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

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 2950 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 center dot 9, P<0 center dot 01], individuals with pre-HCT chest radiation (OR=4 center dot 7, P=0 center dot 05), hypertension (OR=2 center dot 9, P=0 center dot 01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T -> A; OR=2 center dot 8, P<0 center dot 01), HFE (rs1799945, 63C -> G; OR=2 center dot 5, P=0 center dot 05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G -> A; OR=4 center dot 3, P<0 center dot 01). A combined (clinical and genetic) CHF predictive model performed better [area under the curve (AUC), 0 center dot 79] than the genetic (AUC=0 center dot 67) or the clinical (AUC=0 center dot 69) models alone.