The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic <i>transthyretin</i> expression

Pathak, Gita A; Lillo, Antonella De; Wendt, Frank R.; Angelis, Flavio De; Koller, Dóra; Cabrera‐Mendoza, Brenda; Jacoby, Daniel; Miller, Edward J.; Buxbaum, Joel N.; Polimanti, Renato

doi:10.1080/13506129.2021.2018678

Cited by 2 publications

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“…Indeed, the expression of hepatic TTR is increased by a high‐fat diet and obesity and, at the same time promotes insulin resistance (He et al., 2021 ). Interestingly, a large genotypic and phenotypic analysis conducted in humans showed an association between low TTR hepatic expression and lower body height (Pathak et al., 2022 ). Increased TTR expression also increases mitochondrial density whereas its insufficiency triggers a higher degree of oxidative phosphorylation in the liver (Alemi et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Association between rat decompression sickness resistance, transthyretin single nucleotide polymorphism, and expression: A pilot study

Orsat,

Guernec,

Le Maréchal

et al. 2024

Physiological Reports

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Decompression sickness (DCS) is a systemic syndrome that can occur after an environmental pressure reduction. Previously, we showed that the plasmatic tetrameric form of transthyretin (TTR) nearly disappeared in rats suffering DCS but not in asymptomatic ones. In this pilot study, we assessed whether the resistance to DCS could be associated with polymorphism of the gene of TTR. For this study, Sanger sequencing was performed on purified PCR products from the liver of 14‐week‐old male and female standard and DCS‐resistant rats (n = 5 per group). Hepatic TTR mRNA expression was assessed by RT‐qPCR in 18–19 week‐old male and female standard and resistant rats (n = 6 per group). There is a synonymous single nucleotide polymorphism (SNP) on the third base of codon 46 (c.138 C > T). The thymine allele was present in 90% and 100% of males and females standard, respectively. However, this allele is present in only 30% of DCS‐resistant males and females (p = 0.0002301). In the liver, there is a significant effect of the resistance to DCS (p = 0.043) and sex (p = 0.047) on TTR expression. Levels of TTR mRNA were lower in DCS‐resistant animals. To conclude, DCS resistance might be associated with a SNP and a lower expression of TTR.

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Section: Discussionmentioning

confidence: 99%

Association between rat decompression sickness resistance, transthyretin single nucleotide polymorphism, and expression: A pilot study

Orsat,

Guernec,

Le Maréchal

et al. 2024

Physiological Reports

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“…However, population comparisons have mostly been limited to cohorts of European and East Asian descent for most TTR amyloidogenic mutations (e.g., TTR Val30Met, rs28933979) and to individuals of African descent for TTR Val122Ile mutation (rs76992529) [ 8 , 10 , 12 ]. Recently, molecular and computational studies demonstrated that non-coding mechanisms regulating transcriptomic and epigenetic variation of the TTR gene partially explain hATTR clinical heterogeneity [ 13 – 16 ], including the differences among diverse populations [ 17 – 19 ]. However, the knowledge of the clinical presentation associated with TTR amyloidogenic mutations is still too limited for several human populations.…”

Section: Introductionmentioning

confidence: 99%

Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins

De Lillo,

Pathak,

Low

et al. 2024

Hum Genomics

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Purpose Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations. Methods We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank. Results In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10− 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003). Conclusions Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.

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The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic transthyretin expression

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 2 publications

References 65 publications

Association between rat decompression sickness resistance, transthyretin single nucleotide polymorphism, and expression: A pilot study

Association between rat decompression sickness resistance, transthyretin single nucleotide polymorphism, and expression: A pilot study

Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins

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