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

TitleCommon Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction.
Publication TypeJournal Article
Year of Publication2018
AuthorsMacri, V, Brody, JA, Arking, DE, Hucker, WJ, Yin, X, Lin, H, Mills, RW, Sinner, MF, Lubitz, SA, Liu, C-T, Morrison, AC, Alonso, A, Li, N, Fedorov, VV, Janssen, PM, Bis, JC, Heckbert, SR, Dolmatova, EV, Lumley, T, Sitlani, CM, L Cupples, A, Pulit, SL, Newton-Cheh, C, Barnard, J, Smith, JD, Van Wagoner, DR, Chung, MK, Vlahakes, GJ, O'Donnell, CJ, Rotter, JI, Margulies, KB, Morley, MP, Cappola, TP, Benjamin, EJ, Muzny, DM, Gibbs, RA, Jackson, RD, Magnani, JW, Herndon, CN, Rich, SS, Psaty, BM, Milan, DJ, Boerwinkle, E, Mohler, PJ, Sotoodehnia, N, Ellinor, PT
JournalCirc Genom Precis Med
Volume11
Issue5
Paginatione001663
Date Published2018 05
ISSN2574-8300
KeywordsBiophysical Phenomena, Electrocardiography, Genetic Association Studies, Haplotypes, Heart Conduction System, Humans, Ion Channel Gating, Mutation, Missense, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract

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

METHODS: We sequenced the 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 (  =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium (  ≥0.72) with a common 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%, =0.03, and I962V+V1073A, 22.4±0.8%, =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%, =0.03).

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

DOI10.1161/CIRCGEN.116.001663
Alternate JournalCirc Genom Precis Med
PubMed ID29752399
PubMed Central IDPMC6377236
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
HHSN268201500001I / NHLBI NIH HHS / National Heart, Lung, and Blood Institute / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
UL1 TR002548 / TR / NCATS NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / NHLBI NIH HHS / National Heart, Lung, and Blood Institute / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268201000011C / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
R01 HL128914 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL088456 / HL / NHLBI NIH HHS / United States
R01 HL090620 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
UL1 RR024989 / NCRR NIH HHS / National Center for Research Resources / United States
HHSN268200800007C / NHLBI NIH HHS / National Heart, Lung, and Blood Institute / United States
R01 HL105993 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
R01 HL111314 / HL / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
R01 HL088577 / HL / NHLBI NIH HHS / United States
UC2 HL102924 / HL / NHLBI NIH HHS / United States
R01 HL115580 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 HL135109 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
HHSN268201800001C / NHLBI NIH HHS / National Heart, Lung, and Blood Institute / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States
R01 HL111089 / HL / NHLBI NIH HHS / United States
R01 HL116747 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States