Exploring the Pleiotropic Genes and Therapeutic Targets Associated with Heart Failure and Chronic Kidney Disease by Integrating metaCCA and SGLT2 Inhibitors’ Target Prediction

Author:

Li Huanqiang1ORCID,Mai Ziling12ORCID,Yu Sijia13,Wang Bo1ORCID,Lai Wenguang12,Chen Guanzhong14ORCID,Zhou Chunyun1,Liu Jin1ORCID,Yang Yongquan1,Chen Shiqun1ORCID,Liu Yong1234ORCID,Chen Jiyan1234ORCID

Affiliation:

1. Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China

2. Guangdong Provincial People’s Hospital, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510080, China

3. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515 Guangdong, China

4. Guangdong Provincial People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510515, China

Abstract

Background. Previous studies have shown that heart failure (HF) and chronic kidney disease (CKD) have common genetic mechanisms, overlapping pathophysiological pathways, and therapeutic drug—sodium-glucose cotransporter 2 (SGLT2) inhibitors. Methods. The genetic pleiotropy metaCCA method was applied on summary statistics data from two independent meta-analyses of GWAS comprising more than 1 million people to identify shared variants and pleiotropic effects between HF and CKD. Targets of SGLT2 inhibitors were predicted by SwissTargetPrediction and DrugBank databases. To refine all genes, we performed using versatile gene-based association study 2 (VEGAS2) and transcriptome-wide association studies (TWAS) for HF and CKD, respectively. Gene enrichment and KEGG pathway analyses were used to explore the potential functional significance of the identified genes and targets. Results. After metaCCA analysis, 4,624 SNPs and 1,745 genes were identified to be potentially pleiotropic in the univariate and multivariate SNP-multivariate phenotype analyses, respectively. 21 common genes were detected in both metaCCA and SGLT2 inhibitors’ target prediction. In addition, 169 putative pleiotropic genes were identified, which met the significance threshold both in metaCCA analysis and in the VEGAS2 or TWAS analysis for at least one disease. Conclusion. We identified novel variants associated with HF and CKD using effectively incorporating information from different GWAS datasets. Our analysis may provide new insights into HF and CKD therapeutic approaches based on the pleiotropic genes, common targets, and mechanisms by integrating the metaCCA method, TWAS and VEGAS2 analyses, and target prediction of SGLT2 inhibitors.

Funder

Natural Science Foundation of Guangdong Province

Publisher

Hindawi Limited

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine

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