Epigenomic Profiles of African-American Val122Ile Carriers Reveals Putatively Dysregulated Amyloid Mechanisms

Overview

Journal Circ Genom Precis Med

Specialties Cardiology & Vascular Diseases
Genetics

Date 2021 Jan 11

PMID 33428857

Citations 3

Authors

Gita A Pathak

Frank R Wendt

Antonella De Lillo

Yaira Z Nunez

Aranyak Goswami

Flavio De Angelis

Maria Fuciarelli

Henry R Kranzler

Joel Gelernter

Renato Polimanti

Affiliations

Soon will be listed here.

Abstract

Background: The Val122Ile mutation in () 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 (≤2.1×10) in genes-, , , , and an intergenic site near RP11-550A5.2, and one differentially methylated region containing and (=1.1×10) were associated with heart disease. For OS, we observe 4 sites-2 sites in and , and other 2 in intergenic regions (≤1.8×10) and 3 regions overlapping , , , and (≤3.9×10). Functional protein-interaction module analysis identified (=0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites (; =4.1×10). We replicated 2 CpG sites (cg18546846 and cg06641417; <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 (, , ); cardiac fibrosis (); and muscle tissue regulation (, ).

Conclusions: These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.

Citing Articles

Hereditary transthyretin amyloidosis: a myriad of factors that influence phenotypic variability.

Carvalho E, Dias A, Coelho T, Sousa A, Alves-Ferreira M, Santos M J Neurol. 2024; 271(9):5746-5761.

PMID: 38907862 PMC: 11377651. DOI: 10.1007/s00415-024-12509-8.

Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins.

De Lillo A, Pathak G, Low A, De Angelis F, Abou Alaiwi S, Miller E Hum Genomics. 2024; 18(1):31.

PMID: 38523305 PMC: 10962184. DOI: 10.1186/s40246-024-00596-7.

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

Pathak G, De Lillo A, Wendt F, De Angelis F, Koller D, Cabrera Mendoza B Amyloid. 2021; 29(2):110-119.

PMID: 34935565 PMC: 9213571. DOI: 10.1080/13506129.2021.2018678.

References

Mankad A, Shah K . Transthyretin Cardiac Amyloidosis. Curr Cardiol Rep. 2017; 19(10):97. DOI: 10.1007/s11886-017-0911-5. View

Unnikrishnan A, Freeman W, Jackson J, Wren J, Porter H, Richardson A . The role of DNA methylation in epigenetics of aging. Pharmacol Ther. 2018; 195:172-185. PMC: 6397707. DOI: 10.1016/j.pharmthera.2018.11.001. View

Zhang W, Song M, Qu J, Liu G . Epigenetic Modifications in Cardiovascular Aging and Diseases. Circ Res. 2018; 123(7):773-786. DOI: 10.1161/CIRCRESAHA.118.312497. View

Hachiya T, Furukawa R, Shiwa Y, Ohmomo H, Ono K, Katsuoka F . Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies. NPJ Genom Med. 2017; 2:11. PMC: 5677974. DOI: 10.1038/s41525-017-0016-5. View

Horvath S, Gurven M, Levine M, Trumble B, Kaplan H, Allayee H . An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 2016; 17(1):171. PMC: 4980791. DOI: 10.1186/s13059-016-1030-0. View

Suresh R, Grogan M, Maleszewski J, Pellikka P, Hanna M, Dispenzieri A . Advanced cardiac amyloidosis associated with normal interventricular septal thickness: an uncommon presentation of infiltrative cardiomyopathy. J Am Soc Echocardiogr. 2014; 27(4):440-7. PMC: 3972307. DOI: 10.1016/j.echo.2013.12.010. View

Polimanti R, Di Girolamo M, Manfellotto D, Fuciarelli M . Functional variation of the transthyretin gene among human populations and its correlation with amyloidosis phenotypes. Amyloid. 2013; 20(4):256-62. DOI: 10.3109/13506129.2013.844689. View

Schaich C, Maurer M, Nadkarni N . Amyloidosis of the Brain and Heart: Two Sides of the Same Coin?. JACC Heart Fail. 2019; 7(2):129-131. PMC: 6515925. DOI: 10.1016/j.jchf.2018.12.014. View

De Lillo A, De Angelis F, Di Girolamo M, Luigetti M, Frusconi S, Manfellotto D . 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. DOI: 10.1007/s00439-019-02078-6. View

10.

Milandri A, Farioli A, Gagliardi C, Longhi S, Salvi F, Curti S . 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. DOI: 10.1002/ejhf.1742. View

11.

Iorio A, De Lillo A, De Angelis F, Di Girolamo M, Luigetti M, Sabatelli M . Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. Eur J Hum Genet. 2017; 25(9):1055-1060. PMC: 5558178. DOI: 10.1038/ejhg.2017.95. View

12.

Li C, Wang Z, Hardy T, Huang Y, Hui Q, Crusto C . Association of Obesity with DNA Methylation Age Acceleration in African American Mothers from the InterGEN Study. Int J Mol Sci. 2019; 20(17). PMC: 6747309. DOI: 10.3390/ijms20174273. View

13.

Montojo J, Zuberi K, Rodriguez H, Bader G, Morris Q . GeneMANIA: Fast gene network construction and function prediction for Cytoscape. F1000Res. 2014; 3:153. PMC: 4168749. DOI: 10.12688/f1000research.4572.1. View

14.

Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S . Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2012; 49(2):359-367. PMC: 3780611. DOI: 10.1016/j.molcel.2012.10.016. View

15.

Revett T, Baker G, Jhamandas J, Kar S . Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. J Psychiatry Neurosci. 2012; 38(1):6-23. PMC: 3529221. DOI: 10.1503/jpn.110190. View

16.

Yang K, Nerbonne J . Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling. Trends Cardiovasc Med. 2015; 26(3):209-18. PMC: 4715991. DOI: 10.1016/j.tcm.2015.07.002. View

17.

Bishop E, Brown E, Fajardo J, Barouch L, Judge D, Halushka M . Seven factors predict a delayed diagnosis of cardiac amyloidosis. Amyloid. 2018; 25(3):174-179. DOI: 10.1080/13506129.2018.1498782. View

18.

Plante-Bordeneuve V, Said G . Familial amyloid polyneuropathy. Lancet Neurol. 2011; 10(12):1086-97. DOI: 10.1016/S1474-4422(11)70246-0. View

19.

Maurer M, Mundayat R, Rapezzi C . Reply: Val122Ile mt-ATTR Has a Worse Survival Than wt-ATTR Cardiac Amyloidosis. J Am Coll Cardiol. 2017; 69(6):758-759. DOI: 10.1016/j.jacc.2016.11.047. View

20.

Tajuddin S, Hernandez D, Chen B, Noren Hooten N, Mode N, Nalls M . Novel age-associated DNA methylation changes and epigenetic age acceleration in middle-aged African Americans and whites. Clin Epigenetics. 2019; 11(1):119. PMC: 6700815. DOI: 10.1186/s13148-019-0722-1. View