title: 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.
authors.affiliation: Division of Nephrology, Kidney and Dialysis Research Laboratory, Caritas St. Elizabeth's Medical Center, Boston, MA 02135, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Perianayagam
authors.forename: Orfeas
authors.initials: O
authors.lastname: Liangos
authors.forename: Alexey Y
authors.initials: AY
authors.lastname: Kolyada
authors.forename: Ron
authors.initials: R
authors.lastname: Wald
authors.forename: Robert W
authors.initials: RW
authors.lastname: MacKinnon
authors.forename: Lijun
authors.initials: L
authors.lastname: Li
authors.forename: Madhumati
authors.initials: M
authors.lastname: Rao
authors.forename: Vaidyanathapuram S
authors.initials: VS
authors.lastname: Balakrishnan
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Pereira
authors.forename: Bertrand L
authors.initials: BL
authors.lastname: Jaber
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D000368:Aged; D001483:Base Sequence; D015415:Biomarkers / Q000097:blood; D002374:Catalase / Q000235:genetics*; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics*; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D017582:Renal Replacement Therapy; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D015415:Biomarkers; D017931:DNA Primers; C002744:3-nitrotyrosine; D014443:Tyrosine; D002374:Catalase; D019255:NADPH Oxidases; C086986:CYBA protein, human