A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes

• Published in: Immunogenetics (New York) Vol. 55; no. 3; pp. 149 - 156
• Main Authors: Bassuny, Wafaa M, Ihara, Kenji, Sasaki, Yuka, Kuromaru, Ryuichi, Kohno, Hitoshi, Matsuura, Nobuo, Hara, Toshiro
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.06.2003
• Subjects: Cell activation; Chromosomes; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Dinucleotide Repeats; DNA-Binding Proteins - genetics; Enhancer Elements, Genetic; Female; Forkhead protein; Forkhead Transcription Factors; Foxp3 protein; Gene polymorphism; Genes; Genetic Predisposition to Disease; Homeostasis; Humans; Introns; Lymphocytes T; Male; Microsatellites; Nucleotides; Polymorphism; Polymorphism, Genetic; Promoter Regions, Genetic; Single-nucleotide polymorphism
• ISSN: 0093-7711; 1432-1211
• DOI: 10.1007/s00251-003-0559-8

FOXP3/Scurfin, a member of forkhead/winged-helix proteins, is involved in the regulation of T-cell activation, and essential for normal immune homeostasis. The FOXP3/Scurfin gene is located on chromosome Xp11.23, which includes one of the type 1 diabetes susceptible loci. Therefore, we investigated whether the human FOXP3/Scurfin gene might be a new candidate gene for type 1 diabetes. We first screened the human FOXP3/Scurfin gene for microsatellite and single nucleotide polymorphisms. Next, we performed an association study between the FOXP3/Scurfin gene and type 1 diabetes. Then, the evaluation of promoter/enhancer activity of the intron with (GT)(n) polymorphism was performed by dual luciferase reporter assay. We demonstrated two regions contained microsatellite polymorphisms; one was (GT)(n), located on intron zero and the other (TC)(n) on intron 5, which were under linkage-disequilibrium. The (GT)(15) allele showed a significantly higher frequency in patients with type 1 diabetes than in controls (43.1% vs 32.6%, P=0.0027). The genotype frequencies of (GT)(15)/(GT)(15) in female patients and of (GT)(15) in male patients tended to be higher than those in female ( P=0.064) and male ( P=0.061) controls, respectively. A significant difference in the enhancer activity between (GT)(15) and (GT)(16) dinucleotide repeats was detected. In conclusion, the FOXP3/Scurfin gene appears to confer a significant susceptibility to type 1 diabetes in the Japanese population.