Gita A Pathak1,2, Frank R Wendt1,2, Antonella De Lillo3, Yaira Z Nunez1,2, Aranyak Goswami1,2, Flavio De Angelis1,2,3, Maria Fuciarelli3, Henry R Kranzler4, Joel Gelernter1,2, Renato Polimanti1,2. 1. 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.). 2. 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.). 3. Department of Biology, University of Rome Tor Vergata, Italy (A.D.L., F.D.A., M.F.). 4. University of Pennsylvania Perelman School of Medicine and VISN 4 MIRECC, Crescenz VAMC, Philadelphia (H.R.K.).
Abstract
BACKGROUND: The Val122Ile mutation in Transthyretin (TTR) 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. METHODS: We conducted first-ever epigenome-wide association study using the Illumina's EPIC array, in Val122Ile carriers of African descent for heart disease and multiple OSs-an 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. RESULTS: Five differentially methylated sites (P≤2.1×10-8) in genes-FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2, and one differentially methylated region containing KCNA6 and GALNT3 (P=1.1×10-12) were associated with heart disease. For OS, we observe 4 sites-2 sites in UBE2E3 and SEC14L5, and other 2 in intergenic regions (P≤1.8×10-7) and 3 regions overlapping SH3D21, EVA1B, LTB4R2, and CIDEB (P≤3.9×10-7). Functional protein-interaction module analysis identified ABCA1 (P=0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; P=4.1×10-24). We replicated 2 CpG sites (cg18546846 and cg06641417; P<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 (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B). CONCLUSIONS: These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.
BACKGROUND: The Val122Ile mutation in Transthyretin (TTR) 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. METHODS: We conducted first-ever epigenome-wide association study using the Illumina's EPIC array, in Val122Ile carriers of African descent for heart disease and multiple OSs-an 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. RESULTS: Five differentially methylated sites (P≤2.1×10-8) in genes-FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2, and one differentially methylated region containing KCNA6 and GALNT3 (P=1.1×10-12) were associated with heart disease. For OS, we observe 4 sites-2 sites in UBE2E3 and SEC14L5, and other 2 in intergenic regions (P≤1.8×10-7) and 3 regions overlapping SH3D21, EVA1B, LTB4R2, and CIDEB (P≤3.9×10-7). Functional protein-interaction module analysis identified ABCA1 (P=0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; P=4.1×10-24). We replicated 2 CpG sites (cg18546846 and cg06641417; P<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 (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B). CONCLUSIONS: These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.
Authors: Antonella De Lillo; Flavio De Angelis; Marco Di Girolamo; Marco Luigetti; Sabrina Frusconi; Dario Manfellotto; Maria Fuciarelli; Renato Polimanti Journal: Hum Genet Date: 2019-10-29 Impact factor: 4.132
Authors: Steve Horvath; Michael Gurven; Morgan E Levine; Benjamin C Trumble; Hillard Kaplan; Hooman Allayee; Beate R Ritz; Brian Chen; Ake T Lu; Tammy M Rickabaugh; Beth D Jamieson; Dianjianyi Sun; Shengxu Li; Wei Chen; Lluis Quintana-Murci; Maud Fagny; Michael S Kobor; Philip S Tsao; Alexander P Reiner; Kerstin L Edlefsen; Devin Absher; Themistocles L Assimes Journal: Genome Biol Date: 2016-08-11 Impact factor: 13.583
Authors: Gita A Pathak; Antonella De Lillo; Frank R Wendt; Flavio De Angelis; Dora Koller; Brenda Cabrera Mendoza; Daniel Jacoby; Edward J Miller; Joel N Buxbaum; Renato Polimanti Journal: Amyloid Date: 2021-12-22 Impact factor: 6.571