Single-Nucleotide Variations in Cardiac Arrhythmias: Prospects for Genomics and Proteomics Based Biomarker Discovery and Diagnostics

Abunimer, Ayman; Smith, Krista; Wu, Tsung-Jung; Lam, Phuc; Simonyan, Vahan; Mazumder, Raja

doi:10.3390/genes5020254

Title: Single-Nucleotide Variations in Cardiac Arrhythmias: Prospects for Genomics and Proteomics Based Biomarker Discovery and Diagnostics

Journal Article · Thu Mar 27 00:00:00 EDT 2014 · Genes

DOI:https://doi.org/10.3390/genes5020254· OSTI ID:1628324

Abunimer, Ayman ^[1]; Smith, Krista ^[1]; Wu, Tsung-Jung ^[1]; Lam, Phuc ^[2]; Simonyan, Vahan ^[2]; Mazumder, Raja ^[1]

George Washington University, Washington, DC (United States)
U.S. Food and Drug Administration (FDA), Rockville, MD (United States)

Cardiovascular diseases are a large contributor to causes of early death in developed countries. Some of these conditions, such as sudden cardiac death and atrial fibrillation, stem from arrhythmias—a spectrum of conditions with abnormal electrical activity in the heart. Genome-wide association studies can identify single nucleotide variations (SNVs) that may predispose individuals to developing acquired forms of arrhythmias. Through manual curation of published genome-wide association studies, we have collected a comprehensive list of 75 SNVs associated with cardiac arrhythmias. Ten of the SNVs result in amino acid changes and can be used in proteomic-based detection methods. In an effort to identify additional non-synonymous mutations that affect the proteome, we analyzed the post-translational modification S-nitrosylation, which is known to affect cardiac arrhythmias. We identified loss of seven known S-nitrosylation sites due to non-synonymous single nucleotide variations (nsSNVs). For predicted nitrosylation sites we found 1429 proteins where the sites are modified due to nsSNV. Analysis of the predicted S-nitrosylation dataset for over- or under-representation (compared to the complete human proteome) of pathways and functional elements shows significant statistical over-representation of the blood coagulation pathway. Gene Ontology (GO) analysis displays statistically over-represented terms related to muscle contraction, receptor activity, motor activity, cystoskeleton components, and microtubule activity. Through the genomic and proteomic context of SNVs and S-nitrosylation sites presented in this study, researchers can look for variation that can predispose individuals to cardiac arrhythmias. Such attempts to elucidate mechanisms of arrhythmia thereby add yet another useful parameter in predicting susceptibility for cardiac diseases.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE; U.S. Food and Drug Administration (FDA)

Grant/Contract Number:: SC0014664

OSTI ID:: 1628324

Journal Information:: Genes, Vol. 5, Issue 2; ISSN 2073-4425

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

References (61)

Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project Biesecker, Leslie G. Genetics in Medicine, Vol. 14, Issue 4 https://doi.org/10.1038/gim.2011.78	journal	February 2012
Modulation of Cardiac Performance by Motor Protein Gene Transfer Herron, Todd J.; Devaney, Eric J.; Metzger, Joseph M. Annals of the New York Academy of Sciences, Vol. 1123, Issue 1 https://doi.org/10.1196/annals.1420.011	journal	March 2008
Hearing silence: non-neutral evolution at synonymous sites in mammals Chamary, J. V.; Parmley, Joanna L.; Hurst, Laurence D. Nature Reviews Genetics, Vol. 7, Issue 2 https://doi.org/10.1038/nrg1770	journal	February 2006
Vascular System: Role of Nitric Oxide in Cardiovascular Diseases Bian, Ka; Doursout, Marie-Françoise; Murad, Ferid The Journal of Clinical Hypertension, Vol. 10, Issue 4 https://doi.org/10.1111/j.1751-7176.2008.06632.x	journal	April 2008
GPS-SNO: Computational Prediction of Protein S-Nitrosylation Sites with a Modified GPS Algorithm Xue, Yu; Liu, Zexian; Gao, Xinjiao PLoS ONE, Vol. 5, Issue 6 https://doi.org/10.1371/journal.pone.0011290	journal	June 2010
CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart Chang, K. -C.; Barth, A. S.; Sasano, T. Proceedings of the National Academy of Sciences, Vol. 105, Issue 11 https://doi.org/10.1073/pnas.0709118105	journal	March 2008
Identification of S-nitrosylation motifs by site-specific mapping of the S-nitrosocysteine proteome in human vascular smooth muscle cells Greco, T. M.; Hodara, R.; Parastatidis, I. Proceedings of the National Academy of Sciences, Vol. 103, Issue 19 https://doi.org/10.1073/pnas.0600729103	journal	April 2006
Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study Massy, Z. A. Journal of the American Society of Nephrology, Vol. 15, Issue 2 https://doi.org/10.1097/01.ASN.0000106716.22153.BB	journal	February 2004
Characteristics and Prognostic Implications of Myosin Missense Mutations in Familial Hypertrophic Cardiomyopathy Watkins, Hugh; Rosenzweig, Anthony; Hwang, Dar-San New England Journal of Medicine, Vol. 326, Issue 17 https://doi.org/10.1056/NEJM199204233261703	journal	April 1992
The efficiency of folding of some proteins is increased by controlled rates of translation in vivo Purvis, Ian J.; Bettany, Andrew J. E.; Santiago, T. Chinnappan Journal of Molecular Biology, Vol. 193, Issue 2 https://doi.org/10.1016/0022-2836(87)90230-0	journal	January 1987
Taxol, a microtubule stabilizer, prevents ischemic ventricular arrhythmias in rats Xiao, Junjie; Cao, Huaming; Liang, Dandan Journal of Cellular and Molecular Medicine, Vol. 15, Issue 5 https://doi.org/10.1111/j.1582-4934.2010.01106.x	journal	June 2010
Congenital and acquired long QT syndrome Camm, A. European Heart Journal, Vol. 21, Issue 15 https://doi.org/10.1053/euhj.2000.2222	journal	August 2000
Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome Earle, Nikki; Yeo Han, Dug; Pilbrow, Anna Heart Rhythm, Vol. 11, Issue 1 https://doi.org/10.1016/j.hrthm.2013.10.005	journal	January 2014
Identifying potential functional impact of mutations and polymorphisms: linking heart failure, increased risk of arrhythmias and sudden cardiac death Jagu, Benoît; Charpentier, Flavien; Toumaniantz, Gilles Frontiers in Physiology, Vol. 4 https://doi.org/10.3389/fphys.2013.00254	journal	January 2013
Antithrombotic Therapy for Atrial Fibrillation You, John J.; Singer, Daniel E.; Howard, Patricia A. Chest, Vol. 141, Issue 2 https://doi.org/10.1378/chest.11-2304	journal	February 2012
Modeling the Heart--from Genes to Cells to the Whole Organ Noble, D. Science, Vol. 295, Issue 5560 https://doi.org/10.1126/science.1069881	journal	March 2002
Common variants in KCNN3 are associated with lone atrial fibrillation Ellinor, Patrick T.; Lunetta, Kathryn L.; Glazer, Nicole L. Nature Genetics, Vol. 42, Issue 3 https://doi.org/10.1038/ng.537	journal	February 2010
Fine Tuning of Proteomic Technologies to Improve Biological Findings: Advancements in 2011–2013 Mayne, Janice; Starr, Amanda E.; Ning, Zhibin Analytical Chemistry, Vol. 86, Issue 1 https://doi.org/10.1021/ac403551f	journal	November 2013
Identification of RNA editing sites in the SNP database Eisenberg, E. Nucleic Acids Research, Vol. 33, Issue 14 https://doi.org/10.1093/nar/gki771	journal	August 2005
The sounds of silence: synonymous mutations affect function Sauna, Zuben E.; Kimchi-Sarfaty, Chava; Ambudkar, Suresh V. Pharmacogenomics, Vol. 8, Issue 6 https://doi.org/10.2217/14622416.8.6.527	journal	June 2007
Associations between Genetic Variants in the NOS1AP (CAPON) Gene and Cardiac Repolarization in the Old Order Amish Post, Wendy; Shen, Haiqing; Damcott, Coleen Human Heredity, Vol. 64, Issue 4 https://doi.org/10.1159/000103630	journal	January 2007
Myocardial Diseases Roberts, R.; Schwartz, K. Circulation, Vol. 102, Issue Supplement 4 https://doi.org/10.1161/01.CIR.102.suppl_4.IV-34	journal	November 2000
A framework for organizing cancer-related variations from existing databases, publications and NGS data using a High-performance Integrated Virtual Environment (HIVE) Wu, Tsung-Jung; Shamsaddini, Amirhossein; Pan, Yang Database, Vol. 2014 https://doi.org/10.1093/database/bau022	journal	January 2014
A Bioinformatics Workflow for Variant Peptide Detection in Shotgun Proteomics Li, Jing; Su, Zengliu; Ma, Ze-Qiang Molecular & Cellular Proteomics, Vol. 10, Issue 5 https://doi.org/10.1074/mcp.M110.006536	journal	March 2011
Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure Nackley, A. G.; Shabalina, S. A.; Tchivileva, I. E. Science, Vol. 314, Issue 5807, p. 1930-1933 https://doi.org/10.1126/science.1131262	journal	December 2006
Monogenic atrial fibrillation as pathophysiological paradigms Mahida, S.; Lubitz, S. A.; Rienstra, M. Cardiovascular Research, Vol. 89, Issue 4 https://doi.org/10.1093/cvr/cvq381	journal	November 2010
A method and server for predicting damaging missense mutations Adzhubei, Ivan A.; Schmidt, Steffen; Peshkin, Leonid Nature Methods, Vol. 7, Issue 4 https://doi.org/10.1038/nmeth0410-248	journal	April 2010
SNVDis: A Proteome-wide Analysis Service for Evaluating nsSNVs in Protein Functional Sites and Pathways Karagiannis, Konstantinos; Simonyan, Vahan; Mazumder, Raja Genomics, Proteomics & Bioinformatics, Vol. 11, Issue 2 https://doi.org/10.1016/j.gpb.2012.10.003	journal	April 2013
Secondary Variants in Individuals Undergoing Exome Sequencing: Screening of 572 Individuals Identifies High-Penetrance Mutations in Cancer-Susceptibility Genes Johnston, Jennifer J.; Rubinstein, Wendy S.; Facio, Flavia M. The American Journal of Human Genetics, Vol. 91, Issue 1 https://doi.org/10.1016/j.ajhg.2012.05.021	journal	July 2012
Silent (Synonymous) SNPs: Should We Care About Them? Hunt, Ryan; Sauna, Zuben E.; Ambudkar, Suresh V. Methods in Molecular Biology https://doi.org/10.1007/978-1-60327-411-1_2	book	January 2009
S -Nitrosylation in Cardiovascular Signaling Lima, Brian; Forrester, Michael T.; Hess, Douglas T. Circulation Research, Vol. 106, Issue 4 https://doi.org/10.1161/CIRCRESAHA.109.207381	journal	March 2010
Common variants at ten loci modulate the QT interval duration in the QTSCD Study Pfeufer, Arne; Sanna, Serena; Arking, Dan E. Nature Genetics, Vol. 41, Issue 4 https://doi.org/10.1038/ng.362	journal	March 2009
The “missing” link in atrial fibrillation heritability Parvez, Babar; Darbar, Dawood Journal of Electrocardiology, Vol. 44, Issue 6 https://doi.org/10.1016/j.jelectrocard.2011.07.027	journal	November 2011
Protein S-nitrosylation: purview and parameters Hess, Douglas T.; Matsumoto, Akio; Kim, Sung-Oog Nature Reviews Molecular Cell Biology, Vol. 6, Issue 2 https://doi.org/10.1038/nrm1569	journal	February 2005
Cardiac electrophysiological effects of nitric oxide Tamargo, Juan; Caballero, Ricardo; Gómez, Ricardo Cardiovascular Research, Vol. 87, Issue 4 https://doi.org/10.1093/cvr/cvq214	journal	June 2010
FFAS03: a server for profile-profile sequence alignments Jaroszewski, L.; Rychlewski, L.; Li, Z. Nucleic Acids Research, Vol. 33, Issue Web Server https://doi.org/10.1093/nar/gki418	journal	July 2005
Proteome-Wide Analysis of Disease-Associated SNPs That Show Allele-Specific Transcription Factor Binding Butter, Falk; Davison, Lucy; Viturawong, Tar PLoS Genetics, Vol. 8, Issue 9 https://doi.org/10.1371/journal.pgen.1002982	journal	September 2012
A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization Arking, Dan E.; Pfeufer, Arne; Post, Wendy Nature Genetics, Vol. 38, Issue 6 https://doi.org/10.1038/ng1790	journal	April 2006
Proteome-Wide Analysis of Single-Nucleotide Variations in the N-Glycosylation Sequon of Human Genes Mazumder, Raja; Morampudi, Krishna Sudeep; Motwani, Mona PLoS ONE, Vol. 7, Issue 5 https://doi.org/10.1371/journal.pone.0036212	journal	May 2012
Screening of KCNN3 in patients with early-onset lone atrial fibrillation Olesen, Morten S.; Jabbari, Javad; Holst, Anders G. EP Europace, Vol. 13, Issue 7 https://doi.org/10.1093/europace/eur007	journal	March 2011
Database resources of the National Center for Biotechnology Information Sayers, E. W.; Barrett, T.; Benson, D. A. Nucleic Acids Research, Vol. 40, Issue D1 https://doi.org/10.1093/nar/gkr1184	journal	December 2011
Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart Cutler, M. J.; Plummer, B. N.; Wan, X. Proceedings of the National Academy of Sciences, Vol. 109, Issue 44 https://doi.org/10.1073/pnas.1210565109	journal	October 2012
Human Genome Sequencing in Health and Disease Gonzaga-Jauregui, Claudia; Lupski, James R.; Gibbs, Richard A. Annual Review of Medicine, Vol. 63, Issue 1 https://doi.org/10.1146/annurev-med-051010-162644	journal	February 2012
Cardiac channelopathies Marbán, Eduardo Nature, Vol. 415, Issue 6868 https://doi.org/10.1038/415213a	journal	January 2002
Identification of a Schizophrenia-Associated Functional Noncoding Variant in NOS1AP Wratten, Naomi S.; Memoli, Holly; Huang, Yungui American Journal of Psychiatry, Vol. 166, Issue 4 https://doi.org/10.1176/appi.ajp.2008.08081266	journal	April 2009
Genetic variation in SCN10A influences cardiac conduction Chambers, John C.; Zhao, Jing; Terracciano, Cesare M. N. Nature Genetics, Vol. 42, Issue 2 https://doi.org/10.1038/ng.516	journal	January 2010
Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias Herren, Anthony W.; Bers, Donald M.; Grandi, Eleonora American Journal of Physiology-Heart and Circulatory Physiology, Vol. 305, Issue 4 https://doi.org/10.1152/ajpheart.00306.2013	journal	August 2013
Detection and Validation of Non-synonymous Coding SNPs from Orthogonal Analysis of Shotgun Proteomics Data Bunger, Maureen K.; Cargile, Benjamin J.; Sevinsky, Joel R. Journal of Proteome Research, Vol. 6, Issue 6 https://doi.org/10.1021/pr0700908	journal	June 2007
Genomics, heart failure and sudden cardiac death Darbar, Dawood Heart Failure Reviews, Vol. 15, Issue 3 https://doi.org/10.1007/s10741-008-9095-9	journal	April 2008
Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders Yang, Yaping; Muzny, Donna M.; Reid, Jeffrey G. New England Journal of Medicine, Vol. 369, Issue 16 https://doi.org/10.1056/NEJMoa1306555	journal	October 2013
Congenital long QT syndrome: The race to refine risk Vickers Saarel, Elizabeth; Etheridge, Susan P. Heart Rhythm, Vol. 11, Issue 1 https://doi.org/10.1016/j.hrthm.2013.10.041	journal	January 2014
The role of the cytoskeleton in heart failure Hein, S. Cardiovascular Research, Vol. 45, Issue 2 https://doi.org/10.1016/s0008-6363(99)00268-0	journal	January 2000
Regulation of Protein Function and Signaling by Reversible Cysteine S-Nitrosylation Gould, Neal; Doulias, Paschalis-Thomas; Tenopoulou, Margarita Journal of Biological Chemistry, Vol. 288, Issue 37 https://doi.org/10.1074/jbc.r113.460261	journal	September 2013
Global analysis of disease-related DNA sequence variation in 10 healthy individuals: Implications for whole genome-based clinical diagnostics Moore, Barry; Hu, Hao; Singleton, Marc Genetics in Medicine, Vol. 13, Issue 3 https://doi.org/10.1097/gim.0b013e31820ed321	journal	February 2011
Red Blood Cell Nitric Oxide as an Endocrine Vasoregulator: A Potential Role in Congestive Heart Failure Datta, Borunendra; Tufnell-Barrett, Timothy; Bleasdale, Robert A. Circulation, Vol. 109, Issue 11 https://doi.org/10.1161/01.cir.0000124450.07016.1d	journal	March 2004
Hypertrophic cardiomyopathy mutation is expressed in messenger RNA of skeletal as well as cardiac muscle. Yu, Q. T.; Ifegwu, J.; Marian, A. J. Circulation, Vol. 87, Issue 2 https://doi.org/10.1161/01.cir.87.2.406	journal	February 1993
Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Parts I and II Priori, Silvia G.; Barhanin, Jacques; Hauer, Richard N. W. Circulation, Vol. 99, Issue 4 https://doi.org/10.1161/01.cir.99.4.518	journal	February 1999
Common Variants in Myocardial Ion Channel Genes Modify the QT Interval in the General Population: Results From the KORA Study Pfeufer, Arne; Jalilzadeh, Shapour; Perz, Siegfried Circulation Research, Vol. 96, Issue 6 https://doi.org/10.1161/01.res.0000161077.53751.e6	journal	April 2005
Increased Expression of Cytoskeletal, Linkage, and Extracellular Proteins in Failing Human Myocardium Heling, Annette; Zimmermann, René; Kostin, Sawa Circulation Research, Vol. 86, Issue 8 https://doi.org/10.1161/01.res.86.8.846	journal	April 2000
Myocardial Diseases Roberts, Robert; Schwartz, Ketty Circulation, Vol. 102, Issue suppl_4 https://doi.org/10.1161/circ.102.suppl_4.iv-34	journal	November 2000
Interpreting Secondary Cardiac Disease Variants in an Exome Cohort Ng, David; Johnston, Jennifer J.; Teer, Jamie K. Circulation: Cardiovascular Genetics, Vol. 6, Issue 4 https://doi.org/10.1161/circgenetics.113.000039	journal	August 2013

Cited By (2)

Molecular recognition of S-nitrosothiol substrate by its cognate protein denitrosylase Stomberski, Colin T.; Zhou, Hua-Lin; Wang, Liwen Journal of Biological Chemistry, Vol. 294, Issue 5 https://doi.org/10.1074/jbc.ra118.004947	journal	February 2019
Human germline and pan-cancer variomes and their distinct functional profiles Pan, Yang; Karagiannis, Konstantinos; Zhang, Haichen Nucleic Acids Research, Vol. 42, Issue 18 https://doi.org/10.1093/nar/gku772	journal	September 2014

Similar Records

Mutations that Cause Human Disease: A Computational/Experimental Approach

Technical Report · Wed Jan 11 00:00:00 EST 2006 · OSTI ID:1628324

Beernink, P; Barsky, D; Pesavento, B

Comparative genomic and proteomic analyses of Clostridium acetobutylicum Rh8 and its parent strain DSM 1731 revealed new understandings on butanol tolerance

Journal Article · Fri Aug 08 00:00:00 EDT 2014 · Biochemical and Biophysical Research Communications · OSTI ID:1628324

Bao, Guanhui; Dong, Hongjun; Zhu, Yan; +5 more

High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation

Journal Article · Thu Jan 01 00:00:00 EST 2015 · Toxicology and Applied Pharmacology · OSTI ID:1628324

Chapalamadugu, Kalyan C.; Panguluri, Siva K.; Bennett, Eric S.; +1 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
cardiac arrhythmia
SNP
genome-wide association
proteomics
next-generation sequencing
S-nitrosylation
cysteine
nsSNV
biocuration

Title: Single-Nucleotide Variations in Cardiac Arrhythmias: Prospects for Genomics and Proteomics Based Biomarker Discovery and Diagnostics

Citation Formats

References (61)

Cited By (2)

Similar Records

Related Subjects