Abstract
BackgroundTransthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. We conducted a literature survey to define the clinical landscape of TTR amyloidosis across populations worldwide. Then, we investigated whether the genetically determined TTR expression differs among human populations, contributing to the differences observed in patients. Polygenic scores for genetically determined TTR expression in 14 clinically relevant tissues were constructed using data from the GTEx (Genotype-Tissue Expression) project and tested in the samples from the 1,000 Genomes Project.ResultsWe observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. Scandinavian populations differed in their genetically determined TTR expression of skeletal muscle tissue with respect to Southern Europeans (p = 6.79*10â6). This is in line with epidemiological data related to Swedish and Portuguese TTR Val30Met endemic areas. Familial amyloidotic cardiomyopathy (TTR deposits occur primarily in heart tissues) presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined TTR expression in heart tissues (i.e., Atrial Appendage p = 4.55*10â28; Left Ventricle p = 6.54*10â35).ConclusionsGenetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis.
Highlights
Transthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation
In conclusion, the current study advances the knowledge of TTR amyloidosis in terms of both data regarding the inter-population variability of the disease and methodology that can be applied
The Genotype-Tissue Expression (GTEx) Project investigated a multi-ethnic cohort with limited sample size that cannot completely detect the effects of genetic variability on gene expression across human populations
Summary
Transthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. In Val30Met Portuguese families, the disease shows early-onset, strong severity, and high penetrance [8, 9], whereas Val30Met Swedish patients have late-onset, intermediate severity, and low penetrance [10] This complex genotype-phenotype correlation indicates that the clinical presentation is regulated by the disease-causing mutation. Non-coding variation regulates genome functions, especially through its key role in transcriptional mechanisms across human tissues [16] On this basis, we hypothesized that, in presence of an amyloidogenic mutation, the non-coding regulation of TTR gene expression across tissues contributes the distribution of TTR-derived amyloid fibrils and, the disease presentation. In accordance with this hypothesis, a recent study demonstrated that, the liver is the main TTR organ source, TTR gene expression in other tissues can be involved in the processes related to the disease phenotype [17]
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