title: A combined DPA1~DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer.
abstract: Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n = 5,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket. This may help explain the differential pattern of allele frequency distribution observed for this locus relative to the other class II loci. These findings further support the notion that allele-level associations in disease and transplantation may not be the most important unit of analysis, and that they should be considered instead in the molecular context.
authors.affiliation: National Marrow Donor Program, Minneapolis, MN, USA. jhollenbach@chori.org
authors.forename: Jill A
authors.initials: JA
authors.lastname: Hollenbach
authors.forename: Abeer
authors.initials: A
authors.lastname: Madbouly
authors.forename: Loren
authors.initials: L
authors.lastname: Gragert
authors.forename: Cynthia
authors.initials: C
authors.lastname: Vierra-Green
authors.forename: Susan
authors.initials: S
authors.lastname: Flesch
authors.forename: Stephen
authors.initials: S
authors.lastname: Spellman
authors.forename: Ann
authors.initials: A
authors.lastname: Begovich
authors.forename: Harriet
authors.initials: H
authors.lastname: Noreen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Trachtenberg
authors.forename: Tom
authors.initials: T
authors.lastname: Williams
authors.forename: Neng
authors.initials: N
authors.lastname: Yu
authors.forename: Bronwen
authors.initials: B
authors.lastname: Shaw
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernandez-Vina
authors.forename: Martin
authors.initials: M
authors.lastname: Maiers
mesh_terms: D000596:Amino Acids; D018604:Epitope Mapping; D000939:Epitopes; D005787:Gene Frequency; D005838:Genotype; D059867:HLA-DP alpha-Chains / Q000235:genetics*; D059868:HLA-DP beta-Chains / Q000235:genetics*; D006239:Haplotypes; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D008958:Models, Molecular; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics
chemical_list: D000596:Amino Acids; D000939:Epitopes; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen