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    • P1233Differential Effects of Five Risk Variants for Atrial Fibrillation at the 4q25 Region on L-type Calcium Current and Transient Inward Currents in Human Atrial Myocytes

    C. Tarifa,A. Herraiz-Martinez,A. Llach,V. Jimenez-Sabado,H. Colino, E. Lozano-Velazquez,D. Franco, E. Rosello,E. Rodriguez-Font,J. Cinca,L. Hove-Madsen

    European heart journal（2019）SCI 1区

    CSIC

    Cited 0|Views77
    Abstract
    Abstract Background An increasing number of single nucleotide polymorphisms (SNPs) at the chromosomal region 4q25 have been associated with risk of atrial fibrillation (AF) and we have recently reported that carriers of the rs13143308 risk variant have an increased incidence of spontaneous calcium release-induce transient inward currents (ITI). However, it is not known if different 4q25 variants have similar effects. Purpose This study aimed to compare the effects of five SNPs at 4q25 on L-type calcium current (ICa) and ITI frequency, features that are altered in patients with AF. Methods To avoid confounding effects of AF on calcium homeostasis, atrial samples from 63 patients without AF were genotyped and divided into groups according to the genotype of the SNPs rs1448818, rs6817105, rs13143308, rs6843082, rs3853443 ordered according to their location and identified by the three last digits + an R for risk or N for normal variants. ICa density and ITI frequency were measured with perforated patch clamp technique in atrial myocytes from these patients. Results Three SNPs 818, 308 and 443 segregated independently of the genotype at the other loci. The 105 and 082 loci always co-segregated with 308 but never together. The ICa density was smaller in carriers of 818R and 443N variants (−1.6±0.3pA/pF, p=0.01) or 818N and 443R variants (−1.6±0.4pA/pF, p=0.02) than in patients with 818N and 443N variants (−3.2±0.4pA/pF), independently of the genotype at 105, 308 and 082 (these loci did not affect ICa). In contrast, to this, the ITI frequency was increased only in myocytes from patients carrying 105R, 308R and 082N (1.4±0.2events/min, p<0.001) or 105N, 308R and 082R (1.6±0.5events/min, p=0.002) when compared to patients with 105N, 308N and 082N (0.36±0.09events/min) independently of the genotypes at 818 and 443, or when compared to patients without risk at any of the five loci (0.55±0.30events/min). The table shows schematically the qualitative effects of the different risk variants. Risk variant rs1448818C rs6817105C rs13143308T rs6843082T rs3853445C ICa Decreased Unchanged Unchanged Unchanged Decreased ITI Unchanged Increased Increased Increased Unchanged Conclusion Different SNPs at the chromosomal region 4q25 are associated with differential pathological changes in intracellular calcium homeostasis. Risk variants at rs1448818 or rs3853445 cause loss of ICa without affecting ITI frequency while a risk variant at rs13143308 elevates the ITI frequency without affecting ICa. These findings afford a framework for stratification of pharmacological therapy based on the functional effects of the 4q25 risk variants Acknowledgement/Funding SAF2017-88019; Marato2015-20-30; SGR2017-1769; CIBERCV
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    【要点】：研究揭示了位于4q25区域的五个风险单核苷酸多态性（SNPs）对人心房肌细胞L型钙电流（ICa）和短暂内向电流（ITI）的不同影响，为基于风险变异功能效应的心房颤动（AF）药物治疗分层提供了框架。
    

    【方法】：通过基因分型将63名无房颤患者的 atrial 样本分为不同组别，利用穿孔膜片钳技术测量了人心房肌细胞的 ICa 密度和 ITI 频率。
    

    【实验】：实验在无房颤患者的 atrial myocytes 上完成，使用的数据集为患者基因分型及电流测量结果。研究发现，携带 rs1448818 或 rs3853445 风险变异的患者 ICa 降低而不影响 ITI 频率，而 rs13143308 风险变异则增加 ITI 频率而不影响 ICa。
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