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) = 2·9, 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.
Department of Population Sciences, Outcomes Research, City of Hope, Duarte, CA, USA.
Saro H
SH
Armenian
Yan
Y
Ding
George
G
Mills
Canlan
C
Sun
Kalyanasundaram
K
Venkataraman
Florence Lennie
FL
Wong
Susan L
SL
Neuhausen
David
D
Senitzer
Shirong
S
Wang
Stephen J
SJ
Forman
Smita
S
Bhatia
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D018943:Anthracyclines / Q000009:adverse effects*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006333:Heart Failure / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D008223:Lymphoma / Q000150:complications / Q000628:therapy; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017741:Survivors; D055815:Young Adult
C000715087:ABCC2 protein, human; D018943:Anthracyclines; D000089762:Multidrug Resistance-Associated Protein 2
anthracyclines; congestive heart failure; genetic susceptibility; haematopoietic cell transplantation; late effects