Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension
Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension
复制标题
DOI：
10.1093/hmg/ddm112
复制
发表时间：
2007-07-01
影响因子：
3.5
通讯作者：
Cusi, Daniele
中科院分区：
文献类型：
--
作者：
Barlassina, Cristina;Dal Fiume, Chiara;Cusi, Daniele
肾脏对钠(Na+)的重吸收异常可能在盐敏感性的发病机制中起作用。在肾脏中，氯通道ClC-KA(CLCNKA基因)和ClC-KB(CLCNKB基因)及其亚基Barttin(BSND基因)在控制Na+和水的动态平衡方面具有重要作用。我们研究了CLCNKA、CLCNKB和BSND基因座的单核苷酸多态(SNPs)或单倍型是否影响高血压患者的盐敏感性。对314例从未接受治疗的高血压患者静脉注射钠离子后血压变化与15个跨越CLCNKA和CLCNKB长度的SNP以及6个跨越BSND长度的SNP之间的关系进行了研究。生理盐水(300 mM氯化钠，2I-H2O，120min)。4个SNPs与钠负荷后血压变化显著相关。Rs848307(P=0.0026)和rs1739843(P=0.0023)位于CLCNKA基因5‘端上游。非编码的Rs1010069(P=0.0006)和非同义的rs1805152(Thr447AIa；P=0.0078)位于CLCNKA内。此外，基础血浆肾素活性和心率(在钠负荷前测量)在携带与钠负荷后平均血压升高较大相关的等位基因的患者中显著降低，表明这些等位基因与慢性容量扩张有关。本研究支持CLCNKA作为一种新的盐敏感敏感基因的候选。
Abnormal renal reabsorption of sodium (Na+) is likely to play a role in the pathogenesis of salt-sensitivity. In the kidney, chloride channels CLC-Ka (gene CLCNKA) and CLC-Kb (gene CLCNKB) and their subunit Barttin (gene BSND) have important effects on the control of Na+ and water homeostasis. We investigated if single nucleotide polymorphisms (SNPs) or haplotypes within CLCNKA, CLCNKB and BSND loci affect salt-sensitivity in hypertensive subjects. Associations between blood pressure (BP) change after Na+-load and 15 SNPs spanning the length of CLCNKA and CLCNKB and six SNPs spanning the length of BSND were studied in 314 never treated essential hypertensives who underwent an i.v. infusion of saline (300 mm NaCl in 2 I H2O in 120 min). Four SNPs were significantly associated with BP change after Na-load. Rs848307 (P=0.0026) and rs1739843 (P=0.0023) map upstream the 5' of CLCNKA. Non-coding Rs1010069 (P = 0.0006) and non-synonymous rs1805152 (Thr447AIa; P = 0.0078) map within CLCNKA. Moreover, basal plasma renin activity and heart rate (measured before Na-load) were significantly lower in patients carrying the alleles associated with the larger mean BP increase after Na-load, indicating that such alleles are associated with chronic volume expansion. This study supports the candidacy of CLCNKA as a new susceptibility gene for salt-sensitivity.