered a test case for feasible population-based genetic screening, with the potential to reduce health disparities by bringing effective therapies to patients. However, key evidence gaps must first be addressed. More data are needed to define: (1) at-risk populations, (2) penetrance, (3) testing accessibility and result follow-through, (4) impact of early treatment, and (5) cost considerations. The long latency of V142I-associated ATTR-CM provides an opportunity to determine the utility of pre-diagnostic screening for improving patient-related and health outcomes in a cost-effective manner. This call-to-action reviews the evidence gaps for V142I screening in at-risk populations.

Population Considerations

The V142I variant has West African ancestral origin, although most studies have investigated prevalence in cohorts of people of self-reported Black race.^1–3 Recognizing that race is a sociopolitical construct that should not be conflated with ancestry, race may be the more accessible identifier until the availability of genetic ancestry is more ubiquitous.⁴ More than 47 million Americans self-identify their race as Black; a V142I carrier prevalence of 3%–4%, thus, equates to approximately 1.5 million carriers.³ Among self-identified Black individuals, the available evidence suggests that V142I accounts for 50%–80% of ATTR-CM at amyloid referral centers.³ Carrier prevalence among individuals of self-reported Hispanic/Latino ethnicity is 1.3% in the United States, with estimates greater than 7% from Caribbean and Central American countries, resulting from genetic admixture.¹ Therefore, further understanding allele frequencies in populations across diverse ancestral backgrounds will be important to determine appropriate populations for screening and to consider pan-ethnic screening approaches.

The natural history of ATTR amyloidosis, including fully defined genotype-phenotype associations, is unknown. As such, the ideal population for screening is currently elusive. Genetic testing for V142I-associated ATTR-CM in self-reported Black individuals once a cardiac phenotype is already manifest (eg, HF or left ventricular hypertrophy) misses an opportunity for identification of at-risk individuals.⁵ In a related matter, 5% of patients with carpal tunnel syndrome will develop ATTR-CM, representing another risk enhancer for screening.⁶ In V142I ATTR-CM, the 10-year risk for HF hospitalization increases near age 63, while all-cause mortality increases at age 72.² Therefore, incorporating genetic testing for self-reported Black individuals or those with known West African ancestry at age 50 may be rational, because manifest disease is uncommon at earlier ages. Population-specific screening for genetic disorders is not a novel concept, as individuals with Ashkenazi Jewish ancestry have historically been offered testing, included as part of preconception counseling, for diseases with high carrier rates in this population. Alternatively, pan-ethnic screening may limit the risk of omitting potential carriers not captured by crude identification of race- or ancestry-specific assumptions, at the expense of diagnostic and cost efficiency.

Penetrance

All V142I carriers over age 65 exhibit some degree of cardiac amyloid deposition on autopsy, but most carriers do not experience HF events.⁷ In self-identified Black and Hispanic carriers with HF, the use of advanced imaging (technetium pyrophosphate scanning) identified that 39% of V142I carriers had evidence of transthyretin amyloid deposition.⁵ Critically, disease penetrance among unselected carriers remains unknown; incomplete penetrance might cause unnecessary anxiety in carriers who may never develop ATTR-CM. Of note, the American College of Medical Genetics has recently incorporated transthyretin variants into recommendations for reporting of secondary findings because of their clinical relevance and actionability.

Testing Considerations

Advances in genetic-testing technologies, including decreasing costs and ease-of-use of saliva kits, make scalability for screening theoretically feasible. To contextualize V142I screening, among other variants, population-based screening for Centers for Disease Control and Prevention Tier 1 genes has been shown to be cost-effective but has not been broadly implemented.⁸ Reasons for this likely center around ownership of cost from insurers, governmental agencies and health systems and the need for policies to support implementation. The Women Informed to Screen Depending on Measures of Risk (WISDOM) is currently testing precision medicine approaches to breast-cancer screening, incorporating genetic testing. BRCA1/BRCA2 prevalence is estimated at 0.2%–0.3%, in contrast to the 3%–4% V142I prevalence in self-reported Black individuals. However, screening considerations specific to V142I must be addressed before implementation. Health care systems would need to assemble multidisciplinary teams of experts in genetics, epidemiology, community engagement, HF, and amyloid care. Existing workforce shortages of genetic counselors may impact timeliness for both pre- and post-testing counseling. Further, carriers would have to be seen regularly by an experienced care team, given age-dependent penetrance. The type and frequency of surveillance methods is a major unknown requiring additional research.

Understandably, Black individuals may have concerns about this approach, considering the historical misuse of genetic information and research data, which limits trust in clinical care. Additionally, Black individuals are under-represented in genetic research studies, which, at least impart, reflects socioeconomic disparities that heighten barriers to equitable care. Community engagement, including disease education and implications of testing on insurability, will be essential to secure public trust by populations where social determinants of health contribute to disparate health outcomes.

Finally, screening for TTR variants could be integrated into a panel-based approach rather than a singular screening for variants in 1 gene only. Although it increases complexity, this approach may improve cost-effectiveness and broaden applicability at the population level.

Early Detection and Treatment

Despite increasing awareness and the availability of non-invasive phenotyping modalities, the diagnosis of ATTR-CA is frequently missed or delayed, and V142I carriers face higher hospitalization burdens and poorer survival rates.² Specifically, V142I carriers live, on average, 2–2.5 fewer years than noncarriers, and Black American carriers over age 50 will cumulatively lose ~1 million years of life due to the variant.² Emphasizing the importance of early detection, the efficacy of available targeted TTR therapy is inversely related to ATTR-CM disease severity at diagnosis.⁶ These data, in a historically marginalized population, underscore the critical need to intervene. Finally, whether prophylactic use of targeted TTR therapies can prevent the devastating complications of ATTR-CM manifest disease will need to be addressed.

Cost Considerations

Targeted therapies with disease-modifying capacity have created a paradigm shift for ATTR-CM. Tafamidis, a transthyretin protein stabilizer approved in 2019, slows progression of ATTR-CM and, most meaningfully, benefits patients with HF and lower symptom burdens (ie, New York Heart Association functional class I or II). Current costs for tafamidis are $225,000/year, although the cost-effective threshold has been estimated as $16,000/year.⁹ Emerging targeted therapies for ATTR-CM, including novel transthyretin stabilizers, silencers or gene-editing techniques, may be rational early in the disease process. However, these options are also anticipated to come with a high cost burden, unless the pricing structure is appropriately considered within a value framework.

The cost impact to patients, health systems and payers must be weighed, especially when patients identified early will require longer durations of therapy. In this context, diflunisal, a nonsteroidal anti-inflammatory with nonselective transthyretin-stabilization properties repurposed for off-label use in ATTR-CM, was largely replaced as treatment in manifest ATTR-CM after tafamidis approval, but it may merit consideration for broader use in early disease, at an estimated cost of $1000/year.⁶ Further, asymptomatic carriers might face higher costs or denial of disability, life and long-term care insurance (not covered by the Genetic Information Nondiscrimination Act), highlighting the importance of counseling and building trust. The integrated care necessary, including genetic counseling, clinical testing (ie, advanced imaging, biopsies), and health care teams equipped to handle complex hurdles in prescribing therapies, is not widely available, limiting access to care and potentially widening disparities.

In conclusion, growing evidence supports broader genetic screening efforts for V142I; a focus on targeted screening among self-reported Black individuals and people of West African ancestry over age 50 may allow for more efficient and earlier identification. However, more research is needed to address the aforementioned evidence gaps, while the willingness of health systems, payers and government agencies to implement these strategies needs to be determined.¹⁰ Optimal implementation requires multidisciplinary leadership to support the robust clinical infrastructure needed to care optimally for the estimated 435,000 Black Americans over age 50 carrying V142I.² Stated another way, minimizing both sins of omission (missed opportunities to identify individuals at-risk for a lethal and treatable disease) and sins of commission (inabilities of systems to follow-through equitably with clinical care) will be needed. Although the challenges are significant, they should not deter implementation efforts but, rather, inspire the pursuit of novel and equitable solutions (Central Illustration).

Central Illustration.

Knowledge gaps, Research strategies and implementation for V142I ATTR-CM. Prior to initiating systematic screening for the amyloidogenic V142I transthyretin variant, efforts are needed to address key knowledge gaps regarding (1) at-risk populations, (2) penetrance, (3) testing accessibility, (4) impact of early treatment, and (5) cost considerations. To narrow these gaps, research in large prospective cohorts of diverse individuals with detailed phenotyping paired with community-engagement efforts to garner public trust will be critical. Clinical implementation will require multidisciplinary teams to build infrastructure for follow-through of test results and commitment by stakeholders to ensure pharmacoequity. ATTR-CM, ransthyretin cardiomyopathy. Created with Biorender.com

Supplementary Material

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.cardfail.2024.08.055.

Biography

Jessica Regan