title: Association of Hashimoto's thyroiditis with cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and inducible co-stimulator (ICOS) genes in a Kuwaiti population.
abstract: Analysing two CTLA-4 markers [exon 1 A49G single nucleotide polymorphism (SNP) and exon 4 3'UTR (AT)n repeat] and the ICOS intron 4 (GT)n marker for their potential association with HT, and exploring the effect of the tested SNPs on the CTLA-4 isoform expression at the mRNA and protein levels. Total of 270 age-gender-ethnically matched subjects were genotyped by fluorescent-labelled restriction fragment length polymorphism, multiplex PCR, and fragment analysis. Sequencing was used to confirm the genotyping results. Expression of the full-length and soluble CTLA-4 mRNAs analysed using real-time PCR. Sera from subjects were screened for sCTLA-4 using ELISA. Tested subjects revealed ten alleles and sixteen genotypes of CTLA-4 3'UTR(AT)n. The 3'UTR(AT)n was significantly associated with HT: allele (AT)15 and genotype 15/15 were found to cause susceptibility to HT (P = 0.004, OR = 2.13, 95 % CI = 1.26-3.58 and P = 0.029, OR = 2.77, 95 % CI = 1.1-6.94, respectively), whereas allele (AT)6 and genotype 6/6 were found to be protective of HT (P = 0.00002, OR = 0.36, 95 % CI = 0.227-0.57 and P = 0.001, OR = 0.357, 95 % CI = 0.1980.64, respectively). SNP A49G and ICOS(GT)n revealed no significant association with HT (P > 0.05). The expression of sCTLA-4 was inversely proportional to the number of 3'UTR(AT)n repeats, with heterozygous and longer (AT)n repeats showing lower levels of sCTLA-4 mRNA than those with shorter alleles in HC and HT (P = 0.001 and P = 0.04, respectively). Significant increase in the serum level of sCTLA-4 was observed in HT patients compared with the HC (P = 0.0007). The novel finding in our study is that the CTLA-4 3'UTR(AT)n proven to be a key player in the pathogenesis of HT.
authors.affiliation: Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, P.O. Box 31470, Sulaibekhat, Kuwait. s.alfadhli@hsc.edu.kw
authors.forename: Suad
authors.initials: S
authors.lastname: Alfadhli
authors.forename: Qamar
authors.initials: Q
authors.lastname: Almutawa
authors.forename: Jasem M K
authors.initials: JM
authors.lastname: Abbas
authors.forename: Suhail A R
authors.initials: SA
authors.lastname: Doi
mesh_terms: D000328:Adult; D000483:Alleles; D060908:CTLA-4 Antigen / Q000235:genetics*; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D050031:Hashimoto Disease / Q000235:genetics* / Q000276:immunology; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics*; D007730:Kuwait; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D060908:CTLA-4 Antigen; D060889:Inducible T-Cell Co-Stimulator Protein