Length polymorphism in heme oxygenase-1 is associated with arteriovenous fistula patency in hemodialysis patients

Abstract

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation, producing carbon monoxide (CO), which carries potent antiproliferative and anti-inflammatory effects in the vascular walls. Transcription of the HO-1 gene is regulated by the length polymorphism of dinucleotide guanosine thymine repeat (GT)(n) in the promoter region, which was measured in this study to determine its association with arteriovenous fistula (AVF) failure in Chinese hemodialysis (HD) patients in Taiwan. L allele means (GT)(n)>or=30 and S allele means (GT)n<30. Therefore, there are two L alleles for L/L genotype, one L and one S allele for L/S genotype, and two S alleles for S/S genotype. Among the 603 HD patients who were enrolled in this study, 178 patients had history of AVF failure, while 425 patients did not. Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.004 month), lower pump flow (0.993 ml/min), higher dynamic venous pressure (1.010 mmHg), location of AVF on the right side (1.587 vs left side) and upper arm (2.242 vs forearm), and L/L and L/S genotypes of HO-1 (2.040 vs S/S genotype). The proportion of AVF failure increased from 20.3% in S/S genotype and 31.0% in L/S genotype to 35.4% in L/L genotype (P=0.011). Relative incidences were 1/87.6 (1 episode per 87.6 patient-months), 1/129, and 1/224.9 for HD patients with L/L, L/S, and S/S genotypes, respectively (P<0.002). The unassisted patency of AVF at 5 years decreased significantly from 83.8% (124/148) to 75.1% (223/297) and 69% (109/158) in S/S, L/S, and L/L genotypes, respectively (P<0.0001). In comparison with HD patients with S/S genotype, those with L/L genotype had a higher prevalence of coronary artery disease (29.1 vs 14.2%; P=0.005). A longer length polymorphism with (GT)(n) >or=30 in the HO-1 gene was associated with a higher frequency of access failure and a poorer patency of AVF in HD patients. The longer GT repeat in the HO-1 promoter might inhibit gene transcription, and consequently offset the CO-mediated protective effect against vascular injury.

Induction of Heme Oxygenase-1 is a Beneficial Response in a Murine Model of Venous Thrombosis

“…We suggest that these findings may offer insights into the recent observation that polymorphisms in the HO-1 gene, characterized by long GT repeats, may increase the risk for recurrent venous thrombosis 20 and for dysfunction of arteriovenous fistulas the latter caused, in part, by thrombosis occurring in the venous limbs of these fistulas. 49 …”

“…29 Interestingly, dysfunction and failure of arteriovenous fistulas are more likely to occur in patients exhibiting polymorphisms in the HO-1 gene characterized by long GT repeats. 49 Long GT repeats in the HO-1 promoter, as shown by others, may lead to reduced expression or inducibility of HO-1. [17][18][19] We suggest that the exaggerated inflammatory response and the markedly impaired resolution of venous clot, as observed in the present study, may be germane to the premature cessation of blood flow that we recently observed in arteriovenous fistulas created in HO-1 deficient mice.…”

‘Hardy’s Law’ and genomics in Anaesthesia

“…Such omissions are not confined to the anaesthetic literature. Studying polymorphisms for genes that code for the enzyme heme-oxygenase-1 as a risk factor for arteriovenous fistula impotency in patients with renal failure, Lin et al [26] were criticised for their oversight in not reporting adherence of their measured alleles to Hardy's Law [27]. Indeed, general guidance issued on the proper conduct and reporting of genotype-phenotype association studies confirms Hardy's Law as an essential step in the quality control process [28].…”

Novel Paradigms for Dialysis Vascular Access

“…Moreover, HO-1 may also have intrinsic protective properties against inflammation, oxidant stress, and vascular proliferation. In a seminal clinical study, Lin et al demonstrated that patients with gene polymorphisms of HO-1 characterized by long GT repeats (less production of HO-1) were more likely to have worse AVF patency (25). A subsequent experimental study published by Juncos et al in a murine model of AVF, where the HO-1 gene was knocked out, evaluated the functional and biologic significance of HO-1 in AVF development (26).…”