Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
3258915 | Clinical Immunology | 2006 | 10 Pages |
Abstract
In this study, we evaluated the A/G(â1661), C/T(â318), A/G49 and A/G6230 single nucleotide polymorphisms (SNPs) of the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene for association with Graves' disease (GD) in 126 Russian simplex families. The conditional TDT analysis revealed significant overtransmission of the A(â1661)G(â318) haplotype (PÂ =Â 0.033) and undertransmission of the GT haplotype (PÂ =Â 0.0043) from parents homozygous for both +49 and +6230 polymorphisms. Parents homozygous for both (â1661) and (â318) markers significantly overtransmitted the G49G6230 haplotype (PÂ =Â 0.0013) and undertransmitted the AG haplotype (PÂ =Â 0.035) to affected offspring. This suggests in favor of the independent genetic effects of the 3â² and 5â²ends of CTLA-4 in conferring the susceptibility to GD. Both SNPs located at the 5â² untranslated region of CTLA-4 were functionally analyzed using the luciferase reporter assay. We observed differential activation of the C/T(â318) promoter variant when Jurkat T cells and HeLa cells were cotransfected with a plasmid expressing lymphoid enhancing factor 1 (LEF1) and various CTLA-4 promoter constructs. The (â318) SNP modifies a putative binding site for LEF1 so that it alters the stimulating effect of LEF1 on the expression ability of the CTLA-4 promoter. The (â1661) dimorphism modifies a potential binding site for myocyte enhancer factor 2 (MEF2). No significant correlation between the (â1661) SNP and MEF2 activity in cotransfection experiments was found. Observed data help for further understanding a functional role of CTLA-4 promoter polymorphisms in the pathogenic mechanism of GD.
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Authors
Dimitry A. Chistiakov, Kirill V. Savost'anov, Rustam I. Turakulov, Ilya A. Efremov, Lev M. Demurov,