ABSTRACT
Differentiation of B lymphocytes is accompanied by a regulated switch in the expression pattern and stability of surface and secretory immunoglobulins (Igs). Several lines of evidence show that autoimmune responses evolving in much autoimmune pathologies were associated with a high level of humoral Ig, but their pathogenic role remains elusive. The aim of this study was to test the hypothesis that variants at the immunoglobulin heavy-chain IGH locus are genetic determinants to T1D susceptibility. Here, we tested the genetic association of the variants of the immunoglobulin heavy-chain IGH locus as a genetic determinant to T1D susceptibility. A total of 255 subjects from 59 Tunisian families were genotyped for 15 SNPs mapping in 4 regions in IGH locus. We found that rs1950942, rs2180790, rs1808152, and rs1956596 of IGHM and rs2516751 variant located in the IGHA1/IGHG2 region were significantly associated with a risk for T1D p = 7E-3; p = 0.03; p = 0.02; p = 0.043; and p = 3.65E-5, respectively. The TATGG haplotype derived from LD across three SNPs from IGHM gene and two SNPs from IGHD gene was significantly over-transmitted from parents to affect offspring. Our results suggest that genetic variants at the IGH locus are associated with T1D susceptibility. These variations may predispose to IgG AutoAbs production against pancreatic antigens and AutoAbs multi-reactivity, leading to T1D development.
Subject(s)
Diabetes Mellitus, Type 1 , Immunoglobulin mu-Chains , Diabetes Mellitus, Type 1/genetics , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Immunoglobulin mu-Chains/genetics , Immunoglobulins/genetics , Polymorphism, Single NucleotideABSTRACT
Type 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin-producing ß-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 TCRß 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 TCRß/CD3z seem to contribute to the susceptibility to the disease in our population. However, this finding has to be confirmed in further studies.
