Genetic background and transplantation outcomes: insights from genome-wide association studies

The current review summarizes recent advances in the genetic studies of transplantation outcomes, including new genome-wide association studies for acute rejection, allograft survival, pharmacogenomics, and common transplant comorbidities.

Genetic studies of kidney transplantation outcomes have begun to address the question of genetic compatibility beyond human leukocyte antigens, including the role of genome-wide mismatches in missense variants, and the 'genomic collision' hypothesis under which the risk of rejection may be increased in recipients homozygous for loss-of-function variants with grafts from nonhomozygous donors. In recent pilot studies, missense mismatch scores for transmembrane and secreted proteins were associated with antibodies against the mismatched peptides and reduced allograft survival. A 'genomic collision' at the LIMS1 locus involving a common deletion near LIMS1 gene was associated with anti-LIMS1 antibody response and increased risk of rejection. Additional genetic factors under active investigation include genome-wide polygenic risk scores for renal function and apolipoprotein L1 risk genotypes in African-American kidney donors. Due to the heterogeneity and complexity of clinical outcomes, new genome-wide association studies for rejection, allograft survival, and specific transplant comorbidities will require larger multicenter meta-analyses.

Genetic compatibilities between donor and recipient represent an important determinant of rejection and long-term allograft survival. Genetic background of transplant donors may be additionally predictive of allograft function, while recipient's genomes are likely determinant of a wide range of transplantation outcomes, from rejection susceptibility to pharmacogenetics and various comorbidities related to prolonged immunosuppression.