Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M, Glorioso N, Lanzani C, Manunta P, Righetti M, Rivera R, Stella P, Troffa C, Zagato L, Bianchi G
Postgraduate School of Nephrology, University of Milan, Italy.
Lancet. 1997 May 10;349(9062):1353-7. doi: 10.1016/S0140-6736(97)01029-5.
Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an alpha/beta heterodimeric protein found in the renal tubule is thought to regulate ion transport through changes in the actin cytoskeleton. We investigated whether an alpha-adducin polymorphism (Gly 460 Trp) is involved in essential hypertension in two separate populations.
Linkage analysis of three DNA markers at different distances from the alpha-adducin locus (20-2500 kb) was done in 137 hypertensive sibling-pairs. 477 hypertensive and 322 normotensive individuals were genotyped for the alpha-adducin polymorphism. The blood-pressure response to acute and chronic changes in sodium balance was studied in hypertensive individuals with and without the 460 Trp alpha-adducin allele.
Significant linkage was found for all three markers in the sibling-pair study. The extra shared alleles (9.1%, 6.5%, and 4.7%) and the significance level for linkage (p = 0.0006, p = 0.0119, and p = 0.0211) both decreased with increasing distance from the alpha-adducin locus. There was a significant association between the 460 Trp mutation and hypertension (p = 0.0003). In the salt-sensitivity test, to assess the acute blood-pressure response to changes in body sodium in 86 hypertensive patients, the decrease in mean arterial pressure was greater in 65 patients who were heterozygous for the mutant allele (Gly/Trp) than in 21 wild-type homozygotes (Gly/Gly) (mean decrease 15.9 [SE 2.0] vs 7.4 [1.3] mm Hg; p = 0.001). Similarly, 21 heterozygous hypertensive patients showed a greater fall in mean arterial pressure in response to 2 months' treatment with hydrochlorothiazide than did 37 wild-type homozygous hypertensive patients (mean decrease 14.7 [2.2] vs 6.8 [1.4] mm Hg; p = 0.002).
Our findings of significant linkage of the alpha-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with the mutant allele suggest that alpha-adducin is associated with a salt-sensitive form of essential hypertension. We suggest the alpha-adducin polymorphism may identify hypertensive patients who will benefit from diuretic treatment or manoeuvres to reduce total body sodium.
肾钠转运异常可能与高血压有关。内收蛋白是一种在肾小管中发现的α/β异二聚体蛋白，被认为通过肌动蛋白细胞骨架的变化来调节离子转运。我们在两个不同的人群中研究了α-内收蛋白多态性（Gly 460 Trp）是否与原发性高血压有关。
对137对高血压同胞进行了与α-内收蛋白基因座距离不同（20 - 2500 kb）的三个DNA标记的连锁分析。对477名高血压患者和322名血压正常者进行了α-内收蛋白多态性的基因分型。在有和没有460 Trpα-内收蛋白等位基因的高血压患者中，研究了钠平衡急性和慢性变化时的血压反应。
在同胞对研究中，所有三个标记均发现显著连锁。额外共享等位基因（9.1%、6.5%和4.7%）以及连锁的显著性水平（p = 0.0006、p = 0.0119和p = 0.0211）均随着与α-内收蛋白基因座距离的增加而降低。460 Trp突变与高血压之间存在显著关联（p = 0.0003）。在盐敏感性试验中，为评估86名高血压患者体内钠变化时的急性血压反应，65名突变等位基因杂合子（Gly/Trp）患者的平均动脉压下降幅度大于21名野生型纯合子（Gly/Gly）患者（平均下降15.9 [标准误2.0] vs 7.4 [1.3] mmHg；p = 0.001）。同样，21名杂合子高血压患者在接受氢氯噻嗪治疗2个月后的平均动脉压下降幅度大于37名野生型纯合子高血压患者（平均下降14.7 [2.2] vs 6.8 [1.4] mmHg；p = 0.002）。
我们发现α-内收蛋白基因座与原发性高血压存在显著连锁，且突变等位基因患者对钠平衡变化更敏感，这表明α-内收蛋白与一种盐敏感性原发性高血压有关。我们认为α-内收蛋白多态性可能有助于识别能从利尿剂治疗或降低总体钠的措施中获益的高血压患者。
