Sequence Feature Variant Type (SFVT) Analysis of the HLA Genetic Association in Juvenile Idiopathic Arthritis


Glenys Thomson1, Nishanth Marthandan2, Jill A. Hollenbach3, Steven J. Mack3, Henry A. Erlich3,4, Richard M. Single5, Matthew J. Waller6, Steven G.E. Marsh6,7, Paula A. Guidry8, David R. Karp9, Richard H. Scheuermann6, Susan D. Thompson10, David N. Glass10, Wolfgang Helmberg11



1Department of Integrative Biology, University of California, Berkeley, CA, USA; 2Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3Children's Hospital Oakland Research Institute, Oakland, CA, USA; 4Roche Molecular Systems, Pleasanton, CA, USA; 5Department of Mathematics and Statistics, University of Vermont, Burlington, VA, USA; 6Anthony Nolan Research Institute, Royal Free khspital, London, UK; 7UK and UCL Cancer Institute, Royal Free Campus London, UK; 8Department of Pathology, 9Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 10Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; 11Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria

Email: glenys@berkeley.edu


Pacific Symposium on Biocomputing 15:359-370(2010)



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).


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