TTR rs72555369: What Your Genotype Means

What each genotype means

Variant Details and Genomic Location

The single nucleotide polymorphism rs72555369 is located within the transthyretin (TTR) gene on human chromosome 18. At the molecular level, this variation represents a single-base substitution that alters the coding sequence of the transthyretin protein. In legacy clinical literature, it is widely designated as V122I because earlier numbering omitted the 20-amino-acid signal peptide; modern standardized nomenclature labels it p.Val142Ile (or V142I). This change substitutes the branched-chain amino acid valine with isoleucine. Although seemingly subtle, this single amino acid change occurs in a region critical to the stability of the quaternary structure of the circulating protein. Under physiological conditions, normal transthyretin operates as a stable four-subunit complex (tetramer). The presence of the isoleucine replacement facilitates the progressive dissociation of the tetramer into individual monomeric units, which are prone to unfolding, self-assembling into protofibrils, and accumulating as insoluble amyloid fibrils in extracellular spaces.

Normal Function of the TTR Gene

The TTR gene provides the molecular instructions for synthesizing transthyretin, a carrier protein produced primarily in the liver and to a lesser extent in the choroid plexus of the brain and the retinal pigment epithelium. Transthyretin circulates in the bloodstream and cerebrospinal fluid, where its primary physiological role is the transportation of two essential molecules: the thyroid hormone thyroxine (T4) and retinol (vitamin A). To bind and deliver thyroxine efficiently, four identical transthyretin monomers assemble into a stable homotetramer. For vitamin A transport, this tetrameric structure forms a secondary complex with retinol-binding protein. In healthy individuals, the native tetrameric conformation is highly resilient, resisting premature degradation. However, mutations that compromise the physical bonds holding the four units together promote structural dissociation. When these subunits detach, they misfold, initiating the cascade of pathological fibril formation that characterizes systemic and organ-specific forms of transthyretin amyloidosis.

Health Associations and Evidence Strength

The rs72555369 variant is classified in medical databases such as ClinVar as a pathogenic factor for hereditary transthyretin-mediated (ATTRv) amyloidosis, specifically amyloid cardiomyopathy. Evidence shows that carriers have a substantially elevated risk of late-onset infiltrative heart disease, typically emerging in the seventh or eighth decade of life. Amyloid fibrils gradually accumulate in the myocardial wall, resulting in progressive wall thickening, restrictive cardiomyopathy, arrhythmias, and congestive heart failure. Clinical cohort studies, including the Dallas Heart Study and the Atherosclerosis Risk in Communities (ARIC) study, confirm that carriers display higher left ventricular wall thickness and increased rates of heart failure admissions after age 70. Penetrance is incomplete, meaning not all carriers develop symptomatic disease during their lifetime. While cataloged under limited or variable penetrance due to many individuals remaining asymptomatic well into older age, the causal biological link between the variant and cardiac amyloid fibril deposition is well validated.

Population Distribution and Ancestry Patterns

The distribution of rs72555369 is strikingly ancestry-specific. Large-scale population genetic surveys demonstrate that the variant is found almost exclusively in individuals of African descent, with carrier rates estimated between 3% and 4% among African Americans and up to 5% in certain West African populations. In contrast, the allele is exceptionally rare or entirely absent in cohorts of European, East Asian, and Indigenous American ancestries. Historical and population data indicate that the variant likely arose in West Africa and persisted across generations without altering childhood survival or reproductive fitness, as the associated clinical phenotype rarely presents before age 60. Because of its prevalence in specific demographic groups, it is recognized as a major underdiagnosed contributor to heart failure and restrictive cardiomyopathy among older adults of African ancestry, underscoring the importance of ancestral context when interpreting personal genomic findings.

What You Can and Cannot Do With This Information

Discovering an rs72555369 risk allele on a personal genomic report does not constitute a clinical diagnosis of cardiac amyloidosis. Because the variant exhibits age-dependent, incomplete penetrance, many individuals carrying one copy live normal lifespans without developing cardiac dysfunction. Commercial consumer tests cannot replace clinical diagnostic evaluations, which require specialized cardiology assessments such as echocardiography, cardiac magnetic resonance imaging, or technetium-labeled bone scintigraphy. You should never alter prescription medications, change dosages, or start new supplements based on direct-to-consumer genetic data alone. Instead, individuals carrying this variant can share their results with a qualified healthcare provider or genetic counselor, particularly if there is a personal or family history of unexplained heart failure, heart rhythm disturbances, or bilateral carpal tunnel syndrome, which often precedes cardiac symptoms by several years.

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Sources & further reading

Related variants in TTR