Journal Article

Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis

David R. Karp, Nishanth Marthandan, Steven G.E. Marsh, Chul Ahn, Frank C. Arnett, David S. DeLuca, Alexander D. Diehl, Raymond Dunivin, Karen Eilbeck, Michael Feolo, Paula A. Guidry, Wolfgang Helmberg, Suzanna Lewis, Maureen D. Mayes, Chris Mungall, Darren A. Natale, Bjoern Peters, Effie Petersdorf, John D. Reveille, Barry Smith, Glenys Thomson, Matthew J. Waller and Richard H. Scheuermann

in Human Molecular Genetics

Volume 19, issue 4, pages 707-719
Published in print February 2010 | ISSN: 0964-6906
Published online November 2009 | e-ISSN: 1460-2083 | DOI:
Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis

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We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk.

Journal Article.  8144 words.  Illustrated.

Subjects: Genetics and Genomics

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