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