Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed-effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis. We attempted replication in participants from two biobanks with biomarker or ICD-10 (International Classification of Diseases, 10th Revision) diagnostic codes for CKD. We assessed the association of single nucleotide variants (SNVs) at known CHD and stroke loci in CRIC and tested the genetic correlation among CRIC, a biobank-based cohort and published GWAS of cardiovascular disease. Among 3,588 CRIC participants, 1,203 had CHD and 535 had all-cause stroke. We identified six SNVs across three loci (LINC02744, AZIN1-AS1, and ATP6V0A4) associated with all-cause stroke, and two intronic SNVs at the PPARG locus associated with CHD. However, SNV associations were not significant in replication studies. Published SNVs for CHD or stroke were not associated with cardiovascular outcomes in CRIC. When testing the genetic correlations between published GWAS and CRIC GWAS, they were significant for CHD (genetic correlations (rg) range of 0.39 to 0.51, p-value<0.007). These findings suggest some differences in the genetic architecture of CHD and stroke among individuals with CKD compared to those from the general population, although large numbers of CKD participants are needed to assess if findings are related to participant selection and CKD severity, or non-traditional risk factors in people with CKD.

The authors have declared no competing interest.

Funding for this project was obtained through the CRIC Study Opportunity Pool Program and NIH R01-HL163972 to NF and YL. Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902 and U24DK060990). In addition, this work was supported in part by: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases P20 GM109036, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131, Department of Internal Medicine, University of New Mexico School of Medicine Albuquerque, NM R01DK119199. JW was partially supported by NIH T32ES007018. WG was supported by a grant from the National Institutes of Health, USA (NIH grant T32ES007018-46). This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award # BX004821. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

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Ethics committee/IRB of Chronic Renal Insufficiency Cohort Study gave ethical approval for this work.

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All data produced in the present study are available upon reasonable request to the authors