title: Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis.
abstract: 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.
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-8884, USA. david.karp@utsouthwestern.edu
authors.forename: David R
authors.initials: DR
authors.lastname: Karp
authors.forename: Nishanth
authors.initials: N
authors.lastname: Marthandan
authors.forename: Steven G E
authors.initials: SG
authors.lastname: Marsh
authors.forename: Chul
authors.initials: C
authors.lastname: Ahn
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: David S
authors.initials: DS
authors.lastname: Deluca
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Diehl
authors.forename: Raymond
authors.initials: R
authors.lastname: Dunivin
authors.forename: Karen
authors.initials: K
authors.lastname: Eilbeck
authors.forename: Michael
authors.initials: M
authors.lastname: Feolo
authors.forename: Paula A
authors.initials: PA
authors.lastname: Guidry
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Helmberg
authors.forename: Suzanna
authors.initials: S
authors.lastname: Lewis
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Chris
authors.initials: C
authors.lastname: Mungall
authors.forename: Darren A
authors.initials: DA
authors.lastname: Natale
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Effie
authors.initials: E
authors.lastname: Petersdorf
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Barry
authors.initials: B
authors.lastname: Smith
authors.forename: Glenys
authors.initials: G
authors.lastname: Thomson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Waller
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scheuermann
mesh_terms: D014644:Genetic Variation; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics*; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008968:Molecular Conformation; D012595:Scleroderma, Systemic / Q000235:genetics*
chemical_list: D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains