Hyaluronan Synthase 3 Variant Associated With Increased Risk of Anthracycline-Related Cardiomyopathy
In a study reported in the Journal of Clinical Oncology, Wang et al in the Children’s Oncology Group identified a common single nucleotide polymorphism, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that is associated with anthracycline dose–related risk of cardiomyopathy in pediatric cancer patients. They found that the AA genotype is associated with increased risk at higher cumulative anthracycline dose and that there is a gene-environment interaction in patients of all ages, with patients who have the AA genotype being significantly more likely to have received higher cumulative doses. HAS3 produces hyaluronan, which is a component of the extracellular matrix that also acts to inhibit cardiac injury from reactive oxygen species.
In the study, a single nucleotide polymorphism array was used to profile common single nucleotide polymorphisms in 2,100 genes considered relevant to cardiovascular disease in 93 cases with anthracycline-related cardiomyopathy and 194 controls from a Children’s Oncology Group study population (discovery cohort). Cases were aged < 21 years and were matched with randomly selected controls for cancer diagnosis, year of diagnosis within 5 years, and race/ethnicity, with duration of cardiomyopathy-free follow-up exceeding the time from cancer diagnosis to cardiomyopathy in the corresponding case. An independent replication cohort consisted of 76 patients of all ages and racial/ethnic backgrounds from a single institution who were diagnosed with cardiomyopathy after anthracycline exposure.
In the discovery set, cases had received higher cumulative anthracycline exposure vs controls (median, 300 vs 152 mg/m2, P < .001), with 22% vs 8% receiving 251 to 300 mg/m2 and 48% vs 25% receiving > 300 mg/m2. The case and control groups were balanced for sex (57% and 52% female), race/ethnicity (100% white in both), median age at cancer diagnosis (6.9 and 6.3 years) and study participation (19 years in both), primary diagnosis (eg, bone tumors in 24% and 17%, acute lymphoblastic leukemia in 13% and 32%), and length of follow-up (median, 10 and 11 years). Exposure to chest radiation was more common in the case group (25% vs 11%, P = .01). Cases had a median age of 19 years at cardiomyopathy diagnosis.
Increased Risk With AA Genotype
The rs2232228 single nucleotide polymorphism in HAS3 was identified as having a highly significant association with anthracycline dose–dependent cardiomyopathy risk (P = 5.3×10-7). For cases vs controls, HAS3 genotypes were GG in 14% vs 20%, GA in 54% vs 47%, and AA in 32% vs 33%.
On analysis adjusting for age at diagnosis, sex, chest radiation dose, and anthracycline exposure (continuous), risk of cardiomyopathy was nonsignificantly increased in patients with GA (odds ratio [OR] = 2.0, P = .12) and AA genotypes (OR = 1.8, P = .20) vs GG genotype across all anthracycline exposures. In analysis adjusting for age at diagnosis, sex, and chest radiation dose, risk of cardiomyopathy was significantly increased in patients with AA genotype (OR = 9.9, P = .002) and GA genotype (OR = 5.2, P = .007) but not in those with GG genotype (OR = 1.1, P = .9) among patients receiving a cumulative anthracycline dose > 250 mg/m2 (high-dose group).
Among patients receiving > 450 mg/m2, odds ratios were 56.5 for AA, 6.0 for GA, and 0.6 for GG genotypes. Compared with patients with GG genotype, odds ratios for cardiomyopathy were 4.7 (P = .02) for those with GA genotype and 8.9 (P = .003) for those with AA genotype.
Gene-Environment Interaction
In the replication cohort, median cumulative anthracycline exposure was 300 mg/m2. Patients had a median age of 48 years at cancer diagnosis, 55 years at study participation, and 55 years at cardiomyopathy diagnosis. In addition, 58% were female, primary diagnoses included non-Hodgkin lymphoma in 47% and Hodgkin lymphoma in 18%, median follow-up was 4 years, 29% had anthracycline exposure of 251 to 300 mg/m2 and 36% had exposure > 300 mg/m2, 62% had exposure to chest radiation, and HAS3 genotypes were GG in 18%, GA in 42%, and AA in 40%.
Analysis showed a gene-environment interaction, with odds ratios for being in the high-dose anthracycline group of 3.6 (P = .07) for the GA genotype and 4.5 (P = .04) for the AA genotype vs the GG genotype. In a model including hypertension and diabetes, the odds ratio for being in the high-dose anthracycline group was 4.9 (P = .04) for the AA genotype vs GG genotype. In analysis combining cases from the discovery and replication sets, the odds ratio for AA genotype being in the high-dose anthracycline group was 3.7 (P = .01) vs the GG genotype.
In a study of heart samples, HAS3 mRNA levels tended to be lower among individuals with AA vs GA genotypes (P = .09).
The investigators concluded: “Hyaluronan…produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, [hyaluronan] is known to reduce reactive oxygen species (ROS)-induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.”
Smita Bhatia, MD, MPH, of City of Hope, Duarte, California, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants from the National Institutes of Health, Leukemia and Lymphoma Society, and American Lebanese Syrian Associated Charities. The study authors reported no potential conflicts of interest.
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