Luo Fang, Wang Yibo, Wang Xiaojian, Sun Kai, Zhou Xianliang, Hui Rutai
Hypertension Division, FuWai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, China.
Hypertension. 2009 Oct;54(4):796-801. doi: 10.1161/HYPERTENSIONAHA.109.135103. Epub 2009 Jul 27.
NEDD4L is involved in the regulation of plasma volume and blood pressure by controlling cell surface expression of the kidney epithelial Na(+) channel. Previously, the cryptic splice variant rs4149601(G/A) A allele of NEDD4L, generating isoform I, was estimated to decrease blood pressure by downregulating Na(+) reabsorption. However, a recent functional study showed that isoform I should lead to abnormal Na(+) reabsorption increases by antagonistically downregulating epithelial Na(+) channel activities. To determine whether the variant rs4149601 A allele is a risk factor for hypertension, has an impact on the antihypertensive response to hydrochlorothiazide, and is associated with orthostatic hypotension, we performed a case-control study of hypertension (n=1686), a 4-week clinical trial (n=542), and a case-control study of orthostatic hypotension (n=793) in Chinese subjects. We found that the A allele was significantly associated with hypertension after appropriate adjustment (odds ratio: 1.39; 95% CI: 1.13 to 1.72; P=0.002). The blood pressure reduction in A carriers after hydrochlorothiazide treatment was greater than that in GG carriers, with differences of 6.1 mm Hg (P=0.009) in systolic blood pressure and 2.7 mm Hg (P=0.027) in diastolic blood pressure. The A allele was significantly associated with orthostatic hypotension after adjustment for cardiovascular risk factors (odds ratio: 0.68; 95% CI: 0.48 to 0.98; P=0.039). In conclusion, rs4149601 is a genetic risk factor for hypertension and a protective factor against orthostatic hypotension in hypertensive subjects, and the antihypertensive response to hydrochlorothiazide is more sensitive in A allele carriers than in GG carriers. Consequently, the A allele may be a useful marker for predicting hypertension, orthostatic hypotension, and antihypertensive response to hydrochlorothiazide.
NEDD4L通过控制肾上皮钠通道的细胞表面表达参与血浆容量和血压的调节。此前，据估计，NEDD4L的隐秘剪接变体rs4149601（G/A）的A等位基因产生异构体I，通过下调钠重吸收来降低血压。然而，最近的一项功能研究表明，异构体I应通过拮抗下调上皮钠通道活性导致异常的钠重吸收增加。为了确定rs4149601变体的A等位基因是否为高血压的危险因素、是否影响对氢氯噻嗪的降压反应以及是否与体位性低血压相关，我们在中国受试者中进行了一项高血压病例对照研究（n = 1686）、一项为期4周的临床试验（n = 542）以及一项体位性低血压病例对照研究（n = 793）。我们发现，经过适当调整后，A等位基因与高血压显著相关（比值比：1.39；95%置信区间：1.13至1.72；P = 0.002）。氢氯噻嗪治疗后，A等位基因携带者的血压降低幅度大于GG携带者，收缩压差异为6.1 mmHg（P = 0.009），舒张压差异为2.7 mmHg（P = 0.027）。在调整心血管危险因素后，A等位基因与体位性低血压显著相关（比值比：0.68；95%置信区间：0.48至0.98；P = 0.039）。总之，rs4149601是高血压的遗传危险因素，也是高血压患者体位性低血压的保护因素，并且A等位基因携带者对氢氯噻嗪的降压反应比GG携带者更敏感。因此，A等位基因可能是预测高血压、体位性低血压以及对氢氯噻嗪降压反应的有用标志物。
