The HLA genes, the most polymorphic genes in the human genome, constitute the strongest single genetic susceptibility factor for autoimmune diseases, transplantation alloimmunity and infections. HLA imputation via statistical inference of alleles based on single-nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) with alleles is a powerful first-step screening tool. Due to different LD structures between populations, the accuracy of HLA imputation may benefit from matching the imputation reference with the study population. To evaluate the potential advantage of using population-specific reference in HLA imputation, we constructed an HLA reference panel consisting of 1150 Finns with 5365 major histocompatibility complex region SNPs consistent between genome builds. We evaluated the accuracy of the panel against a European panel in an independent test set of 213 Finnish subjects. We show that the Finnish panel yields a lower imputation error rate (1.24% versus 1.79%). More than 30% of imputation errors occurred in haplotypes enriched in Finland. The frequencies of imputed HLA alleles were highly correlated with clinical-grade HLA allele frequencies and allowed accurate replication of established HLA–disease associations in ∼102 000 biobank participants. The results show that a population-specific reference increases imputation accuracy in a relatively isolated population within Europe and can be successfully applied to biobank-scale genome data collections.
HLA matching is a prerequisite for successful allogeneic hematopoietic stem cell transplantation (HSCT) because it lowers the occurrence and severity of graft-versus-host disease (GVHD). However, matching a few alleles of the classic HLA genes only may not ensure matching of the entire MHC region. HLA haplotype matching has been reported to be beneficial in HSCT because of the variation relevant to GVHD risk in the non-HLA region. Because polymorphism in the MHC is highly population specific, we hypothesized that donors from the Finnish registry are more likely to be matched at a higher level for the Finnish patients than donors from other registries. In the present study we determined 25 single nucleotide polymorphisms (SNPs) of the complement component 4 (C4) gene in the g-block segment of MHC from 115 Finnish HSCT patients and their Finnish (n = 201) and non-Finnish (n = 280) donor candidates. Full matching of HLA alleles and C4 SNPs, independently or additively, occurred more likely in the FinnishÀFinnish group as compared with the FinnishÀnon-Finnish group (P < .003). This was most striking in cases with HLA haplotypes typical of the Finnish population. Patients with ancestral HLA haplotypes (AH) were more likely to find a full HLA and C4 matched donor, regardless of donor origin, as compared with patients without AH (P < .0001). Despite the clear differences at the population level, we could not find a statistical association between C4 matching and clinical outcome. The results suggest that screening C4 SNPs can be advantageous when an extended MHC matching or HLA haplotype matching in HSCT is required. This study also supports the need for small population-specific stem cell registries.
Autochthonous hepatitis E (HEV) cases have been increasingly recognized and reported in Europe, caused predominantly by the zoonotic HEV genotype 3. The clinical picture is highly variable, from asymptomatic to acute severe or prolonged hepatitis in immunocompromised patients. The main route of transmission to humans in Europe is the ingestion of undercooked pork meat. Transfusion-transmitted HEV infections have also been reported. The aim of the study was to determine the HEV epidemiology and risk in the Finnish blood donor population. A total of 23,137 samples from Finnish blood donors were screened for HEV RNA from individual samples and 1012 samples for HEV antibodies. Additionally, laboratory-confirmed hepatitis E cases in 2016–2022 were extracted from national surveillance data. The HEV RNA prevalence data was used to estimate the risk of transfusion transmission of HEV in the Finnish blood transfusion setting. Four HEV RNA-positive were found, resulting in 1:5784 (0.02%) RNA prevalence. All HEV RNA-positive samples were IgM-negative, and genotyped samples represented genotype HEV 3c. HEV IgG seroprevalence was 7.4%. From the HEV RNA rate found in this study and data on blood component usage in Finland in 2020, the risk estimate for a severe transfusion-transmitted HEV infection is 1:1,377,000 components or one in every 6–7 years. In conclusion, the results indicate that the risk of transfusion-transmitted HEV (HEV TTI) in Finland is low. However, continuous follow-up of the HEV epidemiology in relation to the transfusion risk landscape in Finland is necessary, as well as promoting awareness in the medical community of the small risk for HEV TTI, especially for immunocompromised patients.
Genetic variation in the MICA and MICB genes located within the major histocompatibility complex region has been reported to be associated with transplantation outcome and susceptibility to autoimmune diseases and infections. Only limited data of polymorphism in these genes in different populations are available. We here report allelic variation at 2‐field resolution and the haplotypes of the MICA and MICB genes in Finland (n = 1032 individuals), a north European population with historical bottleneck and founder effects. Altogether 24 MICA and 18 MICB alleles were found, forming 70 estimated MICA‐MICB haplotypes. As compared to other populations frequency differences were found, for example, MICA*010:01 was found to be at an allele frequency of 0.133 in Finland which is higher than in other European populations (0.021–0.077), but close to Asian populations (0.151–0.220). Three novel alleles with amino acid change are described. The results demonstrate a relatively high level of polymorphism and population differences in MICA and MICB allele distribution.
Background Allogeneic therapeutic cells may be rejected if they express HLA alleles not found in the recipient. As finding cell donors with a full HLA match to a recipient requires vast donor pools, the use of HLA homozygous cells has been suggested as an alternative. HLA homozygous cells should be well tolerated by those who carry at least one copy of donor HLA alleles. HLA-A-B homozygotes could be valuable for HLA-matched thrombocyte products. We evaluated the feasibility of blood donor biobank and HLA imputation for the identification of potential cell donors homozygous for HLA alleles. Methods We imputed HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and -DPB1 alleles from genotypes of 20,737 Finnish blood donors in the Blood Service Biobank. We confirmed homozygosity by sequencing HLA alleles in 30 samples and by examining 36,161 MHC-located polymorphic DNA markers. Results Three hundred and seventeen individuals (1.5%), representing 41 different haplotypes, were found to be homozygous for HLA-A, -B, -C, -DRB1, -DQA1 and -DQB1 alleles. Ten most frequent haplotypes homozygous for HLA-A to -DQB1 were HLA-compatible with 49.5%, and three most frequent homozygotes to 30.4% of the Finnish population. Ten most frequent HLA-A-B homozygotes were compatible with 75.3%, and three most frequent haplotypes to 42.6% of the Finnish population. HLA homozygotes had a low level of heterozygosity in MHC-located DNA markers, in particular in HLA haplotypes enriched in Finland. Conclusions The present study shows that HLA imputation in a blood donor biobank of reasonable size can be used to identify HLA homozygous blood donors suitable for cell therapy, HLA-typed thrombocytes and research. The homozygotes were HLA-compatible with a large fraction of the Finnish population. Regular blood donors reported to have positive attitude to research donation appear a good option for these purposes. Differences in population frequencies of HLA haplotypes emphasize the need for population-specific collections of HLA homozygous samples.
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