Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjögren's syndrome.
OBJECTIVE
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator of the T cell immune response, and the CTLA4 gene is highly polymorphic. Many positive associations between CTLA4 single-nucleotide polymorphisms (SNPs) and various autoimmune diseases have been identified. Two CTLA4 SNPs that are important relative to genetic susceptibility in human autoimmune diseases are the +49GA polymorphism in exon 1 and the CT60A/G polymorphism in the 3'-untranslated region. Using these 2 polymorphisms as markers, we investigated possible genetic associations of CTLA4 in Australian patients with primary Sjögren's syndrome.


METHODS
One hundred eleven Australian Caucasian patients with primary SS and 156 population-based controls were genotyped for CTLA4 by polymerase chain reaction-restriction fragment length polymorphism methods, using the restriction enzymes BseXI (+49G/A) and HpyCh4 IV (CT60).


RESULTS
The CT60 and +49G/A SNPs were in strong linkage disequilibrium, and only 3 haplotypes were observed. Significant differences in the haplotype frequencies between patients with primary SS and controls (P = 0.032) were observed, with susceptibility to primary SS associated with both the +49A;CT60A haplotype and the +49A;CT60G haplotype, whereas the +49G;CT60G haplotype was protective against primary SS. The +49A;CT60G haplotype association was predominantly with Ro/La autoantibody-positive primary SS, and the dose of this haplotype influenced the severity of daytime sleepiness (P = 0.036). The +49A;CT60A haplotype appeared to be protective against the development of Raynaud's phenomenon in patients with primary SS (odds ratio 0.49, 95% confidence interval 0.27-0.91).


CONCLUSIONS
The CTLA4 +49G/A and CT60 haplotypes are associated with susceptibility to primary SS and with some extraglandular manifestations of the disease.
Downie-Doyle
Sarah
S
Hanson Institute and The Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Bayat
Noushin
N
Rischmueller
Maureen
M
Lester
Susan
S
D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics* / Q000276:immunology; D060908:CTLA-4 Antigen; D016172:DNA Fingerprinting; D006970:Disorders of Excessive Somnolence / Q000209:etiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D015183:Restriction Mapping; D012859:Sjogren's Syndrome / Q000150:complications / Q000235:genetics / Q000276:immunology; D014570:Urologic Diseases / Q000209:etiology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human