<i>In silico</i>analysis of<i>TTR</i>gene (coding and non-coding regions, and interactive network) and its implications in transthyretin-related amyloidosis

Polimanti, Renato; Girolamo, Marco Di; Manfellotto, Dario; Fuciarelli, Maria

doi:10.3109/13506129.2014.900487

Cited by 18 publications

(15 citation statements)

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“…Although these ancestry differences are likely biased by the rare disease prevalence and the variability of the clinical practice guidelines across different countries, the inter-population diversity of the molecular mechanisms involved in the genotype-phenotype correlation surely plays an important role in the clinical presentation observed in patients with different ancestry backgrounds. Our previous investigations indicated that TTR non-coding regions are affected by human population diversity with potential consequences on gene regulation [12, 14, 15]. Our hypothesis is in agreement with many studies about the regulatory role of non-coding variation on gene expression and other gene functions [24, 25].…”

Section: Discussionsupporting

confidence: 92%

“…We observed an enrichment for non-coding regulatory variants located in heart-related transcription-factor binding sites in African populations, suggesting a contribution to the cardiomyopathy observed in patients of African ancestry [12]. We also investigated the haplotype structures of Val30Met and Val122Ile [rs76992529, c.424G > A, p.Val142Ile] mutations, observing in both cases independent haplotypes carrying the same disease-causing mutation [14, 15]. Non-coding variation regulates genome functions, especially through its key role in transcriptional mechanisms across human tissues [16].…”

Section: Introductionmentioning

confidence: 99%

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Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

et al. 2017

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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*10−6). 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*10−28; Left Ventricle p = 6.54*10−35).ConclusionsGenetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3646-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

et al. 2017

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“…4,25 The re-sequencing analysis of the TTR gene (coding and noncoding regions) in Italian patients allowed us to deepen our previous finding on the role of non-coding TTR variations in the disease genotype-phenotype correlation. [15][16][17] Investigating the TTR haplotypic structure, we observed that the correlation between the Val30Met mutation and the ocular manifestation can be attributed to a specific Val30Met haplotype, which includes two regulatory non-coding variants. As also reported in genetic studies of different phenotypic traits, 38,39 the ocular manifestation in TTR amylodosis in our sample is due to a combination of the effects of a coding amylodogenic mutation and SNPs located in non-coding elements.…”

Section: Discussionmentioning

confidence: 99%

“…15 Then, we analyzed the haplotypes associated with the Val122Ile (rs76992529, c.424G4A, p.(Val142Ile)) and Val30Met mutations, and identified independent haplotypes for the same mutation, suggesting multiple mutational events and different origins for these disease-causing mutations. 16,17 As non-coding variants located in regulatory elements can affect gene expression, 18 we hypothesize that these variations influence the distribution and accumulation of TTR-derived fibrils across different tissues and organs, modulating consequently the disease phenotype.…”

Section: Introductionmentioning

confidence: 99%

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

et al. 2017

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Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.

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“…Others have hypothesized that variation at transcription factor binding sites within populations resulting in different transcription levels presumably increased, resulting in increased serum TTR concentrations, could also be responsible for different degrees of clinical penetrance (Polimanti et al. ). While there are no available data regarding hepatic TTR transcription in different carriers of the same amyloidogenic allele, we think this unlikely since serum TTR concentrations tend to be lower rather than higher in carrier subjects even before there is detectable tissue deposition.…”

Section: Discussionmentioning

confidence: 99%

The prevalence and distribution of the amyloidogenic transthyretin ( TTR ) V122I allele in Africa

Jacobson

Alexander

Tagoe

et al. 2016

Mol Genet Genomic Med

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BackgroundTransthyretin (TTR) pV142I (rs76992529‐A) is one of the 113 variants in the human TTR gene associated with systemic amyloidosis. It results from a G to A transition at a CG dinucleotide in the codon for amino acid 122 of the mature protein (TTR V122I). The allele frequency is 0.0173 in African Americans.Methods PCR‐based assays to genotype 2767 DNA samples obtained from participants in genetic studies from various African populations supplemented with sequencing data from 529 samples within the 1000 Genomes Project.ResultsThe rs76992529‐A variant allele was most prevalent (allele frequency 0.0253) in the contiguous West African countries of Sierra Leone, Guinea, Ivory Coast, Burkina Faso, Ghana, and Nigeria. In other African countries, the mean allele frequency was 0.011.ConclusionsOur data are consistent with a small number of founder carriers of the amyloidogenic TTR V122I (p.Val142Ile) allele in southern West Africa, with no apparent advantage or disadvantage of an allele carrying newborn reaching adulthood. In U.S. African Americans, the allele represents a significant risk for congestive heart failure late in life. If clinical penetrance is similar in African countries with high allele frequencies, then cardiac amyloidosis could also represent a significant cause of heart disease in the elderly in those populations.

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In silicoanalysis ofTTRgene (coding and non-coding regions, and interactive network) and its implications in transthyretin-related amyloidosis

Abstract: Our data provided new insights into the pathogenesis of TTR-related amyloidosis that, if they were to be confirmed through experimental investigations, could significantly improve our understanding of the disease.

Cited by 18 publications

References 55 publications

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

The prevalence and distribution of the amyloidogenic transthyretin ( TTR ) V122I allele in Africa

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