Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction

Vincenzo Macri; Jennifer A Brody; Dan E Arking; William J Hucker; Xiaoyan Yin; Honghuang Lin; Robert W Mills; Moritz F Sinner; Steven A Lubitz; Ching-Ti Liu; Alanna C Morrison; Alvaro Alonso; Ning Li; Vadim V Fedorov; Paul M Janssen; Joshua C Bis; Susan R Heckbert; Elena V Dolmatova; Thomas Lumley; Colleen M Sitlani; L Adrienne Cupples; Sara L Pulit; Christopher Newton-Cheh; John Barnard; Jonathan D Smith; David R Van Wagoner; Mina K Chung; Gus J Vlahakes; Christopher J O'Donnell; Jerome I Rotter; Kenneth B Margulies; Michael P Morley; Thomas P Cappola; Emelia J Benjamin; Donna Muzny; Richard A Gibbs; Rebecca D Jackson; Jared W Magnani; Caroline N Herndon; Stephen S Rich; Bruce M Psaty; David J Milan; Eric Boerwinkle; Peter J Mohler; Nona Sotoodehnia; Patrick T Ellinor

doi:10.1161/CIRCGEN.116.001663

Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction

Circ Genom Precis Med. 2018 May;11(5):e001663. doi: 10.1161/CIRCGEN.116.001663.

Authors

Vincenzo Macri¹, Jennifer A Brody², Dan E Arking³, William J Hucker^{1

4}, Xiaoyan Yin^{5

6}, Honghuang Lin^{5

7}, Robert W Mills¹, Moritz F Sinner⁸, Steven A Lubitz^{1

4}, Ching-Ti Liu⁶, Alanna C Morrison⁹, Alvaro Alonso¹⁰, Ning Li¹¹, Vadim V Fedorov¹¹, Paul M Janssen¹¹, Joshua C Bis², Susan R Heckbert^{2

12}, Elena V Dolmatova¹, Thomas Lumley¹², Colleen M Sitlani², L Adrienne Cupples^{5

6}, Sara L Pulit^{1

13}, Christopher Newton-Cheh^{1

14

15}, John Barnard¹⁶, Jonathan D Smith^{17

18}, David R Van Wagoner^{17

19}, Mina K Chung^{17

19}, Gus J Vlahakes²⁰, Christopher J O'Donnell²⁰, Jerome I Rotter²¹, Kenneth B Margulies^{22

23}, Michael P Morley^{22

23}, Thomas P Cappola^{22

23}, Emelia J Benjamin^{24

25

26}, Donna Muzny²⁷, Richard A Gibbs²⁷, Rebecca D Jackson²⁸, Jared W Magnani²⁹, Caroline N Herndon³⁰, Stephen S Rich³¹, Bruce M Psaty³², David J Milan^{1

4}, Eric Boerwinkle^{9

27}, Peter J Mohler¹¹, Nona Sotoodehnia^{33

34}, Patrick T Ellinor^{1

4

30}

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital, Charlestown (V.M., W.J.H., R.W.M., S.A.L., E.V.D., S.L.P., C.N.-C., D.J.M., P.T.E.).
² Cardiovascular Health Research Unit, Department of Medicine (J.A.B., J.C.B., S.R.H., C.M.S., N.S.).
³ University of Washington, Seattle. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.).
⁴ Cardiac Arrhythmia Service (W.J.H., S.A.L., D.J.M., P.T.E.).
⁵ Massachusetts General Hospital, Boston. NHLBI's & Boston University's Framingham Heart Study, MA (X.Y., H.L., L.A.C.).
⁶ Department of Biostatistics (X.Y., L.A.C., C.-T.L.).
⁷ School of Public Health, Boston University, MA. Computational Biomedicine Section (H.L.).
⁸ Department of Medicine, Boston University School of Medicine, MA. German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance, Germany and Department of Medicine I, University Hospital Munich, Ludwig-Maximilian's University, Munich, Germany (M.F.S.).
⁹ Human Genetics Center, University of Texas Health Science Center at Houston (A.C.M., E.B.).
¹⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).
¹¹ Department of Physiology & Cell Biology and Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (N.L., V.V.F., P.M.J., P.J.M.).
¹² Department of Epidemiology (S.R.H., T.L.).
¹³ Department of Statistics, University of Auckland, New Zealand (S.L.P.).
¹⁴ Center for Genomic Medicine (C.N.-C.).
¹⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (C.N.-C.).
¹⁶ Department of Quantitative Health Sciences, Lerner Research Institute (J.B.).
¹⁷ Department of Cardiovascular Medicine, Heart and Vascular Institute (J.D.S., D.R.V.W., M.K.C.).
¹⁸ Department of Cellular and Molecular Medicine Biology, Lerner Research Institute (J.D.S.).
¹⁹ Department of Molecular Cardiology, Lerner Research Institute (D.R.V.W., M.K.C.).
²⁰ Cardiology Division (G.J.V., C.J.O.).
²¹ Cleveland Clinic, OH. Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute & Department of Pediatrics, Harbor-UCLA Medical Center, Torrance (J.I.R.).
²² Penn Cardiovascular Institute, Perelman School of Medicine (K.B.M., M.P.M., T.P.C.).
²³ Department of Medicine, Perelman School of Medicine (K.B.M., M.P.M., T.P.C.).
²⁴ Department of Epidemiology (E.J.B.).
²⁵ Preventive Medicine Section (E.J.B.).
²⁶ Cardiology Section (E.J.B.).
²⁷ University of Pennsylvania, Philadelphia. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (D.M.M., R.A.G., E.B.).
²⁸ Division of Endocrinology, Diabetes and Metabolism, College of Medicine, The Ohio State University, Columbus (R.D.J.).
²⁹ Division of Cardiology, Department of Medicine, UPMC Heart and Vascular Institute (J.W.M.).
³⁰ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (C.N.H., P.T.E.).
³¹ Center for Public Health Genomics, University of Virginia, Charlottesville (S.S.R.).
³² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle; and Kaiser Permanente Washington Health Research Institute, Seattle, WA. (B.M.P.).
³³ Cardiovascular Health Research Unit, Department of Medicine (J.A.B., J.C.B., S.R.H., C.M.S., N.S.) [email protected].
³⁴ Division of Cardiology (N.S.).

Abstract

Background: Genetic variants at the SCN5A/SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized.

Methods: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

Results: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (r ²=0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, P=1.52×10^-14) and QRS intervals (rs6599251, QRS β=-0.73; P=1.2×10^-4), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium (r ²≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P=0.03, and I962V+V1073A, 22.4±0.8%, P=0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P=0.03).

Conclusions: Our findings suggest an association between genetic variation in SCN10A, the late sodium current, and alterations in cardiac conduction.

Keywords: Na+ channels; atrial fibrillation; electrocardiography; genetics; haplotypes; population.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biophysical Phenomena
Electrocardiography
Genetic Association Studies*
Haplotypes / genetics
Heart Conduction System / metabolism*
Humans
Ion Channel Gating / genetics*
Mutation, Missense / genetics
NAV1.8 Voltage-Gated Sodium Channel / genetics*
Polymorphism, Single Nucleotide / genetics*
Quantitative Trait Loci / genetics

Substances

NAV1.8 Voltage-Gated Sodium Channel
SCN10A protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding