Introduction: Acute rejection (AR) in the 1st year post-cardiac transplant remains a significant clinical issue, and predisposes recipients to subsequent chronic allograft vasculopathy. Genetic factors such as HLA play roles in graft rejection. Non-HLA sources of genetic variation underpinning rejection include homozygous deletion copy number variants (CNVs) spanning whole gene or exon regions and loss-of-function (LoF) variants which can ablate two copies of a given gene, resulting in incompatibility across the proteomes of donor & recipient (D-R) pairs.

Methods: iGeneTRAiN, an international transplant genomics consortium, includes 1022 heart allograft recipients & 758 donors. All samples were genotyped with the TxArray, a genotyping array comprising >780K genome-wide markers with denser content in important transplantation region, and additional genetic variants were imputed using standard approaches. We conducted a genome-wide association study (GWAS) for AR in the 1st year post-transplantation, testing over 13 million variants in 1022 recipients. Second, effects of genetic variants were annotated with our LoF pipeline. For each D-R pair, genes were identified that are inactive in both copies in a transplant recipient but present in at least one functional copy in the respective donor. These genes were tested for AR-association using Cox proportional hazard models. D-R age, sex, study center, transplantation year and 10 PCs for D-Rs were included as covariates.

Results: We identified variants in two gene regions on chromosome 6 associated with AR in the 1st year post-transplantation (P<5×10^-8). One association resides in an HLA genic region, and the other is in an independent region 92 million bases distal to the HLA signal. In total we identified 695 genes to be inactivated in both copies in recipients but active in the donor in at least one D-R pair. We identified three 2-copy knockout genes on Chromosome 1,2 & 4 that are statistically associated with time to 1st biopsy proven rejection (P<3×10^-5).

Conclusions: Using GWAS & LoF analyses, we identified two SNPs and three LoF genes associated with heart allograft AR.

CITATION INFORMATION: van Setten J, Cole B, Chang B, de Jonge N, Holmes M, Baan C, Manintveld O, Peeters A, Dominguez F, Khush K, Garcia-Pavia P, Huibers M, de Weger R, Moore J, Asselbergs F, Keating B. Genome-Wide Genotyping in 1022 Heart Transplantation Recipients & 758 Donors Reveal Association with Acute Allograft Rejection. Am J Transplant. 2017;17 (suppl 3).

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