Functional variation of the transthyretin gene among human populations and its correlation with amyloidosis phenotypes

Heterogeneity in the genotype-phenotype correlation of transthyretin (TTR)-related amyloidosis has been reported, suggesting that other factors may interact with disease-causing mutations. Additional genetic variants in the TTR gene and its surrounding regions may influence disease phenotype. To explore this hypothesis, we analyzed the TTR variation among human populations to identify functional inter-ethnic differences that could influence the TTR-related amyloidosis.

Using the 1000 Genomes Project database, we analyzed a 20 kb region in 1092 apparently healthy individuals who belonged to 14 human populations. In silico analyses were performed to determine the functional impact of genetic variants.

These analyses showed that significant ethnic differences are present in the TTR gene, and some differences may affect TTR gene function. Specifically, the non-coding variants potentially associated with regulatory function showed a significant diversity between African and non-African individuals.

Our results highlighted that cis-regulatory variants may contribute to the cardiac TTR-related amyloidosis observed in patients carrier of Val122Ile mutation, the most common in population with African origin. Indeed, non-coding variants differentiated in Africans are, in some cases, located in binding sites of transcription factors involved in cardiac development and function (i.e. E2F3_2, REST, and TEAD).