title: Sequence feature variant type (SFVT) analysis of the HLA genetic association in juvenile idiopathic arthritis.
abstract: The immune response HLA class II DRB1 gene provides the major genetic contribution to Juvenile Idiopathic Arthritis (JIA), with a hierarchy of predisposing through intermediate to protective effects. With JIA, and the many other HLA associated diseases, it is difficult to identify the combinations of biologically relevant amino acid (AA) residues directly involved in disease due to the high level of HLA polymorphism, the pattern of AA variability, including varying degrees of linkage disequilibrium (LD), and the fact that most HLA variation occurs at functionally important sites. In a subset of JIA patients with the clinical phenotype oligoarticular-persistent (OP), we have applied a recently developed novel approach to genetic association analyses with genes/proteins sub-divided into biologically relevant smaller sequence features (SFs), and their "alleles" which are called variant types (VTs). With SFVT analysis, association tests are performed on variation at biologically relevant SFs based on structural (e.g., beta-strand 1) and functional (e.g., peptide binding site) features of the protein. We have extended the SFVT analysis pipeline to additionally include pairwise comparisons of DRB1 alleles within serogroup classes, our extension of the Salamon Unique Combinations algorithm, and LD patterns of AA variability to evaluate the SFVT results; all of which contributed additional complementary information. With JIA-OP, we identified a set of single AA SFs, and SFs in which they occur, particularly pockets of the peptide binding site, that account for the major disease risk attributable to HLA DRB1. These are (in numeric order): AAs 13 (pockets 4 and 6), 37 and 57 (both pocket 9), 67 (pocket 7), 74 (pocket 4), and 86 (pocket 1), and to a lesser extent 30 (pockets 6 and 7) and 71 (pockets 4, 5, and 7).
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, CA, USA. glenys@berkeley.edu
authors.forename: Glenys
authors.initials: G
authors.lastname: Thomson
authors.forename: Nishanth
authors.initials: N
authors.lastname: Marthandan
authors.forename: Jill A
authors.initials: JA
authors.lastname: Hollenbach
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Mack
authors.forename: Henry A
authors.initials: HA
authors.lastname: Erlich
authors.forename: Richard M
authors.initials: RM
authors.lastname: Single
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Waller
authors.forename: Steven G E
authors.initials: SG
authors.lastname: Marsh
authors.forename: Paula A
authors.initials: PA
authors.lastname: Guidry
authors.forename: David R
authors.initials: DR
authors.lastname: Karp
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scheuermann
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.forename: David N
authors.initials: DN
authors.lastname: Glass
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Helmberg
mesh_terms: D001171:Arthritis, Juvenile / Q000235:genetics* / Q000276:immunology*; D016022:Case-Control Studies; D002648:Child; D019295:Computational Biology; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium
chemical_list: D059811:HLA-DRB1 Chains