SNP analysis of genes implicated in T cell proliferation in primary biliary cirrhosis.
Previous studies on primary biliary cirrhosis (PBC) have focused on the role of T lymphocytes as potential effectors of tissue injury. We hypothesized that single nucleotide polymorphisms (SNPs) of genes involved in lymphocyte proliferation would be responsible for uncontrolled expansion of T cells and autoreactivity. To address this, we genotyped DNA from 154 patients with PBC and 166 ethnically matched healthy controls for SNPs of five candidate genes (60G/A CTLA-4, 1858 C/T LYP, -IVS9 C/T foxp3, p1323 C/G ICOS and -9606 T/C CD25) using a TaqMan assay. We report herein a statistically significant decrease in homozygosity rate for the 60A*CTLA-4 allele in patients with PBC compared to controls (p = 0.0411). Moreover, we found a significant association of the same allele and of the LYP*T allele with anti-mitochondrial antibody (AMA) serum negativity (p = 0.0304 and 0.0094, respectively). No association between any of the other studied SNPs and PBC susceptibility, progression, or AMA status was observed. In conclusion, given the high prevalence of SNPs in CTLA-4 detected in numerous autoimmune diseases, we encourage a more detailed genetic analysis of this candidate gene. Further, although obtained from a limited number of AMA-negative subjects, our data suggest a potential genetic heterogeneity for this specific subgroup of patients with PBC.
Oertelt
Sabine
S
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, CA 95616, USA.
Kenny
Thomas P
TP
Selmi
Carlo
C
Invernizzi
Pietro
P
Podda
Mauro
M
Gershwin
M Eric
ME
D000368:Aged; D015703:Antigens, CD / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D005260:Female; D005787:Gene Frequency; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein