Human Na+/H+ exchanger genes : identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease.
Human Na+/H+ exchanger genes : identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease.
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人类 Na /H 交换基因：通过辐射杂交作图鉴定多态性和终末期肾病连锁分析。
DOI：
10.1161/01.hyp.35.1.135
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Bowden,DW
中科院分区：
文献类型：
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作者：
Yu,H;Freedman,BI;Rich,SS;Bowden,DW
—Na+/H+ 交换器 (NHE) 是膜结合转运蛋白，可催化细胞外 Na+ 向细胞内 H+ 的电中性移动。 NHE 基因在 pH 稳态和细胞体积调节中发挥着关键作用，可被视为原发性高血压和肾脏疾病的候选基因。本研究旨在确定 NHE 基因是否与终末期肾病 (ESRD) 的遗传易感性有关。迄今为止，已在哺乳动物中克隆了 5 种 NHE 亚型（NHE1 至 NHE5）。 NHE1至NHE3和NHE5的互补DNA(cDNA)序列在人类中是已知的。由于 NHE 基因的染色体结构未知，我们使用 cDNA 序列设计聚合酶链式反应引物，用于辐射杂交作图。 NHE 基因的辐射杂交作图鉴定了 NHE1 至 NHE3 的附近多态性标记（NHE1：D1S197、D1S2677；NHE2：D2S373、D2S1789；和 NHE3：D5S678、D5S2005）。我们在 ESRD 的连锁和关联分析中使用了这些标记以及其他先前鉴定的 NHE5 多态性标记。 NHE1 至 NHE3 和 NHE5 基因座没有显示与 ESRD 关联的证据。然而，NHE5 显示出显着的关联证据（P≤1.0×10−4）。 NHE5 的等位基因 6 观察到了最强的关联证据（P≤0.001 至 0.01）。等位基因 6 似乎具有肾脏保护作用，在对照人群中的频率为 0.15，在 ESRD 患者中的频率为 0.06 至 0.09。事实证明，从 cDNA 设计引物和辐射杂交作图的组合方法可以成功地识别以前只能获得 cDNA 序列的人类基因的多态性。本研究中鉴定的 NHE 引物和相关多态性位点可用于未来高血压和肾衰竭遗传学研究中 NHE 基因的基因组、连锁和关联分析。鉴于等位基因关联，有必要进一步评估 NHE5 在 ESRD 易感性中的作用。
—The Na+/H+ exchangers (NHEs) are membrane-bound transporters that catalyze the electro-neutral movement of extracellular Na+ for intracellular H+. NHE genes play a critical role in pH homeostasis and cellular volume regulation and can be considered candidate genes for essential hypertension and renal disease. This study was performed to determine whether the NHE genes contributed to genetic susceptibility in end-stage renal disease (ESRD). To date, 5 isoforms of NHE have been cloned in mammals (NHE1 to NHE5). The complementary DNA (cDNA) sequences of NHE1 to NHE3 and NHE5 are known in humans. Because the chromosomal structure of the NHE genes is unknown, we used cDNA sequences to design polymerase chain reaction primers for use in radiation hybrid mapping. Radiation hybrid mapping of NHE genes identified nearby polymorphic markers for NHE1 to NHE3 (NHE1:D1S197,D1S2677; NHE2:D2S373,D2S1789; and NHE3:D5S678,D5S2005). We used these markers, and other previously identified polymorphic markers for NHE5, in linkage and association analyses of ESRD. The NHE1 to NHE3 and NHE5 loci did not demonstrate evidence for linkage to ESRD. However, NHE5 showed significant evidence for association (P≤1.0×10−4). The strongest evidence for association was observed with allele 6 of NHE5 (P≤0.001 to 0.01). Allele 6 appeared to have a renoprotective effect, with a frequency of 0.15 in the control population and 0.06 to 0.09 in patients with ESRD. The combined approach of designing primers from cDNA and radiation hybrid mapping has proven successful in identifying polymorphisms for human genes of which only cDNA sequences were previously available. The NHE primers and associated polymorphic loci identified in this study can be used in genomic, linkage, and association analysis of NHE genes in future genetic studies of hypertension and renal failure. Given the allelic association, further evaluation of the role of NHE5 in ESRD susceptibility appears warranted.