{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:18:06Z","timestamp":1780636686049,"version":"3.54.1"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2021,2]]},"abstract":"\n Background:<\/jats:title>\n \n The Val122Ile mutation in\n Transthyretin<\/jats:italic>\n (\n TTR<\/jats:italic>\n ) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other noncardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory\/outpatient surgeries (OSs) in the country.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n We conducted first-ever epigenome-wide association study using the Illumina\u2019s EPIC array, in Val122Ile carriers of African descent for heart disease and multiple OSs\u2014an early disease indicator. Differential methylation across genome wide cytosine-phosphate guanine (CpG) sites was tested between carriers with and without heart disease and OS. Significant CpG sites were investigated for cis-mQTLs loci, followed by gene ontology and protein-protein interaction network. We also investigated the significant CpG sites in a secondary cohort of carriers for replication.<\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Five differentially methylated sites (\n P<\/jats:italic>\n \u22642.1\u00d710\n \u22128<\/jats:sup>\n ) in genes\u2014\n FAM129B<\/jats:italic>\n ,\n SKI<\/jats:italic>\n ,\n WDR27<\/jats:italic>\n ,\n GLS<\/jats:italic>\n , and an intergenic site near RP11-550A5.2, and one differentially methylated region containing\n KCNA6<\/jats:italic>\n and\n GALNT3<\/jats:italic>\n (\n P<\/jats:italic>\n =1.1\u00d710\n \u221212<\/jats:sup>\n ) were associated with heart disease. For OS, we observe 4 sites\u20142 sites in\n UBE2E3<\/jats:italic>\n and\n SEC14L5<\/jats:italic>\n , and other 2 in intergenic regions (\n P<\/jats:italic>\n \u22641.8\u00d710\n \u22127<\/jats:sup>\n ) and 3 regions overlapping\n SH3D21<\/jats:italic>\n ,\n EVA1B<\/jats:italic>\n ,\n LTB4R2<\/jats:italic>\n , and\n CIDEB<\/jats:italic>\n (\n P<\/jats:italic>\n \u22643.9\u00d710\n \u22127<\/jats:sup>\n ). Functional protein-interaction module analysis identified\n ABCA1<\/jats:italic>\n (\n P<\/jats:italic>\n =0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites (\n FAM129B<\/jats:italic>\n ;\n P<\/jats:italic>\n =4.1\u00d710\n \u221224<\/jats:sup>\n ). We replicated 2 CpG sites (cg18546846 and cg06641417;\n P<\/jats:italic>\n <0.05) in an external cohort of biopsy-confirmed cases of TTR (transthyretin) amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits (\n GLS<\/jats:italic>\n ,\n ABCA1<\/jats:italic>\n ,\n FAM129B<\/jats:italic>\n ); cardiac fibrosis (\n SKI<\/jats:italic>\n ); and muscle tissue regulation (\n SKI<\/jats:italic>\n ,\n FAM129B<\/jats:italic>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circgen.120.003011","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T19:06:33Z","timestamp":1610391993000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Epigenomic Profiles of African-American\n Transthyretin<\/i>\n Val122Ile Carriers Reveals Putatively Dysregulated Amyloid Mechanisms"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3943-0895","authenticated-orcid":true,"given":"Gita A.","family":"Pathak","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Yale School of Medicine, Yale University, New Haven (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.)."},{"name":"Veteran Affairs Connecticut Healthcare System, West Haven, CT (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2108-6822","authenticated-orcid":true,"given":"Frank R.","family":"Wendt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale School of Medicine, Yale University, New Haven (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.)."},{"name":"Veteran Affairs Connecticut Healthcare System, West Haven, CT (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., 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Affairs Connecticut Healthcare System, West Haven, CT (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4747-2385","authenticated-orcid":true,"given":"Flavio","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale School of Medicine, Yale University, New Haven (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.)."},{"name":"Veteran Affairs Connecticut Healthcare System, West Haven, CT (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.)."},{"name":"Department of Biology, University of Rome Tor Vergata, Italy (A.D.L., F.D.A., M.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Fuciarelli","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Italy (A.D.L., F.D.A., 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