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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.