Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Relations gène/fonction dans les canalopathies cardiaques

La fonction contractile du cœur dépend de l'organisation et de l'activité électrique de cellules musculaires spécialisées. Cette activité électrique dépend elle-même de l'activité d'une multitude de canaux ioniques responsables de différents courants ioniques. L'altération d'origine génétique de certains canaux, sont responsables de troubles du rythme conduisant à la mort subite. Des mutations du canal sodique cardiaque SCN5A sont responsables du syndrome du QT long, du syndrome de Brugada et de troubles de conduction. Dans un système d'expression recombinant nous avons montré que les troubles de conduction cardiaque étaient dues à une haplo-insuffisance du canal sodique cardiaque SCN5A. Cette haplo-insuffisance, en fonction de la famille atteinte, peut induire des troubles de conduction progressifs ou non progressifs. Nous avons également montré qu'une mutation du gène SCN5A peut induire dans une même famille soit un syndrome de Brugada soit des troubles de conduction. Cette mutation induit une perte de fonction du canal. Des mutations du canal potassique KvLQT1 entraînent les syndromes de Romano-Ward ou Jervell et Lange-Nielsen. La forme récessive (JLN) est associée à une surdité. Nous avons montré que la régulation par la protéine kinase A du complexe canal KvLQT1/Isk, dans les systèmes d'expression hétérologue, nécessite la présence d'une protéine d'ancrage de la protéine kinase A (AKAP). Par une approche de localisation, nous avons montré que dans les cellules COS-7 l'isoforme 2 de KvLQT1 est localisé dans le réticulum endoplasmique (RE) et exerce son effet dominant négative sur l'isoforme 1 (isoforme canal) par rétention dans le RE. Nous montrons également une corrélation entre la conservation de la rétention de l'isoforme 1 dans le RE par l'isoforme 2 de KvLQT1 et les syndromes de RW et de JLN. En effet, contrairement aux isoformes 2 mutées de type RW, les isoformes 2 mutées de type JLN perdent leur capacité à retenir l'isoforme canal dans le RE.The contractile function of the heart depends on the organization and on the electric activity of specialized muscular cells. This electric activity depends on the activity of a multitude of ionic channels responsible for various ionic currents. Genetic alteration of certain channels are responsible for cardiac arrhytmias leading to sudden death. Mutations of the cardiac sodium channel SCN5A are responsible for the long QT syndrome, Brugada syndrome and conduction disorders. In a recombinant expression system we showed that haploinsufficiency of the cardiac sodium channel SCN5A is responsible for the conduction disorders. This haploinsufficiency, according to the affected family, can lead to progressive or not progressive conduction disorders. We also showed that an SCN5A mutation can lead in the same family either Brugada syndrome or conduction disorders. This mutation induces a loss of channel function. Mutations of the potassium channel KVLQT1 have been identified as responsible for both Romano-Ward (RW) and Jervell and Lange-Nielsen (JLN) inhereted long QT syndromes. Récessive JLN syndrome is associated with deafness. We showed that channel-complex KvLQT1/IsK regulation by the A kinase protein in a recombinant expression system requires the presence of an A kinase anchoring protein (AKAP). By an approach of cell localization, we showed that in COS-7 cells the KVLQT1 isoform 2 is localized in the endoplasmic reticulum (ER) and exercises its negative dominance on the isoform 1 (channel isoform) by retention in the ER. We also show a correlation enter the conservation of the isoform 1 retention in the ER by the isoform 2 of KVLQT1 and the RW and JLN syndromes. Indeed, contrary to isoforme 2 RW mutations, isoformes 2 JLN mutations lost their capacity to retain the channel is form in the ER.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Torsades de pointes complicating atrioventricular block: evidence for a genetic predisposition.

BACKGROUND: The prevalence of genetic risk factors has not been systematically evaluated in the setting of complete atriventricular (AV) block complicated by long QT syndrome (LQTS). OBJECTIVE: This study was performed to determine to what extent acquired LQTS in the context of AV block has a genetic substrate. METHODS: Among 420 recipients of pacemakers implanted over a 3-year period, we identified retrospectively 29 patients with complete AV block and a QT interval >600 ms in duration. A second study group included 22 randomly selected patients who had AV block and a QT interval <600 ms. Normal controls were 100 consecutive individuals without medical history. Genetic studies screening for HERG, KCNQ1 KCNE1, KCNE2, and SCN5A mutations were performed. RESULTS: We identified four mutations on genes encoding potassium channels in five patients with AV block and acquired LQTS. These mutations were not found among patients with AV block and a QT interval <600 ms in duration or in healthy volunteers. Functional expression of three HERG mutations (R328C, R696C, and R1047L) had a dominant negative effect on wild-type I(Kr). One KCNE2 mutation (R77W) identified in a patient treated with flecainide did not alter I(Kr). CONCLUSIONS: This study showed that complete AV block complicated by LQTS was associated with HERG mutations in 17% of cases. Further studies are needed to identify factors, genetic or environmental, which may be implicated in bradycardia-related abnormalities of ventricular repolarization