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Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells., Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles., Results: HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10(-4)), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10(-3)), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10(-3)) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr(9) (OR = 1.32 [1.15-1.52] P = 6.95*10(-5)) and HLA-C-Ser(11) (OR = 1.34 [1.15-1.57] P = 2.43*10(-4))., Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons., (© 2016 Associated Professional Sleep Societies, LLC.)

The Genotype List (GL) String grammar for reporting HLA and Killer-cell Immunoglobulin-like Receptor (KIR) genotypes in a text string was described in 2013. Since this initial description, GL Strings have been used to describe HLA and KIR genotypes for more than 40 million subjects, allowing these data to be recorded, stored and transmitted in an easily parsed, text-based format. After a decade of working with HLA and KIR data in GL String format, with advances in HLA and KIR genotyping technologies that have fostered the generation of full-gene sequence data, the need for an extension of the GL String system has become clear. Here, we introduce the new GL String delimiter ?, which addresses the need to describe ambiguity in assigning a gene sequence to gene paralogs. GL Strings that do not include a ? delimiter continue to be interpreted as originally described. This extension represents version 1.1 of the GL String grammar.

The guidelines for the implementation and reporting of HLA nomenclature for the World Marrow Donor Association have served as a reliable standard for communication of HLA data in the hematopoietic cell transplantation process. Wider use of next‐generation sequencing made a special provision of the guidelines increasingly pertinent: how to communicate novel HLA alleles. Novel alleles need to be recognized by the WHO Nomenclature Committee for Factors of the HLA system to obtain official allele designations. Until then they have to be handled according to the specific rules. Leaving the actual rules basically unchanged we give some advice on how to communicate novel alleles to best facilitate the search process for cases where novel alleles are identified on donor or patient side. [ABSTRACT FROM AUTHOR]

We present a catalog of common and well‐documented (CWD) alleles of the German population for the six HLA loci A, B, C, DRB1, DQB1, and DPB1. This study is based on a sample of over 5 million volunteer adult hematopoietic stem cell donors from the 26 German donor centers. To establish the catalog, allele and haplotype frequencies were estimated with a validated implementation of the expectation‐maximization algorithm. CWD criteria similar to existing CWD catalogs were applied in order to be able to put our findings into the context of relevant existing references. Overall, 2155 HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, and ‐DPB1 alleles were identified as CWD in the German donor population representing about 20% of the HLA alleles at two‐field resolution in the IPD‐IMGT/HLA Database release v3.25.0 from July 2016 for these six loci. We found a substantial concordance of CWD alleles between the three catalogs and showed the contribution of the German donor population to the CWD alleles domain. In conclusion, the definition of CWD criteria that allow interoperability, scalability, and flexibility will be crucial for the development of a worldwide CWD catalog. [ABSTRACT FROM AUTHOR]

• HLA-A-B-C-DRB1-DQB1 haplotypes carry significantly differing DPB1 associations. • DPB1 associations impact the likelihood of finding URDs with permissive DPB1 genotype. • The DPB1 associations in Finland differ from the worldwide population. • With increasing data, DPB1 associations could be assessed in different populations. • Predicting DPB1 permissiveness of DPB1 nontyped donors is feasible. Although HLA-DPB1 has long been considered of lesser importance in the selection of an unrelated donor (URD) hematologic stem cell transplantation, currently in many instances the DPB1 type of the donor is relevant or even critical. At present, however, only a minority of registry donors are DPB1 typed. It is also unclear to what extent the DPB1 alleles are linked to the 5-locus HLA-A-, B-, C-, DRB1, -DQB1 haplotypes. We sought to study whether there is such a linkage by using donors in the Finnish Stem Cell Registry as the study population. The 6-locus HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 haplotype frequencies were estimated from a group of 43,365 Finnish registry donors using the German National Bone Marrow Registry algorithm. Five-locus haplotype (HLA-A, -B, -C, -DRB1, -DQB1) and HLA-DPB1 allele frequencies were calculated as marginal frequencies of the estimated 6-locus haplotype frequencies. The Finnish average frequency of individual DPB1 alleles was compared with their respective frequencies in association with individual 5-locus HLA haplotypes (haplotype-specific frequencies). Finally, the probability of DPB1 matching in 10/10 matched URD transplants was assessed. Haplotype-specific DPB1 frequencies differed significantly from the average DPB1 frequencies in 81 of 100 most frequent Finnish 5-locus HLA haplotypes, including some infrequent DPB1 alleles that were associated almost exclusively with certain individual 5-locus haplotypes. Five-locus haplotypes that are enriched in Finland but rare among other Europeans carried stronger DPB1 associations than haplotypes that are frequent European-wide. Finally, 10/10 matched transplants from domestic registry donors were significantly more likely to also be DPB1 matched than those from foreign donors. The results indicate an extension of linkage disequilibrium in the MHC complex in the Finnish population. With continuing upfront DPB1 typing of registry donors, it will be possible to perform similar extended 6-locus haplotype frequency estimations also in other registries. The associations are likely to be population specific but may be weaker in more heterogeneous populations. In the future the results might be used to predict the probability of DPB1 match or permissive/nonpermissive DPB1 mismatch for non-DPB1 typed donors in registry donor searches. [ABSTRACT FROM AUTHOR]