Sequence variation within the major histocompatibility complex subregion centromeric of HLA class II in type 1 diabetes.
The extended major histocompatibility complex (xMHC) has been studied intensively with regard to type 1 diabetes (T1D) predisposition. So far, little attention has been given to the subregion centromeric of MHC class II. We selected five single nucleotide polymorphisms in genes with potential immune-related functions in the genomic regions of death-domain-associated protein 6 (DAXX, apoptosis associated), TAP-binding protein (TAPBP, human leukocyte antigen class I loading) and retinoic acid receptor beta (RXRB, vitamin D receptor function) that may bear relevance to the pathogenesis of T1D. A total of 277 unrelated individuals with juvenile-onset T1D and 286 control subjects were genotyped using sequence-specific priming-polymerase chain reaction. The genotype and allelic frequencies of the markers tested were not significantly different between patients and control subjects. Subsequent haplotype analysis showed six DAXX-TAPBP-RXRB haplotypic configurations. No difference was observed between patients and control cohorts when stratified for T1D high-risk DQ2-DR17 and DQ8-DR4 haplotypes. However, the distribution of these haplotypes affected T1D susceptibility encoded by the intermediate risk haplotypes DQ5-DR1 and DQ2-DR7 by increasing and decreasing susceptibility, respectively. We propose that studying genetic variants in the xMHC may be particularly rewarding to define disease pathways in patients displaying intermediate risk DQ-DR haplotypes.
van der Slik
A R
AR
Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
van den Eng
I
I
Eerligh
P
P
Doxiadis
I I N
II
Koeleman
B P C
BP
Roep
B O
BO
Giphart
M J
MJ
D000483:Alleles; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006680:HLA Antigens; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012306:Risk; D017422:Sequence Analysis, DNA
D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta