Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison's disease.
Although autoimmune Addison's disease (AAD) may occur as a component of the monogenic autoimmune polyendocrinopathy type 1 syndrome (APS1), it is most commonly found as an isolated disorder or associated with the autoimmune polyendocrinopathy type 2 syndrome (APS2). It is likely that sporadic (non-APS1) AAD is inherited as a complex trait; however, apart from the major histocompatibility complex, the susceptibility genes remain unknown. We have examined polymorphisms at two non-major histocompatibility complex candidate susceptibility loci in sporadic (non-APS1) AAD: the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and the autoimmune regulator (AIRE-1) gene. DNA samples from AAD subjects (n = 90) and local controls (n = 144 for CTLA-4; n = 576 for AIRE-1) were analyzed for the CTLA-4A/G polymorphism in exon 1 of the CTLA-4 gene and for the common mutant AIRE-1 allele (964de113) in United Kingdom subjects with APS1, by using the restriction enzymes Bst7II and BsrBI, respectively. There was an association of the G allele at CTLA-4A/G in AAD subjects (P = 0.008 vs. controls), which was stronger in subjects with AAD as a component of APS2 than in subjects with isolated AAD. In contrast, the mutant AIRE-1 964del13 allele was carried in one each of the 576 (0.2%) control subjects and the 90 (1.1%) AAD subjects as a heterozygote (P = 0.254, not significant), suggesting that this common AIRE-1 gene abnormality does not have a major role in sporadic (non-APS1) AAD.
Vaidya
B
B
Department of Medicine, University of Newcastle upon Tyne, United Kingdom.
Imrie
H
H
Geatch
D R
DR
Perros
P
P
Ball
S G
SG
Baylis
P H
PH
Carr
D
D
Hurel
S J
SJ
James
R A
RA
Kelly
W F
WF
Kemp
E H
EH
Young
E T
ET
Weetman
A P
AP
Kendall-Taylor
P
P
Pearce
S H
SH
D000069594:Abatacept; D000224:Addison Disease / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D005838:Genotype; D006801:Humans; D018796:Immunoconjugates; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D014157:Transcription Factors; D000096927:AIRE Protein; C556706:CTLA4 protein, human