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

References

• Vieira M, Saraiva MJ. Transthyretin: a multifaceted protein. Biomol Concepts. 2014;5(1):45–54.
   PubMedGoogle Scholar
• Liz MA, Coelho T, Bellotti V, et al. A narrative review of the role of transthyretin in health and disease. Neurol Ther. 2020;9(2):395–402.
   PubMed Web of Science ®Google Scholar
• van Bennekum AM, Wei S, Gamble MV, et al. Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice. J Biol Chem. 2001;276(2):1107–1113.
   PubMed Web of Science ®Google Scholar
• Episkopou V, Maeda S, Nishiguchi S, et al. Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci U S A. 1993;90(6):2375–2379.
   PubMed Web of Science ®Google Scholar
• Liz MA, Gomes CM, Saraiva MJ, et al. ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity. J Lipid Res. 2007;48(11):2385–2395.
   PubMed Web of Science ®Google Scholar
• Ghadami SA, Chia S, Ruggeri FS, et al. Transthyretin inhibits primary and secondary nucleations of amyloid-beta peptide aggregation and reduces the toxicity of its oligomers. Biomacromolecules. 2020;21(3):1112–1125.
   PubMed Web of Science ®Google Scholar
• Adams D, Koike H, Slama M, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387–404.
   PubMed Web of Science ®Google Scholar
• Si JB, Kim B, Kim JH. Transthyretin misfolding, a fatal structural pathogenesis mechanism. Int J Mol Sci. 2021;22(9):4429.
   PubMed Web of Science ®Google Scholar
• D'Aguanno V, Ralli M, Artico M, et al. Systemic amyloidosis: a contemporary overview. Clin Rev Allergy Immunol. 2020;59(3):304–322.
   PubMed Web of Science ®Google Scholar
• Koike H, Katsuno M. Transthyretin amyloidosis: update on the clinical spectrum, pathogenesis, and disease-modifying therapies. Neurol Ther. 2020;9(2):317–333.
   PubMed Web of Science ®Google Scholar
• Sekijima Y, Yazaki M, Ueda M, et al. First nationwide survey on systemic wild-type ATTR amyloidosis in Japan. Amyloid. 2018;25(1):8–10.
   PubMed Web of Science ®Google Scholar
• Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68(10):1014–1020.
   PubMed Web of Science ®Google Scholar
• Freudenthaler S, Hegenbart U, Schonland S, et al. Amyloid in biopsies of the gastrointestinal tract-a retrospective observational study on 542 patients. Virchows Arch. 2016;468(5):569–577.
   PubMed Web of Science ®Google Scholar
• Rubin J, Alvarez J, Teruya S, et al. Hip and knee arthroplasty are common among patients with transthyretin cardiac amyloidosis, occurring years before cardiac amyloid diagnosis: can we identify affected patients earlier? Amyloid. 2017;24(4):226–230.
   PubMed Web of Science ®Google Scholar
• Takanashi T, Matsuda M, Yazaki M, et al. Synovial deposition of wild-type transthyretin-derived amyloid in knee joint osteoarthritis patients. Amyloid. 2013;20(3):151–155. doi:https://doi.org/10.3109/13506129.2013.803190. 23734638
   PubMed Web of Science ®Google Scholar
• Sekijima Y, Ueda M, Koike H, et al. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13(1):6.
   PubMed Web of Science ®Google Scholar
• Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098.
   PubMed Web of Science ®Google Scholar
• Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.
   PubMed Web of Science ®Google Scholar
• Iorio A, De Lillo A, De Angelis F, et al. Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. Eur J Hum Genet. 2017;25(9):1055–1060.
   PubMed Web of Science ®Google Scholar
• Norgren N, Olsson M, Nystrom H, et al. Gene expression profile in hereditary transthyretin amyloidosis: differences in targeted and source organs. Amyloid. 2014;21(2):113–119.
   PubMed Web of Science ®Google Scholar
• Polimanti R, Nunez YZ, Gelernter J. Increased risk of multiple outpatient surgeries in African-American carriers of transthyretin Val122Ile mutation is modulated by non-coding variants. J Clin Med. 2019;8(2):269.
   Web of Science ®Google Scholar
• Sikora JL, Logue MW, Chan GG, et al. Genetic variation of the transthyretin gene in wild-type transthyretin amyloidosis (ATTRwt). Hum Genet. 2015;134(1):111–121.
   PubMed Web of Science ®Google Scholar
• De Lillo A, De Angelis F, Di Girolamo M, et al. Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses. Hum Genet. 2019;138(11–12):1331–1340.
   PubMed Web of Science ®Google Scholar
• Pathak GA, Wendt FR, De Lillo A, et al. Epigenomic profiles of African-American transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms. Circ Genom Precis Med. 2021;14(1):e003011.
   PubMed Web of Science ®Google Scholar
• De Lillo A, Pathak GA, De Angelis F, et al. Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis. Clin Epigenetics. 2020;12(1):176.
   PubMed Web of Science ®Google Scholar
• Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819–829.
   PubMed Web of Science ®Google Scholar
• Butler JS, Chan A, Costelha S, et al. Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis. Amyloid. 2016;23(2):109–118.
   PubMed Web of Science ®Google Scholar
• Adams D, Slama M. Hereditary transthyretin amyloidosis: current treatment. Curr Opin Neurol. 2020;33(5):553–561.
   PubMed Web of Science ®Google Scholar
• Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. 2021;385(6):493–502.
   PubMed Web of Science ®Google Scholar
• Gamazon ER, Wheeler HE, Shah KP, et al. A gene-based association method for mapping traits using reference transcriptome data. Nat Genet. 2015;47(9):1091–1098.
   PubMed Web of Science ®Google Scholar
• Bycroft C, Freeman C, Petkova D, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203–209.
   PubMed Web of Science ®Google Scholar
• Zhou W, Nielsen JB, Fritsche LG, et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet. 2018;50(9):1335–1341.
   PubMed Web of Science ®Google Scholar
• The GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45(6):580–585.
   PubMed Web of Science ®Google Scholar
• The GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318–1330.
   PubMed Web of Science ®Google Scholar
• Barbeira AN, Dickinson SP, Bonazzola R, et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat Commun. 2018;9(1):1825.
   PubMedGoogle Scholar
• Wen X, Lee Y, Luca F, et al. Efficient integrative multi-SNP association analysis via deterministic approximation of posteriors. Am J Hum Genet. 2016;98(6):1114–1129.
   PubMed Web of Science ®Google Scholar
• Urbut SM, Wang G, Carbonetto P, et al. Flexible statistical methods for estimating and testing effects in genomic studies with multiple conditions. Nat Genet. 2019;51(1):187–195.
   PubMed Web of Science ®Google Scholar
• Barbeira AN, Pividori M, Zheng J, et al. Integrating predicted transcriptome from multiple tissues improves association detection. PLoS Genet. 2019;15(1):e1007889.
   PubMed Web of Science ®Google Scholar
• Qingyuan Z, Jingshu W, Gibran H, et al. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Ann Stat. 2020;48(3):1742–1769.
   Web of Science ®Google Scholar
• Townsend P, Phillimore P, Beattie A. Health and deprivation: inequality and the North. London: Croom Helm Ltd.; 1988.
   Google Scholar
• Zhang X, Zhang R, Moore JB, et al. The effect of vitamin a on fracture risk: a meta-analysis of cohort studies. Int J Environ Res Public Health. 2017;14(9):1043.
   Web of Science ®Google Scholar
• Wu AM, Huang CQ, Lin ZK, et al. The relationship between vitamin a and risk of fracture: Meta-analysis of prospective studies. J Bone Miner Res. 2014;29(9):2032–2039.
   PubMed Web of Science ®Google Scholar
• Promislow JH, Goodman-Gruen D, Slymen DJ, et al. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res. 2002;17(8):1349–1358.
   PubMed Web of Science ®Google Scholar
• Lionikaite V, Gustafsson KL, Westerlund A, et al. Clinically relevant doses of vitamin a decrease cortical bone mass in mice. J Endocrinol. 2018;239(3):389–402.
   PubMed Web of Science ®Google Scholar
• Delitala AP, Scuteri A, Doria C. Thyroid hormone diseases and osteoporosis. J Clin Med. 2020;9(4):1034.
   Web of Science ®Google Scholar
• Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev. 2016;37(2):135–187.
   PubMed Web of Science ®Google Scholar
• Karimifar M, Esmaili F, Salari A, et al. Effects of Levothyroxine and thyroid stimulating hormone on bone loss in patients with primary hypothyroidism. J Res Pharm Pract. 2014;3(3):83–87.
   PubMedGoogle Scholar
• Akasaki Y, Reixach N, Matsuzaki T, et al. Transthyretin deposition in articular cartilage: a novel mechanism in the pathogenesis of osteoarthritis. Arthritis Rheumatol. 2015;67(8):2097–2107.
   PubMed Web of Science ®Google Scholar
• Karam C, Dimitrova D, Christ M, et al. Carpal tunnel syndrome and associated symptoms as first manifestation of hATTR amyloidosis. Neurol Clin Pract. 2019;9(4):309–313.
   PubMedGoogle Scholar
• Pourmemari MH, Heliovaara M, Viikari-Juntura E, et al. Carpal tunnel release: Lifetime prevalence, annual incidence, and risk factors. Muscle Nerve. 2018;58(4):497–502.
   PubMed Web of Science ®Google Scholar
• Milandri A, Farioli A, Gagliardi C, et al. Carpal tunnel syndrome in cardiac amyloidosis: implications for early diagnosis and prognostic role across the spectrum of aetiologies. Eur J Heart Fail. 2020;22(3):507–515.
   PubMed Web of Science ®Google Scholar
• Wixner J, Mundayat R, Karayal ON, et al. THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease. Orphanet J Rare Dis. 2014;9(1):61.
   PubMedGoogle Scholar
• Lobato L, Rocha A. Transthyretin amyloidosis and the kidney. Clin J Am Soc Nephrol. 2012;7(8):1337–1346.
   PubMed Web of Science ®Google Scholar
• Bentellis I, Amarenco G, Game X, et al. Diagnosis and treatment of urinary and sexual dysfunction in hereditary TTR amyloidosis. Clin Auton Res. 2019;29(Suppl 1):65–74.
   PubMedGoogle Scholar
• Yamamoto H, Yokochi T. Transthyretin cardiac amyloidosis: an update on diagnosis and treatment. ESC Heart Fail. 2019;6(6):1128–1139.
   PubMed Web of Science ®Google Scholar
• Sousa JC, Grandela C, Fernandez-Ruiz J, et al. Transthyretin is involved in depression-like behaviour and exploratory activity. J Neurochem. 2004;88(5):1052–1058.
   PubMed Web of Science ®Google Scholar
• Buxbaum JN, Roberts AJ, Adame A, et al. Silencing of murine transthyretin and retinol binding protein genes has distinct and shared behavioral and neuropathologic effects. Neuroscience. 2014;275:352–364. doi:https://doi.org/10.1016/j.neuroscience.2014.06.019. 24956283
   PubMed Web of Science ®Google Scholar
• Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry. 2006;60(5):500–506.
   PubMed Web of Science ®Google Scholar
• Parker MM, Damrauer SM, Tcheandjieu C, et al. Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry. Sci Rep. 2021;11(1):11645.
   PubMed Web of Science ®Google Scholar
• Buxbaum JN, Ruberg FL. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med. 2017;19(7):733–742.
   PubMed Web of Science ®Google Scholar