Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis
Abstract Background Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types...
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-06027-4 |
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| author | Chuchun Fang Xuewei Liu Chen Yu Songlin Li Xueying Liu Shifeng Qiu Hongbin Liang Caiwen Ou Jiancheng Xiu |
| author_facet | Chuchun Fang Xuewei Liu Chen Yu Songlin Li Xueying Liu Shifeng Qiu Hongbin Liang Caiwen Ou Jiancheng Xiu |
| author_sort | Chuchun Fang |
| collection | DOAJ |
| description | Abstract Background Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. Methods This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). Results Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09–1.26, p = 1.33 × 10− 5). Additionally, the inhibition of FGFR1, FLT1, and MAP2K2 exhibited suggestive association with corresponding cardiovascular disease outcomes. Nevertheless, only VEGFA expression and stroke shared a causal variant (93.6%), whereas FGFR1, MAP2K2, and FLT1 did not share causal variants with corresponding cardiovascular diseases in the colocalization analysis. Conclusions This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy. |
| format | Article |
| id | doaj-art-7ed29b8d65a74e85af3143394e2396c8 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-7ed29b8d65a74e85af3143394e2396c82025-01-12T12:37:45ZengBMCJournal of Translational Medicine1479-58762025-01-0123111310.1186/s12967-024-06027-4Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysisChuchun Fang0Xuewei Liu1Chen Yu2Songlin Li3Xueying Liu4Shifeng Qiu5Hongbin Liang6Caiwen Ou7Jiancheng Xiu8Department of Cardiology, Nanfang Hospital, Southern Medical UniversityThe First School of Clinical Medicine, Southern Medical UniversityDepartment of Cardiology, The First Affiliated Hospital of Nanchang UniversityDepartment of Cardiology, Nanfang Hospital, Southern Medical UniversityDepartment of Cardiology, Nanfang Hospital, Southern Medical UniversityDepartment of Cardiology, Nanfang Hospital, Southern Medical UniversityDepartment of Cardiology, Nanfang Hospital, Southern Medical UniversityThe First School of Clinical Medicine, Southern Medical UniversityDepartment of Cardiology, Nanfang Hospital, Southern Medical UniversityAbstract Background Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. Methods This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). Results Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09–1.26, p = 1.33 × 10− 5). Additionally, the inhibition of FGFR1, FLT1, and MAP2K2 exhibited suggestive association with corresponding cardiovascular disease outcomes. Nevertheless, only VEGFA expression and stroke shared a causal variant (93.6%), whereas FGFR1, MAP2K2, and FLT1 did not share causal variants with corresponding cardiovascular diseases in the colocalization analysis. Conclusions This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy.https://doi.org/10.1186/s12967-024-06027-4Cancer-targeted therapyCardiovascular diseasesMendelian randomizationeQTL |
| spellingShingle | Chuchun Fang Xuewei Liu Chen Yu Songlin Li Xueying Liu Shifeng Qiu Hongbin Liang Caiwen Ou Jiancheng Xiu Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis Journal of Translational Medicine Cancer-targeted therapy Cardiovascular diseases Mendelian randomization eQTL |
| title | Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis |
| title_full | Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis |
| title_fullStr | Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis |
| title_full_unstemmed | Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis |
| title_short | Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis |
| title_sort | association of genetically proxied cancer targeted drugs with cardiovascular diseases through mendelian randomization analysis |
| topic | Cancer-targeted therapy Cardiovascular diseases Mendelian randomization eQTL |
| url | https://doi.org/10.1186/s12967-024-06027-4 |
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