title: A genetic variant of hypoxia-inducible factor-1alpha is associated with adverse outcomes in acute kidney injury.
abstract: Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that mediates many cellular responses to tissue hypoxia, a common feature of acute kidney injury (AKI). Here we studied 241 patients with AKI and determined the relationship to adverse outcome of a non-synonymous polymorphism in the coding region of the HIF-1alpha gene where a C to T substitution occurs at position +85 in exon 12, a change known to enhance transactivation. The baseline characteristics of the patients were not different among genotype groups except for a significantly higher prevalence of shock and number of failed organs in T-allele carriers. A significant genotype-phenotype association was found for plasma levels of vascular endothelial growth factor-A but not angiopoietin-2, two downstream targets of HIF-1alpha. Compared to the CC genotype, T-allele carriers had significantly higher adjusted odds for dialysis requirement or in-hospital death; assisted mechanical ventilation or dialysis requirement; and the composite of assisted mechanical ventilation, dialysis requirement or in-hospital death. The trend for higher plasma angiopoietin-2 levels was associated with significantly higher adjusted odds for in-hospital death; dialysis requirement or in-hospital death; and the composite outcome of assisted mechanical ventilation, dialysis, or in-hospital death. Despite the limited cohort size, our study found this particular HIF-1alpha genetic variant to be associated with disease severity and adverse outcomes in AKI. Larger studies are needed to confirm these relationships.
authors.affiliation: Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, Caritas St Elizabeth's Medical Center, Boston, Massachusetts, USA.
authors.forename: Alexey Y
authors.initials: AY
authors.lastname: Kolyada
authors.affiliation: Biostatistics Research Center, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Hocine
authors.initials: H
authors.lastname: Tighiouart
authors.affiliation: Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, Caritas St Elizabeth's Medical Center, Boston, Massachusetts, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Perianayagam
authors.affiliation: Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, Caritas St Elizabeth's Medical Center, Boston, Massachusetts, USA.
authors.forename: Orfeas
authors.initials: O
authors.lastname: Liangos
authors.affiliation: Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, Caritas St Elizabeth's Medical Center, Boston, Massachusetts, USA.
authors.forename: Nicolaos E
authors.initials: NE
authors.lastname: Madias
authors.affiliation: Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, Caritas St Elizabeth's Medical Center, Boston, Massachusetts, USA. Electronic address: bertrand.jaber@caritaschristi.org.
authors.forename: Bertrand L
authors.initials: BL
authors.lastname: Jaber
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000804:Angiotensin II / Q000097:blood; D001483:Base Sequence; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D006435:Renal Dialysis; D012121:Respiration, Artificial; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II