Knez Judita, Salvi Erika, Tikhonoff Valérie, Stolarz-Skrzypek Katarzyna, Ryabikov Andrew, Thijs Lutgarde, Braga Daniele, Kloch-Badelek Malgorzata, Malyutina Sofia, Casiglia Edoardo, Czarnecka Danuta, Kawecka-Jaszcz Kalina, Cusi Daniele, Nawrot Tim, Staessen Jan A, Kuznetsova Tatiana
KU Leuven Department of Cardiovascular Sciences, Research Unit Hypertension and Cardiovascular Epidemiology, University of Leuven, Leuven, Belgium.
Hypertension Division, Department of Internal Medicine, University Clinical Centre Ljubljana, Ljubljana, Slovenia.
BMC Med Genet. 2014 Nov 4;15:121. doi: 10.1186/s12881-014-0121-6.
Left ventricular (LV) function depends on the activity of transmembrane electrolyte transporters. Failing human myocardium has lower Na(+)/K(+) ATPase expression and higher intracellular sodium concentrations. The ATP12A gene encodes a catalytic subunit of an ATPase that can function as a Na(+)/K(+) pump. We, therefore, investigated the association between LV function and common genetic variants in ATP12A.
A random sample of 1166 participants (53.7% women; mean age 49.5 years, 44.8% hypertensive) was recruited in Belgium, Poland, Italy and Russia. We measured transmitral early and late diastolic velocities (E and A) by pulsed wave Doppler, and mitral annular velocities (e' and a') by tissue Doppler. Using principal component analysis, we summarized 7 Doppler indexes - namely, E, A, e' and a' velocities, and their ratios (E/A, e'/a', and E/e') - into a single diastolic score. We genotyped 5 tag SNPs (rs963984, rs9553395, rs10507337, rs12872010, rs2071490) in ATP12A. In our analysis we focused on rs10507337 because it is located within a transcription factor binding site.
In the population-based analyses while adjusting for covariables and accounting for family clusters and country, rs10507337 C allele carriers had significantly higher E/A (P = 0.003), e' (P = 5.8×10(-5)), e'/a' (P = 0.003) and diastolic score (P = 0.0001) compared to TT homozygotes. Our findings were confirmed in the haplotype analysis and in the family-based analyses in 74 informative offspring.
LV diastolic function as assessed by conventional and tissue Doppler indexes including a composite diastolic score was associated with genetic variation in ATP12A. Further experimental studies are necessary to clarify the role of ATP12A in myocardial relaxation.
左心室（LV）功能取决于跨膜电解质转运蛋白的活性。衰竭的人类心肌中钠钾ATP酶表达降低，细胞内钠浓度升高。ATP12A基因编码一种可作为钠钾泵发挥作用的ATP酶催化亚基。因此，我们研究了LV功能与ATP12A常见基因变异之间的关联。
在比利时、波兰、意大利和俄罗斯招募了1166名参与者的随机样本（53.7%为女性；平均年龄49.5岁，44.8%为高血压患者）。我们通过脉冲波多普勒测量二尖瓣舒张早期和晚期速度（E和A），并通过组织多普勒测量二尖瓣环速度（e'和a'）。使用主成分分析，我们将7个多普勒指标——即E、A、e'和a'速度及其比值（E/A、e'/a'和E/e'）——汇总为一个单一的舒张期评分。我们对ATP12A中的5个标签单核苷酸多态性（rs963984、rs9553395、rs10507337、rs12872010、rs2071490）进行基因分型。在我们的分析中，我们重点关注rs10507337，因为它位于一个转录因子结合位点内。
在基于人群的分析中，在调整协变量并考虑家族聚类和国家因素后，与TT纯合子相比，rs10507337 C等位基因携带者的E/A（P = 0.003）、e'（P = 5.8×10⁻⁵）、e'/a'（P = 0.003）和舒张期评分（P = 0.0001）显著更高。我们的发现在单倍型分析和对74名有信息价值的后代进行的基于家族的分析中得到了证实。
通过传统和组织多普勒指标（包括综合舒张期评分）评估的LV舒张功能与ATP12A的基因变异有关。需要进一步的实验研究来阐明ATP12A在心肌舒张中的作用。
