NADPH Oxidase p22phox and Catalase Gene Variants Are Associated with Biomarkers of Oxidative Stress and Adverse Outcomes in Acute Renal Failure

Abstract

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.

Manganese superoxide dismutase, glutathione peroxidase and catalase gene polymorphisms and clinical outcomes in acute kidney injury

“…A study conducted by Perianayagam et al on 200 AKI patients found that C4T polymorphism at position 262 of the CAT gene was not associated with AKI. 29 However, in our study, the genotype distributions of the rs769217 polymorphism of the CAT gene were similar in the AKI and the control groups. It was determined that carrying a T allele in the ninth exon position of the CAT gene was associated with a six-fold increase in intensive care requirements and a ten-fold increase in hospital mortality.…”

“…28 It has been reported that in AKI patients, the NADPH oxidase p22phox gene polymorphism was associated with dialysis requirements and death. 29 In our study, it was similarly determined that gene polymorphism of CAT, an antioxidant enzyme, was also related to intensive care requirements and in-hospital mortality. In addition, a study related to MnSOD gene polymorphisms showed that the gene polymorphisms in this enzyme were related to kidney functions.…”

Searching for Genes That Matter in Acute Kidney Injury

“…In a study of 200 patients with mixed-cause AKI, Perianayagam et al (33) examined the association of polymorphisms in NADPH Oxidase p22phox and Catalase, two enzymes involved with the regulation of reactive oxygen species, with dialysis and mortality. Individuals with the T allele in the NADPH Oxidase p22phox gene possessed a greater risk of dialysis or mortality (unadjusted OR ϭ 2.11).…”

“…No association was demonstrated between the Catalase gene and AKI. This study was unique in that it is one of two studies that examined associations with firm outcomes, i.e., dialysis or mortality (16,33).…”

PPARγ and NAD(P)H oxidase system interaction in glycerol-induced acute renal failure: role ofgp91phoxsubunit of NAD(P)H oxidase

“…In ARF, NAD(P)H oxidase and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes. 23 Additionally, Nishiyama et al have reported that aldosterone-induced renal injury is associated with increases in expression of NAD(P)H oxidase components and ROS levels. 24 Furthermore, in angiotensin II induced oxidative stress, renal damage has been reported to be via the activation of NAD(P)H oxidase.…”