Genetic susceptibility to anthracycline‐related congestive heart failure in survivors of haematopoietic cell transplantation

Abstract

Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2,950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females (Odds Ratio [OR]=2.9, p<0.01), individuals with pre-HCT chest radiation (OR=4.7, p=0.05), hypertension (OR=2.9, p=0.01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR=2.8, p<0.01), HFE (rs1799945, 63C→G; OR=2.5, p=0.05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR=4.3, p<0.01). A combined (clinical and genetic) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC=0.67) or the clinical (AUC=0.69) models alone.

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

“…Previous pharmacogenetic analyses have reported a protective effect of this SNP, particularly at lower cumulative doxorubicin doses [25,26], or detected no association for this variant with anthracyclineinduced cardiotoxicity [12,27]. Conversely, in our study this variant was more common in patients with systolic dysfunction than in control patients.…”

“…If this is a true effect, this silent polymorphism is either tagging a functionally consequential SNP, or this could be another potential example of a synonymous variant that affects protein activity [30]. Risk variants in RAC2 (rs13058338) and NCF4 (rs1883112) were first reported in a large case-control analysis by Wojnowski et al [8] and replicated in independent cohorts [11,12]. Similar to the nominal concordance of the SLC28A3 results, the NCF4 SNP that had been previously reported to increase risk was found more commonly in patients with cardiotoxicity in our cohort, with a slightly lower magnitude of association (1.44 vs 1.88-2.70).…”

“…The threshold EF of 55% was chosen based on the American Society of Echocardiographer's Guidelines [18]. Demographics were compared between cases and controls using Fisher's exact tests for categori- From the 24 SNPs included in the analysis, four were selected a priori as co-primary hypotheses based on previous successful replication (RAC2 rs13058338, NCF4 rs1883112, SLC28A3 rs7853758) [8][9][10][11][12] and biological rationale (TOP2B rs10865801) [13]. For each co-primary hypothesis a predicted genetic model and direction of effect was selected based on prior literature.…”

“…Utilizing a cohort of patients assembled to investigate physiological biomarkers of chronic anthracycline-induced cardiotoxicity, we attempted to replicate the future science group Research Article Hertz, Caram, Kidwell et al influence of candidate SNPs on the development of cardiomyopathy after receiving an anthracycline in the curative setting. We prioritized SNPs in genes that were either previously reported to be associated with cardiotoxicity (RAC2, NCF4, SLC28A3) [8][9][10][11][12] or that had compelling mechanistic rationale but had not been previously investigated to our knowledge (TOP2B) [13]. Additional variants with putative relevance to anthracycline-induced cardiotoxicity, anthracycline exposure, or previous reports of significant association with cardiotoxicity were screened for an association with systolic dysfunction in an uncorrected secondary analysis.…”

Prediction of cardiovascular disease among hematopoietic cell transplantation survivors

“…We and others have shown that despite the strong association between certain variables (eg, anthracycline dose, age, hypertension) and post-HCT HF, there is marked inter-individual variability in risk that is not explained exclusively by these factors alone. 29,51,52 For example, susceptibility due to inherited genetic variations in pathways involved in anthracycline-related toxicity have been shown to account for up to 10% of the HF risk after HCT, 38,39 and may need to be accounted for in future risk prediction estimates. As for CAD, the long latency (;10 years) between HCT and CAD may necessitate longer follow-up of our cohort, allowing us to further refine our risk estimates.…”