EP-010 - HYPOXIA INDUCIBLE FACTOR-1A POLYMORPHISMS ASSOCIATED WITH ADVANCED CHRONIC KIDNEY DISEASE.

S. Movafagh¹, M. sanaei²; ¹Sheanndoah University, Fairfax, VA, USA, ²Kidney and Hypertension Specialists, Fairfax, VA, USA.

Background: Hypoxic signaling plays a critical role in tissue response to injury at early and late stages of chronic kidney disease (CKD). A key mediator of hypoxic signaling is HIF-1. HIF-1 is a transcription factor composed of alpha and beta subunits, that is regulated by low oxygen levels and plays a major role in cellular oxygen homeostasis. Recent studies show polymorphisms in a few coding loci of HIF-1A gene having correlations with kidney diseases(1). Several intronic HIF-1 polymorphisms have also been shown to be associated with disease (2). In this report we examine the association of several HIF-1A polymorphisms with severity of CKD and HIF-1A expression.

Methods: Patients diagnosed stage II-V kidney disease were recruited from our affiliated Kidney and Hypertension Specialists clinic. After consenting patients in accordance with Shenandoah University IRB guidelines, urine and blood samples were collected. Urinary mRNA was quantified using previously defined methods(3). Genotypes were determined using Taqman PCR assays. Six HIF-1A polymorphisms in introns 1 and 6, 5' UTR and regions associated with the oxygen dependent degradation (ODD), phosphorylation and HIF-1B interaction were examined. Genotype frequencies were compared between CKD stages. Urinary mRNA levels were compared with genotypes.

Results: Among the six SNPs studied, the homozygote variant genotype in HIF-1A intron 6 and ODD domain were significantly associated with increased risk of stage IV-V compared to stage II-III CKD (Relative Risk: 1.85, p=0.008 and 2.84, p< 0.0001, respectively). Urinary HIF-1A mRNA was significantly elevated in intron 6 homozygote variants compared to wild type (p=0.02).

Conclusion: In this study we report two polymorphisms in the HIF-1A gene associated with advanced CKD as potential predictive markers of the disease.

1)Kolyada AY, et. al, . A genetic variant of hypoxia-inducible factor-1alpha is associated with adverse outcomes in acute kidney injury. Kidney Int. 75(12):1322-1329 (2009).
2) Roberts KE et. al,. Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease. Gastroenterology 139(1):130-9.e24 (2010).
3) Movafagh s. et. al, Hypoxia Inducible Factor 1: A Urinary Biomarker of Kidney Disease. Clin Transl Sci. 10(3):201-207 (2017).