BACKGROUND
transthyretin  amyloidosis  is a rare, life-threatening, progressively debilitating, autosomal dominant condition characterized by extracellular deposition of ttr-derived amyloid fibrils in peripheral and autonomic nervous system, heart, and other organs, leading to tissue damage and organ failure  <cit> .
the disorder is caused by point mutations in the ttr gene  located in chromosome region 18q <dig>   <cit> .
the disease presents multiple clinical signs, including peripheral neuropathy , autonomic neuropathy, gastrointestinal impairment, cardiomyopathy, nephropathy, and ocular deposition  <cit> .
while these symptoms may be present in patients with different ttr mutations, phenotypes are not always concordant and the same point mutation may be associated with different signs/symptoms  <cit> .
the clinical heterogeneity of the carriers of the ttr amyloidogenic mutations is particularly relevant from a population perspective.
the most striking example of this inter-population diversity is the val30met mutation , which is one of the leading causes of ttr amyloidosis  <cit> .
in the two european val30met endemic areas , val30met patients show two distinct phenotypic presentations.
in val30met portuguese families, the disease shows early-onset, strong severity, and high penetrance  <cit> , whereas val30met swedish patients have late-onset, intermediate severity, and low penetrance  <cit> .
this complex genotype-phenotype correlation indicates that the clinical presentation is not only regulated by the disease-causing mutation.
the amyloidogenic mutation is the cause of the disease, but other factors contribute to the modulation of the disease phenotype .
our previous investigations focused on the role of non-coding variation in the genotype-phenotype correlation of ttr amyloidosis.
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  <cit> .
we also investigated the haplotype structures of val30met and val122ile  mutations, observing in both cases independent haplotypes carrying the same disease-causing mutation  <cit> .
non-coding variation regulates genome functions, especially through its key role in transcriptional mechanisms across human tissues  <cit> .
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, consequently, the disease presentation.
in accordance with this hypothesis, a recent study demonstrated that, although the liver is the main ttr organ source, ttr gene expression in other tissues can also be involved in the processes related to the disease phenotype  <cit> .
recent studies have focused on how gene expression regulates relevant biological processes and how its alteration can lead to the onset of diseases  <cit> .
the genotype-tissue expression  project is investigating genetic variation in relation to gene expression in human tissues  <cit> .
gtex data  provide information about the relationship between genetic variations and gene expression in  <dig> different human tissues  <cit> .
the effects of genetic variants can be used to estimate the genetically determined gene expression to investigate the role of gene expression in multiple tissues with respect to disease pathogenesis  <cit> .
accordingly, the analysis of the genetically determined ttr expression can help to discern its involvement in human tissues with respect to the genotype-phenotype correlation of ttr amyloidosis.
RESULTS
results from literature review
we identified  <dig> worldwide disease-causing mutations with information regarding the ancestry .
our findings indicated that europeans have the highest number of ttr mutations , followed by east asians , americans , central-south asians  and africans .
the ancestry was not specified for the remaining amyloidogenic mutations.
few mutations are reported in multiple ancestry groups  and several symptoms are reported for patients with different ancestries and different mutations  .
however, clinical signs partially occur in an ancestry-specific manner with respect to the amyloidogenic mutation reported .
genetically-predicted ttr expression
as introduced above, we used the data from gtex project  <cit>  to build polygenic scores associated with ttr expression in  <dig> human tissues and tested them in the samples from the  <dig>  genomes project  <cit>  considering both among-ancestry and within-ancestry analyses.
a detailed description of procedures used is reported in the method section.
among-ancestry comparisons
the among-ancestry comparisons showed very significant differences  for genetically predicted ttr expression scores for all investigated tissue  with the exception of the esophagus – muscularis tissue .
post-hoc pairwise analysis of the among-ancestry comparisons indicated that these significant differences are generally present across multiple ancestries and are not due to the diversity of a single population .
the only exception to this general trend is the colon - transverse tissue where the significant result is exclusively driven by the difference between african and non-african populations .
within-ancestry comparisons
within-ancestry comparisons showed less tissue- and ancestry-specific differences than among-ancestry comparisons .
significant differences were observed within european ancestry , within eastern asian ancestry , and within american ancestry  .
the significant results of the post-doc pairwise analysis are reported in fig.
<dig>  in european populations, the diversity of ttr expression scores in the significant tissues is driven by north–south variability, with the most significant diversity between scandinavian populations  and the other european samples .
in eastern asian samples, the diversity for ttr expression scores in nerve - tibial tissue is driven by differences of vietnamese populations  with respect to japanese and chinese populations .
regarding the tissues identified in the american samples, the diversity of ttr expression scores is driven by differences between peruvian population  and other american populations .
permutation analysis confirmed that all within-ancestry observed differences significantly diverge from the null distribution of the permuted results .
the observed z-scores are located in extremely marginal positions with respect to the null distribution of the z-scores generated by the random permutations.fig.
<dig> heatmap of the kruscal-wallis results related to the within-ancestry comparisons.
the colors refer to different significance levels .
fig.
<dig> heatmap of the kruscal-wallis post-hoc analysis results of within-ancestry comparisons.
the colors refer to different significance levels .
information about population definitions are available at http://www.1000genomes.org/about
fig.
<dig> distribution of the z-scores generated from  <dig>  random permutations with respect to the z-scores observed in the kruscal-wallis post-hoc analysis of within-ancestry comparisons.
no significant differences were observed for african ancestry  and central-south asian ancestry  tissue; additional file 8).
discussion
our literature review indicated that few mutations were observed in multiple ancestral groups .
however, these are the mutations detected in most patients affected by ttr amyloidosis and the corresponding clinical signs mainly occur with ancestry-specific patterns.
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  <cit> .
our hypothesis is in agreement with many studies about the regulatory role of non-coding variation on gene expression and other gene functions  <cit> .
ttr gene expression showed a relevant inter-individual variability across human tissues , and the related tissue-specific regulatory mechanisms is likely to be one of the processes involved in the disease genotype-phenotype correlation.
our current findings based on a large multi-ethnic cohort  and gene expression information from multiple human tissues  provide novel insight regarding the regulatory mechanisms of ttr gene.
indeed, very few investigations explored mechanisms related to gene expression in ttr amyloidosis due to limited availability of tissue samples from affected patients.
in  <dig>  norgren and colleagues  <cit>  observed that ttr gene expression is significantly higher in patients’ liver than in healthy controls.
they hypothesized an impaired endoplasmatic reticulum-associated degradation and posited that the endoplasmatic reticulum-assisted folding was caused by an overload of mutated ttr protein.
recently, an in vitro study demonstrated that schwann cells can contribute to neurodegeneration in ttr amyloidosis through the local expression of mutated ttr  <cit> .
accordingly, ttr gene expression patterns across different tissues, including source and target organs, can contribute to the symptoms observed in patients.
to provide novel information regarding this topic, we used data from the gtex project and the  <dig>  genomes project.
specifically, we calculated tissue-specific scores to link genetic variability to ttr gene expression and analyzed the inter-population variability considering both differences among ancestries and among populations within the same ancestral groups.
our data confirmed that non-coding variations affect gene expression with tissue-specific patterns and that human populations have significant differences.
due to the very low disease prevalence and relatively few reports regarding ttr amyloidosis, it is difficult to conduct effective comparisons between epidemiological and molecular data.
however, in some cases, we observed consistency between clinical evidences and our computational results.fig.
<dig>
ttr gene expression across the  <dig> clinically relevant tissues investigated the present study.
this figure was extracted from the gtex portal available at http://www.gtexportal.org/home/
since val30met is the most recurring mutation in patients with ttr amyloidosis, numerous epidemiological studies investigated its distribution across human populations.
as mentioned above, the features of the two endemic val30met foci in europe are well known: swedish patients with late-onset, intermediate severity, and low penetrance vs. portuguese patients with early-onset, severe symptoms, and high penetrance  <cit> .
our molecular outcomes are consistent with these epidemiological data: scandinavian populations  showed the strongest difference with respect to southern european populations  for muscle – skeletal tissue.
the second most recurrent ttr mutation is val122ile that reaches 4% in african-americans and west africans  <cit> .
this mutation is mainly associated with familial amyloidotic cardiomyopathy due to ttr deposits in heart tissue  <cit> .
in our literature survey, we observed that val122ile was reported in multiple ancestry groups with high heterogeneity in the disease features related to the familial amyloidotic cardiomyopathy .
regarding heart tissues , we observed significant differences among the ancestry groups investigated that may be in agreement with the epidemiological data collected.
besides this consistent overlapping of our results with known epidemiological evidences, we observed other strong differences within some ancestry groups that may support future epidemiological investigations.
in the east asian group, our analysis revealed a significant difference between vietnamese population  and japanese and chinese groups  that agrees with previous studies on the genetic structure of east asian populations  <cit> .
regarding ttr amyloidosis, japan is one of the endemic foci of the disease with a prevalence of one per million, and different mutations have been identified along with a marked heterogeneity in the disease phenotypic expression  <cit> .
chinese cases with different ttr mutations  have also been identified  <cit> .
to our knowledge, no reports have been published on vietnamese or other south-eastern asian populations.
further studies on eastern asian patients may indicate strong differences within this ancestry group in accordance with our data.
another intriguing result is related to the admixed american populations of the  <dig>  genomes project .
these population clusters are an admixture of european, african, and native american ancestry and a recent study indicated strong differences in the admixture proportions  <cit> .
previous studies demonstrated that haplotype structure of admixed populations play an important role in gene regulatory mechanisms  <cit> .
our current data suggested that admixture differences could contribute to the heterogeneity observed among patients from admixed american populations.
beyond ttr hereditary amyloidosis, non-coding variants associated with ttr expression could be involved in the pathogenesis of the non-inherited form of ttr amyloidosis, known as senile systemic amyloidosis.
this disorder is caused by a deposition of fibrils derived from ttr in subjects that do not carry amyloidogenic mutations.
it occurs as cardiomyopathy in elderly men with european ancestry, and ttr amyloid fibrils can be found in the hearts of the 25% of elderly individuals over 80 years of age  <cit> .
a recent study provided suggestive evidences regarding the role of non-coding regulatory regions in wild-type ttr amyloidosis  <cit> .
together with these previous findings, our data suggest that ttr non-coding variation and its effect on transcription regulation are strong candidates as casual factors in the non-inherited form of ttr amyloidosis.
CONCLUSIONS
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.
however, our results are affected by some limitations.
the 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.
although our findings provided insights regarding ttr expression regulation, our analysis is based on data from general-population cohort that included subjects without ttr mutations.
therefore, our findings do not account for interactions between the amyloidogenic mutation and ttr gene regulation, which likely contribute to ttr expression variability in the affected patients.
due to the large sample size  used to investigate the role of non-coding variation in the regulation of ttr expression across human tissue, the possibility to experimentally confirm our findings is currently limited by cost and sample availability.
finally, in addition to ttr gene expression, other mechanisms can also contribute to the genotype-phenotype correlation of the disease, and our data may only reflect one of the molecular processes involved.
further in vivo and in vitro investigations are warranted to follow up our results and confirm the role of genetically determined ttr expression in the disease onset and progression.

 transthyretin amyloidosis is a rare, life-threatening, progressively debilitating, autosomal dominant condition characterized by extracellular deposition of ttr-derived amyloid fibrils in peripheral and autonomic nervous system, heart, and other organs, leading to tissue damage and organ failure. the disorder is caused by point mutations in the ttr gene located in chromosome region 18q. the disease presents multiple clinical signs, including peripheral neuropathy, autonomic neuropathy, gastrointestinal impairment, cardiomyopathy, nephropathy, and ocular deposition. while these symptoms may be present in patients with different ttr mutations, phenotypes are not always concordant and the same point mutation may be associated with different signs/symptoms. the clinical heterogeneity of the carriers of the ttr amyloidogenic mutations is particularly relevant from a population perspective. the most striking example of this inter-population diversity is the val30met mutation, which is one of the leading causes of ttr amyloidosis. in the two european val30met endemic areas, val30met patients show two distinct phenotypic presentations. in val30met portuguese families, the disease shows early-onset, strong severity, and high penetrance, whereas val30met swedish patients have late-onset, intermediate severity, and low penetrance. this complex genotype-phenotype correlation indicates that the clinical presentation is not only regulated by the disease-causing mutation. the amyloidogenic mutation is the cause of the disease, but other factors contribute to the modulation of the disease phenotype. our previous investigations focused on the role of non-coding variation in the genotype-phenotype correlation of ttr amyloidosis. 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. we also investigated the haplotype structures of val30met and val122ile mutations, observing in both cases independent haplotypes carrying the same disease-causing mutation. non-coding variation regulates genome functions, especially through its key role in transcriptional mechanisms across human tissues. 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, consequently, the disease presentation. in accordance with this hypothesis, a recent study demonstrated that, although the liver is the main ttr organ source, ttr gene expression in other tissues can also be involved in the processes related to the disease phenotype. recent studies have focused on how gene expression regulates relevant biological processes and how its alteration can lead to the onset of diseases. the genotype-tissue expression project is investigating genetic variation in relation to gene expression in human tissues. gtex data provide information about the relationship between genetic variations and gene expression in different human tissues. the effects of genetic variants can be used to estimate the genetically determined gene expression to investigate the role of gene expression in multiple tissues with respect to disease pathogenesis. accordingly, the analysis of the genetically determined ttr expression can help to discern its involvement in human tissues with respect to the genotype-phenotype correlation of ttr amyloidosis.  results from literature review we identified worldwide disease-causing mutations with information regarding the ancestry. our findings indicated that europeans have the highest number of ttr mutations, followed by east asians, americans, central-south asians and africans. the ancestry was not specified for the remaining amyloidogenic mutations. few mutations are reported in multiple ancestry groups and several symptoms are reported for patients with different ancestries and different mutations. however, clinical signs partially occur in an ancestry-specific manner with respect to the amyloidogenic mutation reported. genetically-predicted ttr expression as introduced above, we used the data from gtex project to build polygenic scores associated with ttr expression in human tissues and tested them in the samples from the genomes project considering both among-ancestry and within-ancestry analyses. a detailed description of procedures used is reported in the method section. among-ancestry comparisons the among-ancestry comparisons showed very significant differences for genetically predicted ttr expression scores for all investigated tissue with the exception of the esophagus – muscularis tissue. post-hoc pairwise analysis of the among-ancestry comparisons indicated that these significant differences are generally present across multiple ancestries and are not due to the diversity of a single population. the only exception to this general trend is the colon - transverse tissue where the significant result is exclusively driven by the difference between african and non-african populations. within-ancestry comparisons within-ancestry comparisons showed less tissue- and ancestry-specific differences than among-ancestry comparisons. significant differences were observed within european ancestry, within eastern asian ancestry, and within american ancestry. the significant results of the post-doc pairwise analysis are reported in fig.  in european populations, the diversity of ttr expression scores in the significant tissues is driven by north–south variability, with the most significant diversity between scandinavian populations and the other european samples. in eastern asian samples, the diversity for ttr expression scores in nerve - tibial tissue is driven by differences of vietnamese populations with respect to japanese and chinese populations. regarding the tissues identified in the american samples, the diversity of ttr expression scores is driven by differences between peruvian population and other american populations. permutation analysis confirmed that all within-ancestry observed differences significantly diverge from the null distribution of the permuted results. the observed z-scores are located in extremely marginal positions with respect to the null distribution of the z-scores generated by the random permutations.fig. heatmap of the kruscal-wallis results related to the within-ancestry comparisons. the colors refer to different significance levels. fig. heatmap of the kruscal-wallis post-hoc analysis results of within-ancestry comparisons. the colors refer to different significance levels. information about population definitions are available at http://www.1000genomes.org/about fig. distribution of the z-scores generated from random permutations with respect to the z-scores observed in the kruscal-wallis post-hoc analysis of within-ancestry comparisons. no significant differences were observed for african ancestry and central-south asian ancestry tissue; additional file 8). discussion our literature review indicated that few mutations were observed in multiple ancestral groups. however, these are the mutations detected in most patients affected by ttr amyloidosis and the corresponding clinical signs mainly occur with ancestry-specific patterns. 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. our hypothesis is in agreement with many studies about the regulatory role of non-coding variation on gene expression and other gene functions. ttr gene expression showed a relevant inter-individual variability across human tissues, and the related tissue-specific regulatory mechanisms is likely to be one of the processes involved in the disease genotype-phenotype correlation. our current findings based on a large multi-ethnic cohort and gene expression information from multiple human tissues provide novel insight regarding the regulatory mechanisms of ttr gene. indeed, very few investigations explored mechanisms related to gene expression in ttr amyloidosis due to limited availability of tissue samples from affected patients. in norgren and colleagues observed that ttr gene expression is significantly higher in patients’ liver than in healthy controls. they hypothesized an impaired endoplasmatic reticulum-associated degradation and posited that the endoplasmatic reticulum-assisted folding was caused by an overload of mutated ttr protein. recently, an in vitro study demonstrated that schwann cells can contribute to neurodegeneration in ttr amyloidosis through the local expression of mutated ttr. accordingly, ttr gene expression patterns across different tissues, including source and target organs, can contribute to the symptoms observed in patients. to provide novel information regarding this topic, we used data from the gtex project and the genomes project. specifically, we calculated tissue-specific scores to link genetic variability to ttr gene expression and analyzed the inter-population variability considering both differences among ancestries and among populations within the same ancestral groups. our data confirmed that non-coding variations affect gene expression with tissue-specific patterns and that human populations have significant differences. due to the very low disease prevalence and relatively few reports regarding ttr amyloidosis, it is difficult to conduct effective comparisons between epidemiological and molecular data. however, in some cases, we observed consistency between clinical evidences and our computational results.fig. ttr gene expression across the clinically relevant tissues investigated the present study. this figure was extracted from the gtex portal available at http://www.gtexportal.org/home/ since val30met is the most recurring mutation in patients with ttr amyloidosis, numerous epidemiological studies investigated its distribution across human populations. as mentioned above, the features of the two endemic val30met foci in europe are well known: swedish patients with late-onset, intermediate severity, and low penetrance vs. portuguese patients with early-onset, severe symptoms, and high penetrance. our molecular outcomes are consistent with these epidemiological data: scandinavian populations showed the strongest difference with respect to southern european populations for muscle – skeletal tissue. the second most recurrent ttr mutation is val122ile that reaches 4% in african-americans and west africans. this mutation is mainly associated with familial amyloidotic cardiomyopathy due to ttr deposits in heart tissue. in our literature survey, we observed that val122ile was reported in multiple ancestry groups with high heterogeneity in the disease features related to the familial amyloidotic cardiomyopathy. regarding heart tissues, we observed significant differences among the ancestry groups investigated that may be in agreement with the epidemiological data collected. besides this consistent overlapping of our results with known epidemiological evidences, we observed other strong differences within some ancestry groups that may support future epidemiological investigations. in the east asian group, our analysis revealed a significant difference between vietnamese population and japanese and chinese groups that agrees with previous studies on the genetic structure of east asian populations. regarding ttr amyloidosis, japan is one of the endemic foci of the disease with a prevalence of one per million, and different mutations have been identified along with a marked heterogeneity in the disease phenotypic expression. chinese cases with different ttr mutations have also been identified. to our knowledge, no reports have been published on vietnamese or other south-eastern asian populations. further studies on eastern asian patients may indicate strong differences within this ancestry group in accordance with our data. another intriguing result is related to the admixed american populations of the genomes project. these population clusters are an admixture of european, african, and native american ancestry and a recent study indicated strong differences in the admixture proportions. previous studies demonstrated that haplotype structure of admixed populations play an important role in gene regulatory mechanisms. our current data suggested that admixture differences could contribute to the heterogeneity observed among patients from admixed american populations. beyond ttr hereditary amyloidosis, non-coding variants associated with ttr expression could be involved in the pathogenesis of the non-inherited form of ttr amyloidosis, known as senile systemic amyloidosis. this disorder is caused by a deposition of fibrils derived from ttr in subjects that do not carry amyloidogenic mutations. it occurs as cardiomyopathy in elderly men with european ancestry, and ttr amyloid fibrils can be found in the hearts of the 25% of elderly individuals over 80 years of age. a recent study provided suggestive evidences regarding the role of non-coding regulatory regions in wild-type ttr amyloidosis. together with these previous findings, our data suggest that ttr non-coding variation and its effect on transcription regulation are strong candidates as casual factors in the non-inherited form of ttr amyloidosis.  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. however, our results are affected by some limitations. the 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. although our findings provided insights regarding ttr expression regulation, our analysis is based on data from general-population cohort that included subjects without ttr mutations. therefore, our findings do not account for interactions between the amyloidogenic mutation and ttr gene regulation, which likely contribute to ttr expression variability in the affected patients. due to the large sample size used to investigate the role of non-coding variation in the regulation of ttr expression across human tissue, the possibility to experimentally confirm our findings is currently limited by cost and sample availability. finally, in addition to ttr gene expression, other mechanisms can also contribute to the genotype-phenotype correlation of the disease, and our data may only reflect one of the molecular processes involved. further in vivo and in vitro investigations are warranted to follow up our results and confirm the role of genetically determined ttr expression in the disease onset and progression. 
transthyretin amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. this might contribute to the genotype-phenotype correlation of ttr amyloidosis. transthyretingenotype-phenotype correlationmutationamyloidgene expressionhttp://dx.doi.org/http://dx.doi.org/ /100004319pfizerinvestigator-initiated researchissue-copyright-statement© the author 2017 polygenic scores for genetically determined ttr expression in clinically relevant tissues were constructed using data from the gtex project and tested in the samples from the genomes project. we conducted a literature survey to define the clinical landscape of ttr amyloidosis across populations worldwide. familial amyloidotic cardiomyopathy presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined ttr expression in heart tissues. we observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. this is in line with epidemiological data related to swedish and portuguese ttr val30met endemic areas. then, we investigated whether the genetically determined ttr expression differs among human populations, contributing to the differences observed in patients. scandinavian populations differed in their genetically determined ttr expression of skeletal muscle tissue with respect to southern europeans. genetically determined ttr expression varied across human populations.
 transthyretin 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 clinically relevant tissues were constructed using data from the gtex project and tested in the samples from the genomes project.  we 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. this is in line with epidemiological data related to swedish and portuguese ttr val30met endemic areas. familial amyloidotic cardiomyopathy presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined ttr expression in heart tissues.  genetically determined ttr expression varied across human populations. this might contribute to the genotype-phenotype correlation of ttr amyloidosis. electronic supplementary material the online version of this article contains supplementary material, which is available to authorized users. keywords transthyretingenotype-phenotype correlationmutationamyloidgene expressionhttp://dx.doi.org/http://dx.doi.org/ /100004319pfizerinvestigator-initiated researchissue-copyright-statement© the author 2017 