细胞膜钙转运ATP酶1基因变异影响高血压及血管功能的机制研究

In the results of genome wide association studies (GWAS) of Global Blood Pressure Genetics (Global BPgen) consortium and the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium, plasma membrane calcium transporting ATPase 1 (ATP2B1) was the unique gene that related to both blood pressure level and hypertension among the 14 highlight loci. In our previous study of Agen BP GWAS and replication in Chinese population, we also confirmed the association of ATP2B1 gene with hypertension. However, all the susceptive loci were at non-coding region, which acted as target only. Accordingly, we developed the following hypotheses: certain functional mutant may locate at ATP2B1 gene, which can reduce the activity of Ca2+-ATPase and increase the intracellular calcium concentration in vascular smooth muscular cell, and then induce hypertension. To identify functional SNPs conferring susceptibility to hypertension, we conducted a case-control study in hypertension family, prospective hypertension cohort and general population. The SNPs were selected according to the latest map of 1000 Genomes Project, including all the rare and common mutants in ATP2B1 gene region. Furthermore, the functional study would be performed to verify the pathogenesis of the susceptive loci.

在CHARGE和Global BPgen血压相关全基因组关联研究结果中，细胞膜钙转运ATP酶1（ATP2B1）是唯一与血压水平和高血压均相关的基因。我们前期参与的东亚人群全基因组关联研究和最近进行的中国人群验证研究，也证实该基因与高血压相关。但发现的阳性位点均处于非编码区，仅起标记作用，无法解释其生物功能。因此我们推测，ATP2B1基因可能存在功能性突变位点，他们可降低钙-ATP酶活性，导致血管平滑肌细胞内钙浓度增高，血管张力增强而引起血压升高。为验证以上假设，我们拟在既往研究基础上进一步深入：1）利用已收集的高血压家系和前瞻性队列，系统筛查ATP2B1基因包括罕见变异在内的全部编码区突变，以发现与高血压及血管功能相关的功能位点；2）在5000例自然人群中，验证发现的阳性位点对于人群血压水平的影响；3）分析阳性位点对蛋白表达及活性的影响。从而阐释ATP2B1基因在高血压发生、发展中的作用。

高血压是世界性的健康问题，遗传因素在其发生过程中起重要作用。多项全基因组关联研究均提示细胞膜钙转运ATP酶1（ATP2B1）与高血压及血压水平密切相关，但是具体生物机制尚不明确。本研究在1040例高血压家系样本和1092例血压正常队列样本中，分别对ATP2B1编码区域的功能位点进行筛查。同时研究了ATP2B1，MTHFR和PLA2G7基因与高血压及高血压动脉硬化的相关性。并且分析了多种炎症因子及血压标志与高血压患者颅内动脉狭窄的相关性。结果发现ATP2B1-rs1401982与高血压患者颅外动脉斑块和钙化相关；rs17249754、rs3741895与rs2070759颅内血管斑块形成相关；rs7975689与颅外动脉狭窄相关；rs17249754与颅外动脉钙化相关；rs12423192与颅内外动脉钙化相关。PLA2G7- rs7756935与颅内动脉斑块形成有关；rs16874967和rs1805018与颅内动脉狭窄相关；rs1805017和rs1421378与颅外动脉狭窄相关；rs76863441与颅外动脉钙化形成相关。血浆Lp-PLA2水平仅与高血压患者颅内动脉狭窄相关而与颅外动脉狭窄无关。还发现血浆同型半胱氨酸与颅内外动脉狭窄相关，而且该相关性受MTHFR-C677T影响。对于血压标志与高血压动脉硬化的分析中，发现双臂间收缩压差值与高血压患者颅外动脉狭窄相关，而舒张压差值与颅内动脉狭窄相关。