Fibroblast growth factor 1 gene and hypertension: from the quantitative trait locus to positional analysis.
Fibroblast growth factor 1 gene and hypertension: from the quantitative trait locus to positional analysis.
复制标题
成纤维细胞生长因子1基因与高血压：从数量性状基因座到位置分析。
DOI：
10.1161/circulationaha.107.710293
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发表时间：
2007
期刊：
影响因子：
37.8
通讯作者：
Dominiczak,AnnaF
中科院分区：
文献类型：
--
作者：
Tomaszewski,Maciej;Charchar,FadiJ;Lynch,MarkD;Padmanabhan,Sandosh;Wang,WilliamYS;Miller,WilliamH;Grzeszczak,Wladyslaw;Maric,Christine;Zukowska-Szczechowska,Ewa;Dominiczak,AnnaF
方法和结果--在Silesian高血压研究中，在这个数量性状座位下的微卫星标记网格(来自2 0 7个波兰高血压家系的6 2 9名个体)为该区域与血压的连锁提供了更多的支持(最大Z=3.5 1，P=0.0002)。精细定位、比较基因组学和功能优先排序确定成纤维细胞生长因子1基因(FGF1)是位置候选基因。基于51个单核苷酸多态的连锁不平衡作图显示，FGF1的3个独立单倍体与相邻的基因外染色体区域之间没有重叠。单、多位点家系分析显示，FGF1单倍区1的遗传变异与高血压相关，并发现常见的内含子单核苷酸多态rs152524是这种关联的主要驱动因素(P=0.0026)。实时定量聚合酶链式反应和Western blotting分析显示，与正常血压对照组相比，高血压患者肾组织中FGF1的mRNA和蛋白表达均增加。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。结论--我们的数据表明，在高血压家系中，FGF1基因变异与血压升高有关，这种关联可能是由肾脏FGF1表达上调所介导的。我们的研究结果需要在其他队列中复制。
Background—The distal portion of the long arm of chromosome 5 is linked to hypertension and contains functional candidate blood pressure–regulating genes.Methods and Results—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 (maximalZ=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.Conclusions—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.