title: Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: family based association study.
abstract: Type 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin-producing β-cells. Several studies support the involvement of T cell activation molecules in the pathogenesis of T1D. In order to underline the role of the genes involved in this activation pathway, we investigated, using the Sequenom MassARRAY platform, 45 single-nucleotide polymorphisms (SNPs) belonging to TCR/CD3, CD28, ZAP70, and PTPN22 genes in 59 T1D Tunisian families. In the current study, we identified an association with rs706 (Z score=2.782; p=0.005) of TCRβ gene. We also demonstrated that rs10918706 in the intron of the CD3z gene was associated with increased risk of T1D (Z score 2.137; p=0.032). In the same region, rs2949655 (Z score=2.101; p=0.035) and rs1214611 (Z score=4.036; p=0.00005) showed a genotype association with the risk of T1D. When haplotypes were constructed, GAA haplotype displayed significant association with T1D (Z score=2.135; p=0.032), while GGA haplotype (Z score=-1.988; p=0.046) was negatively associated with the disease. We also identified an association with rs3181096 (Z score=2.177; p=0.029), rs17695937 (Z score =2.111; p=0.034) and rs2488457 (Z score=2.219; p=0.026), respectively of CD28, ZAP70 and PTPN22 genes. In addition, our results suggest a significant effect on T1D susceptibility for AC (Z score=2.30; p=0.02) and CTGGC (Z score=2.309, p=0.02) haplotypes of ZAP70 and PTPN22 genes, respectively. While, the GTCT (Z score=-2.114, p=0.034) and CTAGG (Z score=-2.121, p=0.033) haplotypes of CD28 and PTPN22 genes, may confer protection against T1D. These findings confirm the role of PTPN22 and CD28 involved in the T cell activation pathway in the development of T1D in Tunisian families. Interestingly, ZAP70 and TCRβ/CD3z seem to contribute to the susceptibility to the disease in our population. However, this finding has to be confirmed in further studies.
authors.affiliation: Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia. Electronic address: zouidi_ferjeni@yahoo.fr.
authors.forename: Zouidi
authors.initials: Z
authors.lastname: Ferjeni
authors.affiliation: Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
authors.forename: D
authors.initials: D
authors.lastname: Bouzid
authors.affiliation: Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
authors.forename: H
authors.initials: H
authors.lastname: Fourati
authors.affiliation: Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
authors.forename: M
authors.initials: M
authors.lastname: Stayoussef
authors.affiliation: Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
authors.forename: O
authors.initials: O
authors.lastname: Abida
authors.affiliation: Pediatric Department, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia.
authors.forename: T
authors.initials: T
authors.lastname: Kammoun
authors.affiliation: Pediatric Department, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia.
authors.forename: M
authors.initials: M
authors.lastname: Hachicha
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Penha-Gonçalves
authors.affiliation: Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
authors.forename: H
authors.initials: H
authors.lastname: Masmoudi
mesh_terms: D000293:Adolescent; D000328:Adult; D018106:CD28 Antigens / Q000235:genetics* / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D014416:Tunisia; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics* / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: CD28; PTPN22; TCR/CD3; Tunisia; Type 1 diabetes; ZAP70