Tomaszewski Maciej, Charchar Fadi J, Lynch Mark D, Padmanabhan Sandosh, Wang William Y S, Miller William H, Grzeszczak Wladyslaw, Maric Christine, Zukowska-Szczechowska Ewa, Dominiczak Anna F
British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Circulation. 2007 Oct 23;116(17):1915-24. doi: 10.1161/CIRCULATIONAHA.107.710293. Epub 2007 Oct 1.
The distal portion of the long arm of chromosome 5 is linked to hypertension and contains functional candidate blood pressure-regulating genes.
Tightening the grid of microsatellite markers under this quantitative trait locus in the Silesian Hypertension Study (629 individuals from 207 Polish hypertensive families) provided enhanced support for linkage of this region to blood pressure (maximal Z=3.51, P=0.0002). The fine mapping, comparative genomics, and functional prioritization identified fibroblast growth factor 1 gene (FGF1) as the positional candidate. Linkage disequilibrium mapping based on 51 single nucleotide polymorphisms spanning the locus showed no overlap between 3 independent haploblocks of FGF1 and the adjacent extragenic chromosomal regions. Single and multilocus family-based analysis revealed that genetic variation within FGF1 haploblock 1 was associated with hypertension and identified a common intronic single nucleotide polymorphism, rs152524, as the major driver of this association (P=0.0026). Real-time quantitative polymerase chain reaction and Western blotting analysis of renal tissue obtained from subjects undergoing unilateral nephrectomy showed an increase in both mRNA and protein FGF1 expression in hypertensive patients compared with normotensive controls. Renal immunohistochemistry revealed that FGF1 was expressed exclusively within the glomerular endothelial and mesangial cells.
Our data demonstrate that genetic variation within FGF1 cosegregates with elevated blood pressure in hypertensive families and that this association is likely to be mediated by upregulation of renal FGF1 expression. The results of our study will need to be replicated in other cohorts.
5号染色体长臂的远端与高血压相关,且包含功能性的候选血压调节基因。
在西里西亚高血压研究(来自207个波兰高血压家族的629名个体)中,收紧该数量性状基因座下的微卫星标记网格,为该区域与血压的连锁提供了更强的支持(最大Z值 = 3.51,P = 0.0002)。精细定位、比较基因组学和功能优先级分析确定成纤维细胞生长因子1基因(FGF1)为位置候选基因。基于跨越该基因座的51个单核苷酸多态性的连锁不平衡图谱显示,FGF1的3个独立单倍体区域与相邻的基因外染色体区域之间没有重叠。基于单基因座和多基因座的家系分析表明,FGF1单倍体区域1内的基因变异与高血压相关,并确定一个常见的内含子单核苷酸多态性rs152524是这种关联的主要驱动因素(P = 0.0026)。对接受单侧肾切除术的受试者的肾组织进行实时定量聚合酶链反应和蛋白质印迹分析表明,与血压正常的对照组相比,高血压患者肾组织中FGF1的mRNA和蛋白质表达均增加。肾脏免疫组织化学显示,FGF1仅在肾小球内皮细胞和系膜细胞中表达。
我们的数据表明,高血压家族中FGF1内的基因变异与血压升高共分离,这种关联可能是由肾FGF1表达上调介导的。我们研究的结果需要在其他队列中进行重复验证。