rs76992529 — TTR Val142Ile (V142I)

The African American Heart Variant — TTR Val142Ile and Late-Onset Cardiac Amyloidosis

Transthyretin (TTR) is a liver-produced protein that transports thyroid hormone and retinol-binding protein through the bloodstream as a stable four-unit complex (tetramer). The Val142Ile variant — a single-letter change replacing valine with isoleucine at position 142 of the precursor protein (position 122 in the older mature protein nomenclature) — destabilizes the tetramer enough to trigger progressive misfolding and amyloid fibril deposition in the heart. The result is hereditary transthyretin cardiac amyloidosis¹¹ hereditary transthyretin cardiac amyloidosis
hATTR-CM: an inherited heart disease where insoluble protein fibrils stiffen the heart muscle over decades, ultimately causing restrictive cardiomyopathy and heart failure (hATTR-CM), a progressive and historically under-diagnosed cause of heart failure in older adults of African ancestry.

Unlike the Val30Met mutation (rs28933979), which is endemic in Portugal, Sweden, and Japan and primarily causes polyneuropathy, Val142Ile (also written V122I) is overwhelmingly a cardiac disease and is concentrated in populations with West African ancestry. Approximately 3–4% of African Americans are heterozygous carriers²² Approximately 3–4% of African Americans are heterozygous carriers
Jacobson et al., NEJM 1997: carrier frequency 3.9% in a community cohort of Black Americans without known amyloidosis; in West Africa, prevalence may exceed 5% in some regions, making this one of the most clinically significant genetic variants in cardiology — affecting roughly 1.3–1.5 million African Americans. Most carriers do not develop symptoms until after age 60, but the disease, once symptomatic, progresses to heart failure with a median survival historically measured in months to a few years from diagnosis. Today, tafamidis changes that trajectory.

The Mechanism

The c.424G>A nucleotide change in TTR (NM_000371.4) substitutes isoleucine for valine at codon 142 of the precursor polypeptide (142 in precursor / 122 in mature protein). Valine's compact side chain is replaced by isoleucine's slightly larger, branched side chain, altering the hydrophobic packing of the TTR monomer³³ hydrophobic packing of the TTR monomer
Each TTR monomer must fold precisely; substitutions in the hydrophobic core reduce thermodynamic stability of the tetramer, promoting dissociation into monomers that misfold into amyloid fibrils. The resulting fibrils are insoluble, resist normal clearance, and accumulate preferentially in the ventricular myocardium — progressively stiffening the heart wall, impairing diastolic relaxation, causing arrhythmias, and ultimately producing a restrictive cardiomyopathy that does not respond to standard heart failure therapies. Carpal tunnel syndrome — often bilateral — is the most common extracardiac manifestation and typically precedes cardiac symptoms by years.

TTR is produced almost entirely by the liver, making its production (and by extension, mutant fibril generation) accessible to hepatically-targeted gene-silencing strategies. Modern therapeutics either stabilize the tetramer to prevent dissociation (tafamidis, acoramidis) or suppress TTR production in the liver (patisiran, inotersen, vutrisiran, eplontersen).

The Evidence

The foundational epidemiological work came from Jacobson et al. (NEJM 1997, N=32 Black patients and 228 controls)⁴⁴ Jacobson et al. (NEJM 1997, N=32 Black patients and 228 controls)
N Engl J Med 336:466–473, 1997, which established that 3.9% of Black Americans carry the Ile122 variant and that all carriers in the case cohort had ventricular amyloid. Critically, the study found that isolated cardiac amyloidosis is four times more common among Blacks than Whites over age 60, a disparity now understood to be largely attributable to Val142Ile.

The therapeutic landmark is the ATTR-ACT trial (Maurer et al., NEJM 2018, N=441 patients with transthyretin cardiomyopathy)⁵⁵ ATTR-ACT trial (Maurer et al., NEJM 2018, N=441 patients with transthyretin cardiomyopathy)
N Engl J Med 379:1007–1016, 2018, which demonstrated that tafamidis reduced all-cause mortality by 30% (hazard ratio 0.70, 95% CI 0.51–0.96) and cardiovascular hospitalization rates by 32% (relative risk 0.68) vs placebo over 30 months. The trial enrolled patients with both Val30Met and non-Val30Met variants, including Val142Ile, confirming the treatment benefit extends across genotypes.

The DISCOVERY study (Akinboboye et al., Amyloid 2020, N=1,001 genotyped patients suspected of cardiac amyloidosis)⁶⁶ DISCOVERY study (Akinboboye et al., Amyloid 2020, N=1,001 genotyped patients suspected of cardiac amyloidosis)
Amyloid 27:200–208, 2020 confirmed that Val122Ile is the most prevalent pathogenic TTR mutation in clinical practice, found in 11% of Black/African American patients undergoing amyloidosis workup. Black ethnicity was the strongest independent predictor of pathogenic TTR mutation status, underscoring the need for targeted screening in this population.

Epigenomic profiling of African American Val122Ile carriers⁷⁷ Epigenomic profiling of African American Val122Ile carriers
Pathak et al., Circ Genomic Precis Med 2021 identified five differentially methylated sites in genes regulating amyloid clearance (ABCA1 pathway) and cardiac fibrosis, providing mechanistic insight into why the same variant produces variable penetrance across carriers.

Practical Actions

Val142Ile is a clinically actionable variant: the disease has a long pre-symptomatic window, early warning signs are identifiable, and FDA-approved treatment now exists. Late diagnosis — which has historically been the rule — means treatment begins after substantial cardiac remodeling has already occurred. Genetic identification creates the opportunity to act earlier.

Carriers who are still asymptomatic should establish care with a cardiologist experienced in amyloidosis for baseline echocardiography, cardiac biomarkers (troponin, BNP/NT-proBNP), and ECG. Bilateral carpal tunnel syndrome in an African American over age 50 — especially without a clear traumatic or occupational cause — is a red-flag symptom warranting TTR amyloidosis evaluation. Unexplained atrial fibrillation, low ECG voltage, or heart failure that does not respond to conventional therapy in an older person of African descent are further indications for workup.

Once hATTR-CM is confirmed, tafamidis (Vyndaqel/Vyndamax) 61 mg daily is the standard of care, supported by the ATTR-ACT trial mortality benefit. Newer agents (acoramidis, gene silencers) are under active study in this population.

Interactions

Val142Ile is a distinct variant from Val30Met (rs28933979), the most common cause of hATTR globally. No documented compound heterozygous case series exists for the combination of both pathogenic TTR variants in one individual. Since both destabilize the TTR tetramer through different structural perturbations, a compound heterozygote would theoretically produce mutant protein from both alleles — but the treatment response would be the same (tetramer stabilizers work regardless of which variant is present).

Wild-type TTR amyloidosis (ATTRwt) — which affects elderly men of all ancestries with no causative mutation — co-exists as an epidemiologically distinct entity. In older African Americans presenting with cardiac amyloidosis, clinical distinction between ATTRwt and hATTR-CM due to Val142Ile requires genetic testing, since both share identical cardiac phenotypes and the same first-line treatment.

Family testing is essential: each child of a Val142Ile carrier has a 50% chance of inheriting the mutation. Testing of adult first-degree relatives (siblings, children ≥18) enables surveillance initiation before symptoms develop.