03950nas a2200685 4500008004100000022001400041245009900055210006900154260001300223300001200236490000700248520197400255100002002229700002302249700001902272700002302291700001702314700001902331700002102350700002202371700002202393700001802415700002402433700001902457700001302476700002202489700002102511700001902532700002302551700002402574700001902598700002402617700002502641700001902666700002902685700001802714700002302732700002602755700001902781700002102800700003002821700002202851700002602873700002302899700002302922700002402945700001702969700002202986700002403008700002203032700002503054700002103079700002003100700002003120700002103140700002103161700002203182700002403204856003603228 2018 eng d a2574-830000aCommon Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction.0 aCommon Coding Variants in Are Associated With the Nav18 Late Cur c2018 May ae0016630 v113 a
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.
1 aMacri, Vincenzo1 aBrody, Jennifer, A1 aArking, Dan, E1 aHucker, William, J1 aYin, Xiaoyan1 aLin, Honghuang1 aMills, Robert, W1 aSinner, Moritz, F1 aLubitz, Steven, A1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aAlonso, Alvaro1 aLi, Ning1 aFedorov, Vadim, V1 aJanssen, Paul, M1 aBis, Joshua, C1 aHeckbert, Susan, R1 aDolmatova, Elena, V1 aLumley, Thomas1 aSitlani, Colleen, M1 aCupples, Adrienne, L1 aPulit, Sara, L1 aNewton-Cheh, Christopher1 aBarnard, John1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aChung, Mina, K1 aVlahakes, Gus, J1 aO'Donnell, Christopher, J1 aRotter, Jerome, I1 aMargulies, Kenneth, B1 aMorley, Michael, P1 aCappola, Thomas, P1 aBenjamin, Emelia, J1 aMuzny, Donna1 aGibbs, Richard, A1 aJackson, Rebecca, D1 aMagnani, Jared, W1 aHerndon, Caroline, N1 aRich, Stephen, S1 aPsaty, Bruce, M1 aMilan, David, J1 aBoerwinkle, Eric1 aMohler, Peter, J1 aSotoodehnia, Nona1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/7802