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Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional
L Martínez-Campelo1, A Blanco-Verea2, T López-Fernández3
1Instituto de Investigación Sanitaria de Santiago, Xenética Cardiovascular, Santiago De Compostela, Spain. laura_94.mc@hotmail.com.
Abstract:
Cancer therapy-related cardiac dysfunction (CTRCD), which commonly includes left ventricular dysfunction and heart failure, is the main adverse effect of anticancer therapy. In recent years several candidate genes studies and genome-wide association studies have identified common genetic variants associated with CTRCD, but evidence remains limited and few genetic variants are robust. A genome-wide meta-analysis of CTRCD was performed with 852 oncology patients receiving cancer therapy. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (N = 852 (380 cases and 472 controls) and extreme phenotypes (N = 618 (78 cases and 472 controls) looking for genetic variants that predispose to CTRCD. The results were validated in a replicate cohort of 1,191 oncology patients (245 cases and 946 controls). Functional mapping of the replicated loci was then performed. The meta-analysis showed 9 and 17 loci suggestively associated (P-value < 1 × 10-5) with CTRCD in case-control and extreme phenotypes analyses, respectively. The 3q28 locus (rs rs7652759, P = 5.64 × 10-6) in the case-control analysis was the strongest signal, with up to 64 SNPs above the suggestive significance threshold. The rs7652759, an intergenic variant between TPRG1 and TP63 genes, was the only variant validated in the replication cohort (P-value = 0.01). Functional mapping of this significant locus revealed up to 5 new genes potentially involved in the CTRCD. We identified the intergenic region near TP63 as a novel CTRCD susceptibility locus. In the future, the genotyping of these markers could be considered in new CTRCD risk scores to improve preventive strategies in cardio-oncology.
Insights
This study identified a new genetic marker near the TP63 gene associated with cancer therapy-related cardiac dysfunction (CTRCD). This finding could improve risk prediction and prevention strategies for heart problems in cancer patients.
Area of Science:
- Cardiology
- Genetics
- Oncology
Background:
- Cancer therapy-related cardiac dysfunction (CTRCD) is a significant adverse effect of anticancer treatments, often leading to left ventricular dysfunction and heart failure.
- Previous genetic studies for CTRCD have yielded limited and often unreproducible results, highlighting the need for robust genetic discoveries.
Purpose of the Study:
- To identify novel genetic variants predisposing individuals to cancer therapy-related cardiac dysfunction (CTRCD) through a genome-wide meta-analysis.
- To validate identified genetic loci in an independent cohort and perform functional mapping to understand their role in CTRCD.
Main Methods:
- A genome-wide meta-analysis was conducted on 852 oncology patients (380 cases, 472 controls) and an extreme phenotypes analysis on 618 patients (78 cases, 472 controls).
- Genotyping and imputation were used to identify associated genetic variants, followed by validation in a separate cohort of 1,191 patients.
- Functional mapping was performed on validated loci to explore potential biological mechanisms.
Main Results:
- The meta-analysis revealed 9 and 17 loci suggestively associated with CTRCD in case-control and extreme phenotypes analyses, respectively.
- A specific locus at 3q28 (rs7652759) showed the strongest association (P=5.64×10⁻⁶) in the case-control analysis and was successfully validated in the replication cohort (P=0.01).
- Functional mapping identified up to 5 new genes potentially involved in CTRCD pathogenesis near the validated locus.
Conclusions:
- The intergenic region near the TP63 gene represents a novel locus for susceptibility to cancer therapy-related cardiac dysfunction.
- Genotyping of identified markers could be incorporated into risk scores to enhance preventive strategies in cardio-oncology.
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