NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure
NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure
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DOI：
10.1681/asn.2006070806
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发表时间：
2007-01-01
影响因子：
13.6
通讯作者：
Jaber, Bertrand L.
中科院分区：
文献类型：
--
作者：
Perianayagam, Mary C.;Liangos, Orfeas;Jaber, Bertrand L.
活性氧是急性肾衰竭（ARF）损伤的重要介质。尽管影响关键促酶和抗氧化酶的多态性可能会改变对氧化应激介导的损伤的易感性，但在 ARF 中，利用遗传流行病学研究氧化应激相关基因却很少受到关注。在200名患有混合原因和严重程度的ARF住院患者的队列中，前瞻性评估了促氧化剂NADPH氧化酶p22phox亚基基因的编码区（位置+242处的C至T替换）和抗氧化酶过氧化氢酶基因的启动子区（位置-262处的C至T替换）中的单核苷酸多态性与不良临床结果的关系。从外周血白细胞中提取基因组DNA，并用限制性片段长度多态性PCR方法进行分析。通过测量循环硝基酪氨酸和过氧化氢酶活性来表征基因型-表型关联。观察到的和预期的基因型频率没有显着差异，并且根据不同基因型组，总体基线特征没有显着差异。 NADPH 氧化酶 p22phox 基因型与血浆硝基酪氨酸水平之间存在基因型-表型关联（P = 0.06），过氧化氢酶基因型与全血过氧化氢酶活性之间也存在关联（P < 0.001）。与NADPH氧化酶p22phox CC基因型组相比，T等位基因组持续住院的累积概率更高（P = 0.03）。与 NADPH 氧化酶 p22phox CC 基因型相比，T 等位基因携带状态与透析需求或住院死亡的几率高 2.1 倍相关（P = 0.01）。在种族调整后，这种关联持续存在，这种综合结果的几率高出 2.0 至 2.2 倍；性别;年龄;以及急性生理学和慢性健康评估 II 评分（P = 0.03）、多器官衰竭评分（P = 0.01）或败血症的存在（P = 0.02）。 +242 位编码 NADPH 氧化酶 p22phox 亚基的基因多态性与 ARF 患者的透析需求或住院死亡相关。需要更大规模的研究来证实这些关系。
Reactive oxygen species are important mediators of injury in acute renal failure (ARF). Although polymorphisms that, affect key pro- and antioxidant enzymes might alter the susceptibility to oxidative stress-mediated injury, the use of genetic epidemiology for the study of oxidative stress-related genes has received little attention in ARF. The relationship of single-nucleotide polymorphisms in the coding region (C to T substitution at position +242) of the pro-oxidant enzyme NADPH oxidase p22phox subunit gene and in the promoter region (C to T substitution at position -262) of the antioxidant enzyme catalase gene to adverse clinical outcomes was evaluated prospectively in a cohort of 200 hospitalized patients with established ARF of mixed cause and severity. Genomic DNA was extracted from peripheral blood leukocytes and analyzed with a restriction fragment length polymorphism PCR method. Genotype-phenotype associations were characterized by measuring circulating nitrotyrosine and catalase activity. Observed and expected genotype frequencies were not significantly different, and overall baseline characteristics were not significantly different according to the various genotype groups. A genotype-phenotype association was demonstrable between the NADPH oxidase p22phox genotypes and plasma nitrotyrosine level (P = 0.06), as well as between the catalase genotypes and whole-blood catalase activity (P < 0.001). Compared with the NADPH oxidase p22phox CC genotype group, the T-allele group had a higher cumulative probability of remaining hospitalized (P = 0.03). Compared with the NADPH oxidase p22phox CC genotype, the T-allele carrier state was associated with 2.1-fold higher odds for dialysis requirement or hospital death (P = 0.01). This association persisted with 2.0- to 2.2-fold higher odds for this composite outcome after adjustment for race; gender; age; and the Acute Physiology and Chronic Health Evaluation II score (P = 0.03), the Multiple Organ Failure score (P = 0.01), or presence of sepsis (P = 0.02). The polymorphism in the gene that encodes the NADPH oxidase p22phox subunit at position +242 is associated with dialysis requirement or hospital death among patients with ARF. Larger studies are needed to confirm these relationships.