Identify New Genetic Variants on Chromosome 6 Associated with Mortality after Heart Transplantation

Abstract

Graft failure in heart transplant recipients is still the leading cumulative cause of death, rejection related injuries likely being an important contributor. In this study we used a genome-wide association approach using whole-genome data from chromosome 6 to analyze genetic associations with survival after heart transplantation. The study included recipient samples from patients who had undergone heart transplantation at Skane University Hospital, Lund, Sweden, between 1988 and 2009. Patients with at least one grade 3 rejection episode and/or survival <10 years were included, as well as individuals in control group with no grade 3 rejection episodes or survival >10 years. Endomyocardial biopsies were sent to the Broad Institute for DNA extraction and whole-genome sequencing. Variant calling and variant recalibration and filtering was conducted with the Genome Analysis Toolkit (GATK). A genome-wide association analysis using PLINK utilizing allelic association using chi-square test was performed. Genome-wide association analysis was conducted on a total of 34 patients using 470502 single nucleotide variants on chromosome 6. Thirteen associations yielded p > 1 × 10-5. We found 3 variants associated with mortality and after heart transplantation, rs66723041 (1.88 × 10-6), rs68123256 (6.28 × 10-6) and rs66758173 (6.28 × 10-6) in the gene HLA-DRB6. This first of its kind genome-wide association analysis demonstrates genetic variants associated with mortality and survival after heart transplantation. No association attained genome-wide significance, but several intriguing findings emerged. Notably, a cluster of low p-value SNVs were observed at HLA-DRB6 associated with mortality after heart transplantation. Genetic approaches such as these may lead to the identification of novel biological pathways and the development of new pharmaceutical targets and biomarkers.