The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation

Abstract

Summary:Hepatic veno-occlusive disease (HVOD) is a serious complication of hematopoietic stem cell transplantation (HSCT). Since the liver is a major site of iron deposition in HFE-associated hemochromatosis, and iron has oxidative toxicity, we hypothesized that HFE genotype might influence the risk of HVOD after myeloablative HSCT. We determined HFE genotypes in 166 HSCT recipients who were evaluated prospectively for HVOD. We also tested whether a common variant of the rate-limiting urea cycle enzyme, carbamyl-phosphate synthetase (CPS), previously observed to protect against HVOD in this cohort, modified the effect of HFE genotype. Risk of HVOD was significantly higher in carriers of at least one C282Y allele (RR ¼ 3.7, 95% CI 1.2-12.1) and increased progressively with C282Y allelic dose (RR ¼ 1.7, 95% CI 0.4-6.8 in heterozygotes; RR ¼ 8.6, 95% CI 1.5-48.5 in homozygotes). The CPS A allele, which encodes a more efficient urea cycle enzyme, reduced the risk of HVOD associated with HFE C282Y. We conclude that HFE C282Y is a risk factor for HVOD and that CPS polymorphisms may counteract its adverse effects. Knowledge of these genotypes and monitoring of iron stores may facilitate risk-stratification and testing of strategies to prevent HVOD, such as iron chelation and pharmacologic support of the urea cycle.

Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: A validated genetic association study

“…Analysis of the initial modeling cohort again demonstrated the clinical relevance of the CPSI T1405N polymorphism in a phenotype where endogenous NO is critically important. Previously, this same polymorphism was implicated in neonatal pulmonary hypertension and hepatovenocclusive disease (HVOD) following bone marrow transplantation (Pearson et al, 2001,Kallianpur et al, 2005. The CPSI T1405N polymorphism is the result of C to A transversion at base 4332 in the 3′ region of the CPSI mRNA, changing the triplet code from the evolutionarily conserved ACC to AAC.…”

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

“…29 Homozygotes and heterozygotes for the common hemochromatosis (HFE) mutation C282Y have increased mean liver iron content and circulating levels of reactive iron. 30,31 Another study in 166 patients from the same HSCT cohort found that HFE C282Y potentiates HVOD and that the CPSI SNP counterbalances this effect 32,33 (Table 2). This study was limited primarily by the lack of quantitative data regarding iron stores in most patients, leaving unanswered the question of the mechanism of increased HVOD in carriers of HFE C282Y.…”

“…Cook et al 58 further demonstrated by donor/recipient KIR genotyping that the HLA-C group of the recipient is also a major factor in determining outcome in HLA-identical sibling-donor HSCT if the recipient has a myeloid leukemia. Patients homozygous for the group 2 HLA-C allele (C2) who by definition lack the C1 allele (ligands for an inhibitory KIR) had reduced overall survival when 60 Cavet et al, 129 Rocha et al, 68 Srivastava et al, 34 Summar et al, 24 Kallianpur et al 32 …”

“…Effects of HFE C282Y (upper panel) and stratification by CPSI T1405N genotype (lower panel) on HVOD and day 60 mortality 32,33 No. of HFE C282Y alleles…”

“…[93][94][95] Prevalent iron-loading genetic mutations such as HFE C282Y may also augment organ toxicity (eg HVOD) by promoting infection, increasing reactive iron levels, and/or impairing the re-uptake of iron that is released during myeloablation. 32,[96][97][98][99][100][101][102][103] These mutations may also predispose HSCT survivors to secondary myelodysplasia and other malignancies. [104][105][106][107][108][109] The effects of iron in the HSCT setting deserve further investigation, since they contribute to long-term morbidity and are potentially modifiable by antioxidant therapy, phlebotomy, and chelation.…”