Browsing by Author "Semenova, Maria"

Liver transplantation (LT) procedure has evolved tremendously over the last 40 years and is nowadays a standard treatment for both end-stage liver disease and acute liver failure. Improved immunosuppressive medication, surgical methods, imaging and intensive care raise the probability of successful transplantation. Despite good prognosis of survival, acute rejection (AR) is still a significant clinical factor that negatively affects LT outcomes. In the last decade, whole genome-wide incompatibility between recipients and donors has emerged as a potential risk factor in both hematopoietic stem cell and kidney transplantations. The role of non-human leukocyte antigen (HLA) factors in LT outcomes has not been comprehensively established. Thus, the aim of this study is to compare patient and donor genomes pairwise, identify mismatches and further, analyze the effect of these mismatches on AR. After data preparation, 666 LT recipient-donor pairs were included in the analyses. Genotype imputation yielded 8 706 949 variants after quality control. From these variants, 28 225 missense variants were identified and utilized in the genome-wide mismatch analyses. In this study, we calculated genome-wide mismatches of missense variants to identify incompatibilities in all, transmembrane and secreted, transmembrane-only and liver-related proteins between recipients and donors. In addition, we analyzed the effect of mismatches in 40 common deletions and also the sum of deletion-mismatches. We estimated the association of genetic mismatches and time to AR by using Cox proportional hazards model adjusted with recipient and donor age, recipient and donor sex, cold-ischemia time, HLA I eplet mismatch and HLA II eplet mismatch. According to the findings of the study, there is no association between missense variant mismatches coding for either all, transmembrane and secreted, transmembrane-only or liver-related proteins and time to AR. There was also no association between quartiles of missense variant mismatches and time to AR. In the genomic collision model, we found mismatch in deletion-tagging variant rs1523688 to be associated with a decreased risk for AR (adjusted hazard ratio (HR) 0.38, 95% confidence interval (CI) 0.16–0.92, P-value 0.032) and mismatch in rs11985201 to be associated with an increased risk for AR (adjusted HR 1.44, 95% CI 1.04–2.00, P-value 0.030). However, neither of these P-values passed the Bonferroni corrected significance level of 0.00125. No association was observed between deletion mismatch sums and time to AR. In conclusion, we observed no statistically significant association between the genome-wide incompatibility and time to AR in the study cohort of 666 LT recipient-donor pairs. To increase detection power, large-scale studies are required to verify the role of genome-wide mismatches in LTs.