Heme oxygenase-1 repeat polymorphism in septic acute kidney injury

Abstract

Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine–thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S–L (short to long) classification, and 27 and 34 repeats for the S–M–L 2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01–1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration ( p <0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk.

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV

“…The HO-1 promoter region contains a (GT) n dinucleotide repeat that modulates basal HO-1 expression and gene inducibility, specifically with shorter HO-1 (GT) n repeats associating with higher basal HO-1 promoter activity (Chen et al 2002;Hirai et al 2003;Rueda et al 2007;Seu et al 2012), as well as better outcomes in inflammatory and oxidative stress-associated diseases (Bai et al 2010;Chen et al 2012;Rueda et al 2007;Seu et al 2012;Vázquez-Armenta et al 2013). Short (S) (GT) n repeat length alleles are defined as those with less than 27 (GT) n repeats, while long (L) alleles are defined as those with more than 34 (GT) n repeats (Gill et al 2018;Kaartokallio et al 2018;Vilander et al 2019).…”

HMOX1 genetic polymorphisms and outcomes in infectious disease: a systematic review

“…Vilander et al enrolled 653 critically ill patients with sepsis from Finland, 300 of whom had severe acute kidney injury (AKI). 40 On average, patients were middle aged (median age 63) and were nearly all emergency admissions (98%). Using the same S/M/L classification as Sponholz et al (<27, S, 27-34 M, >34, L), the presence of any L allele was rare (63/1306, 4.9%), and the presence of an L/L genotype was very rare, with only 1 patient having the L/L genotype.…”

Association between HO‑1 gene promoter polymorphisms and diseases (Review)

“…Therefore, patients with reduced Ho-1 expression caused by l (GT)n repeats may have increased susceptibility to heme-related aKi during cardiac surgery. in a different study, Vilander et al (87) classified the Ho-1 (GT)n repeat sequence in 300 patients with severe aKi sepsis and 353 patients without aKi sepsis. The alleles were classified according to the number of replicates.…”

“…In a different study, Vilander et al ( 87 ) classified the HO-1 (GT)n repeat sequence in 300 patients with severe AKI sepsis and 353 patients without AKI sepsis. The alleles were classified according to the number of replicates.…”