Glorioso Nicola, Herrera Victoria L M, Bagamasbad Pia, Filigheddu Fabiana, Troffa Chiara, Argiolas Giuseppe, Bulla Emanuela, Decano Julius L, Ruiz-Opazo Nelson
Hypertension and Cardiovascular Prevention Center, ASL n. 1-Universita di Sassari, Sassari, Sardinia, Italy.
Circ Res. 2007 May 25;100(10):1522-9. doi: 10.1161/01.RES.0000267716.96196.60. Epub 2007 Apr 19.
Essential hypertension remains a major risk factor for cardiovascular and cerebrovascular diseases. As a complex multifactorial disease, elucidation of susceptibility loci remains elusive. ATP1A1 and Dear are candidate genes for 2 closely linked rat chromosome-2 blood pressure quantitative trait loci. Because corresponding human syntenic regions are on different chromosomes, investigation of ATP1A1 (chromosome [chr]-1p21) and Dear (chr-4q31.3) facilitates genetic analyses of each blood pressure quantitative trait locus in human hypertension. Here we report the association of human ATP1A1 (P<0.000005) and Dear (P<0.03) with hypertension in a relatively isolated, case/control hypertension cohort from northern Sardinia by single-nucleotide polymorphism haplotype analysis. Sex-specific haplotype analyses detected stronger association of both loci with hypertension in males than in females. Haplotype trend-regression analyses support ATP1A1 and Dear as independent susceptibility loci and reveal haplotype-specific association with hypertension and normotension, thus delineating haplotype-specific subsets of hypertension. Although investigation in other cohorts needs to be performed to determine genetic effects in other populations, haplotype subtyping already allows systematic stratification of susceptibility and, hence, clinical heterogeneity, a prerequisite for unraveling the polygenic etiology and polygene-environment interactions in essential hypertension. As hypertension susceptibility genes, coexpression of ATP1A1 and Dear in both renal tubular cells and vascular endothelium suggest a cellular pathogenic scaffold for polygenic mechanisms of hypertension, as well as the hypothesis that ATP1A1 and/or Dear could contribute to the known renal and vascular endothelial dysfunction associated with essential (polygenic) hypertension.
原发性高血压仍然是心血管和脑血管疾病的主要危险因素。作为一种复杂的多因素疾病，其易感基因座仍难以阐明。ATP1A1和Dear是与大鼠2号染色体上两个紧密连锁的血压数量性状基因座相关的候选基因。由于相应的人类同线性区域位于不同染色体上，对ATP1A1（染色体[chr]-1p21）和Dear（chr-4q31.3）的研究有助于对人类高血压中每个血压数量性状基因座进行遗传分析。在此，我们通过单核苷酸多态性单倍型分析，报告了来自撒丁岛北部一个相对隔离的病例/对照高血压队列中，人类ATP1A1（P<0.000005）和Dear（P<0.03）与高血压的关联。性别特异性单倍型分析检测到这两个基因座与男性高血压的关联比女性更强。单倍型趋势回归分析支持ATP1A1和Dear作为独立的易感基因座，并揭示了与高血压和正常血压的单倍型特异性关联，从而划分出高血压的单倍型特异性亚组。尽管需要在其他队列中进行研究以确定其他人群中的遗传效应，但单倍型分型已经允许对易感性进行系统分层，进而对临床异质性进行分层，这是揭示原发性高血压多基因病因和多基因-环境相互作用的先决条件。作为高血压易感基因，ATP1A1和Dear在肾小管细胞和血管内皮细胞中的共表达提示了高血压多基因机制的细胞致病框架，以及ATP1A1和/或Dear可能导致与原发性（多基因）高血压相关的已知肾脏和血管内皮功能障碍的假说。
