Gene Polymorphisms in the Heme Degradation Pathway and Outcome of Severe Human Sepsis

Abstract

Heme and its breakdown products CO, Fe, and bilirubin are being recognized as signaling molecules or even therapeutic agents, but also exert adverse effects when released at high concentrations. Manipulating the pathway confers protection in rodent sepsis models via both control of free heme and formation of its first and higher-order products. Thus, regulatory elements present in human heme oxygenase 1 (HMOX1) and biliverdin reductases (BLVRA/B) genes might impact outcome. We tested whether a highly polymorphic (GT)n microsatellite and single-nucleotide polymorphisms in HMOX1 and BLVRA/B genes are associated with outcome of sepsis. Two cohorts (n = 430 and 398 patients) with severe sepsis were screened for single-nucleotide polymorphisms and/or the microsatellite by fragment length analysis and genotyping techniques. Heme oxygenase 1 plasma levels were determined in additional patients with severe sepsis (n = 92) by enzyme-linked immunosorbent assay. Based on mean Sepsis-related Organ Failure Assessment scores, patients homozygous for rs2071746 A allele or medium length (GT)n microsatellites of HMOX1 showed higher 28-day mortality (P = 0.047 and P = 0.033) in one cohort compared with other genotypes, whereas 90-day mortality rates showed no association. The T allele was less frequently observed in both cohorts than would be expected according to Hardy-Weinberg equilibrium. Heme oxygenase 1 plasma levels were elevated in septic patients, independent of the genotype. Single-nucleotide polymorphisms within BLVRA/B showed no association with outcome. Short (GT)n repeats that are in linkage disequilibrium with the T allele of rs2071746 in HMOX1 are associated with favorable outcome, whereas no association with gene variants of BLVRA/B, involved in the generation of higher-order metabolites, was noticed.

Heme oxygenase-1 promoter (GT) n polymorphism associates with HIV neurocognitive impairment

“…The A(-413)T SNP can affect HO-1 promoter transcriptional activity and disease outcomes, 9 albeit less so than the HO-1 (GT) n repeat length. [10][11][12] The frequency of the "T" A(-413)T SNP was significantly higher in African Americans than in European Americans (66.0% vs 41.8%), whereas the frequency of the "A" SNP was lower (34% vs 58.2%) (figure 1E), and, as expected for Hardy-Weinberg equilibrium, the TT and AT genotypes were more prevalent in African Americans (figure 1F). Also, the A(-413)T SNP and the HO-1 (GT) n allele genotypes were not independently expressed; the "A" SNP associated with medium "M" HO-1 (GT) n alleles, whereas the "T" SNP associated with both short "S" and long "L" HO-1 (GT) n alleles (not shown).…”

“…6 An A(-413)T SNP can affect HO-1 promoter transcriptional activity and disease outcomes, 9 albeit less so than the HO-1 (GT) n repeat length. [10][11][12] Short HO-1 (GT) n repeat alleles associate with better outcomes in inflammatory and oxidative stress-associated diseases, 7,8,[13][14][15] and the prevalence of these short alleles differs significantly among different populations. We recently determined HO-1 (GT) n alleles in individuals in an HIV autopsy cohort (n = 554) and showed that the presence of 1 or more short HO-1(GT) n alleles associated with a lower risk of HIV encephalitis and less brain inflammation (type I interferon responses and T-cell activation).…”

Alternative 5’ Untranslated Regions Are Involved in Expression Regulation of Human Heme Oxygenase-1

“…There exists ample evidence supporting a role for genetic variation of human HMOX1 to impact outcome. In particular, the single nucleotide polymorphism (SNP) rs2071746 and a microsatellite (GT-dinucleotide repeat, (GT) n ) in the promoter region of the gene are associated with incidence, progression, or outcome of various clinical diagnoses as diabetes, sepsis, ARDS, myocardial infarction, and failure of kidney and liver grafts [6–10]. These polymorphisms might be an intrinsic component of the pathogenesis of some of these cases via HMOX1 transcription and/or translation regulation and subsequent HO-1 activity [3].…”

“…Both polymorphisms are in strong linkage disequilibrium [10,13]. The pattern of the (GT) n distribution has been shown to be trimodal with 23, 30 and 37 repeats (named here as N23, N30, N37) as major alleles within the three length classes [10]. Although there have been correlations between (GT) n length and HO-1 expression reported, these data remain not coherent.…”

An Integrated Clinico-transcriptomic Approach Identifies a Central Role of the Heme Degradation Pathway for Septic Complications after Trauma

“…Experimental and clinical studies suggest that HMOX1 is the rate-limiting step of heme degradation, and that its genotypes and underlying regulatory mechanisms are associated with the outcome in sepsis. [44][45][46][47] The particular design of the present study with purposeful selection of patients for the discovery set (secondary sepsis vs. systemic inflammation without infection) and consecutive validation of candidates in the total cohort by an independent method has been conceptualized to overcome possible masking effects by ''non-selective'' whole-genome screening of all patients. In contrast to our results, gene expression patterns in a similar trauma patient cohort in a previous study by the Glue grant consortium were found to be more common than different in patients with ''complicated'' or ''uncomplicated recovery.''…”