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Published in: Immunologic Research 3/2022

20-01-2022 | Type 1 Diabetes | Original Article

Association of IGHM polymorphisms with susceptibility to type 1 diabetes

Authors: Zouidi Ferjeni, Fakhfakh Raouia, O. Abida, C. Penha-Gonçalves, H. Masmoudi

Published in: Immunologic Research | Issue 3/2022

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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.
Literature
1.
go back to reference Watson CT, Breden F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease. Genes Immun. 2012;13(5):363–73.CrossRef Watson CT, Breden F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease. Genes Immun. 2012;13(5):363–73.CrossRef
2.
go back to reference Robinson WH. Sequencing the functional antibody repertoire—diagnostic and therapeutic discovery. Nat Rev Rheumatol. 2015;11(3):171.CrossRef Robinson WH. Sequencing the functional antibody repertoire—diagnostic and therapeutic discovery. Nat Rev Rheumatol. 2015;11(3):171.CrossRef
3.
go back to reference Lefranc M-P, Lefranc G. The immunoglobulin factsbook. Academic press; 2001. Lefranc M-P, Lefranc G. The immunoglobulin factsbook. Academic press; 2001.
4.
go back to reference Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annual review of immunology. 2008;26. Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annual review of immunology. 2008;26.
5.
go back to reference Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJ, Bingley PJ, et al. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes. 2004;53(2):384–92.CrossRef Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJ, Bingley PJ, et al. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes. 2004;53(2):384–92.CrossRef
6.
go back to reference Hoppu S, Härkönen T, Ronkainen MS, Åkerblom HK, Knip M, Group CDiFS. IA-2 antibody epitopes and isotypes during the prediabetic process in siblings of children with type 1 diabetes. Journal of autoimmunity. 2004;23(4):361–70.CrossRef Hoppu S, Härkönen T, Ronkainen MS, Åkerblom HK, Knip M, Group CDiFS. IA-2 antibody epitopes and isotypes during the prediabetic process in siblings of children with type 1 diabetes. Journal of autoimmunity. 2004;23(4):361–70.CrossRef
7.
go back to reference Decraene T, Vandewalle C, Pipeleers D, Gorus F. Increased concentrations of total IgM at clinical onset of type 1 (insulin-dependent) diabetes: correlation with IgM binding to cells. The Belgian Diabetes Registry Clinical chemistry. 1992;38(9):1762–7.PubMed Decraene T, Vandewalle C, Pipeleers D, Gorus F. Increased concentrations of total IgM at clinical onset of type 1 (insulin-dependent) diabetes: correlation with IgM binding to cells. The Belgian Diabetes Registry Clinical chemistry. 1992;38(9):1762–7.PubMed
8.
go back to reference Dean B, Becker F, McNally J, Tarn A, Schwartz G, Gale E, et al. Insulin autoantibodies in the pre-diabetic period: correlation with islet cell antibodies and development of diabetes. Diabetologia. 1986;29(5):339–42.CrossRef Dean B, Becker F, McNally J, Tarn A, Schwartz G, Gale E, et al. Insulin autoantibodies in the pre-diabetic period: correlation with islet cell antibodies and development of diabetes. Diabetologia. 1986;29(5):339–42.CrossRef
9.
go back to reference Hawa MI, Fava D, Medici F, Deng Y-J, Notkins AL, De Mattia G, et al. Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality. Diabetes Care. 2000;23(2):228–33.CrossRef Hawa MI, Fava D, Medici F, Deng Y-J, Notkins AL, De Mattia G, et al. Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality. Diabetes Care. 2000;23(2):228–33.CrossRef
10.
go back to reference Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol. 1995;7(6):812–8.CrossRef Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol. 1995;7(6):812–8.CrossRef
11.
go back to reference Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Investig. 2007;117(3):712–8.CrossRef Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Investig. 2007;117(3):712–8.CrossRef
12.
go back to reference Rolim I, Duarte N, Barata G, Costa J, Gardete-Correia L, Boavida J, et al. Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes. Immunogenetics. 2017;69(7):429–37.CrossRef Rolim I, Duarte N, Barata G, Costa J, Gardete-Correia L, Boavida J, et al. Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes. Immunogenetics. 2017;69(7):429–37.CrossRef
13.
go back to reference Côrte-Real J, Duarte N, Tavares L, Penha-Gonçalves C. Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes. Diabetologia. 2012;55(6):1761–72.CrossRef Côrte-Real J, Duarte N, Tavares L, Penha-Gonçalves C. Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes. Diabetologia. 2012;55(6):1761–72.CrossRef
14.
go back to reference Zouidi F, Stayoussef M, Bouzid D, Fourati H, Abida O, Ayed MB, et al. Contribution of PTPN22, CD28, CTLA-4 and ZAP-70 variants to the risk of type 1 diabetes in Tunisians. Gene. 2014;533(1):420–6.CrossRef Zouidi F, Stayoussef M, Bouzid D, Fourati H, Abida O, Ayed MB, et al. Contribution of PTPN22, CD28, CTLA-4 and ZAP-70 variants to the risk of type 1 diabetes in Tunisians. Gene. 2014;533(1):420–6.CrossRef
15.
go back to reference Consortium WTCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661.CrossRef Consortium WTCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661.CrossRef
16.
go back to reference Hua RX, Fu W, Lin A, Zhou H, Cheng J, Zhang J et al. Role of FTO gene polymorphisms in Wilms tumor predisposition: A five‐center case–control study. The Journal of Gene Medicine. 2021:e3348. Hua RX, Fu W, Lin A, Zhou H, Cheng J, Zhang J et al. Role of FTO gene polymorphisms in Wilms tumor predisposition: A five‐center case–control study. The Journal of Gene Medicine. 2021:e3348.
17.
go back to reference Ren H, Zhuo Z-J, Duan F, Li Y, Yang Z, Zhang J et al. ALKBH5 gene polymorphisms and hepatoblastoma susceptibility in chinese children. Journal of oncology. 2021;2021. Ren H, Zhuo Z-J, Duan F, Li Y, Yang Z, Zhang J et al. ALKBH5 gene polymorphisms and hepatoblastoma susceptibility in chinese children. Journal of oncology. 2021;2021.
18.
go back to reference Zhuo Z, Miao L, Hua W, Chen H, Yang Z, Li Y et al. Genetic variations in nucleotide excision repair pathway genes and hepatoblastoma susceptibility. International journal of cancer. 2021. Zhuo Z, Miao L, Hua W, Chen H, Yang Z, Li Y et al. Genetic variations in nucleotide excision repair pathway genes and hepatoblastoma susceptibility. International journal of cancer. 2021.
19.
go back to reference Hakonarson H, Grant SF, Bradfield JP, Marchand L, Kim CE, Glessner JT, et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature. 2007;448(7153):591–4.CrossRef Hakonarson H, Grant SF, Bradfield JP, Marchand L, Kim CE, Glessner JT, et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature. 2007;448(7153):591–4.CrossRef
20.
go back to reference Cianci R, D’Addabbo P, Gambassi G, Lolli S, Serone E, Rizzi A, et al. Association between IgH enhancer hs1 2 and type 1 diabetes. Acta diabetologica. 2018;55(5):443–8.CrossRef Cianci R, D’Addabbo P, Gambassi G, Lolli S, Serone E, Rizzi A, et al. Association between IgH enhancer hs1 2 and type 1 diabetes. Acta diabetologica. 2018;55(5):443–8.CrossRef
21.
go back to reference Tolusso B, Frezza D, Mattioli C, Fedele AL, Bosello S, Faustini F, et al. Allele* 2 of the HS1, 2A enhancer of the Ig regulatory region associates with rheumatoid arthritis. Ann Rheum Dis. 2009;68(3):416–9.CrossRef Tolusso B, Frezza D, Mattioli C, Fedele AL, Bosello S, Faustini F, et al. Allele* 2 of the HS1, 2A enhancer of the Ig regulatory region associates with rheumatoid arthritis. Ann Rheum Dis. 2009;68(3):416–9.CrossRef
22.
go back to reference Frezza D, Tolusso B, Giambra V, Gremese E, Marchini M, Nowik M, et al. Polymorphisms of the IgH enhancer HS1 2 and risk of systemic lupus erythematosus. Annals of the rheumatic diseases. 2012;71(8):1309–15.CrossRef Frezza D, Tolusso B, Giambra V, Gremese E, Marchini M, Nowik M, et al. Polymorphisms of the IgH enhancer HS1 2 and risk of systemic lupus erythematosus. Annals of the rheumatic diseases. 2012;71(8):1309–15.CrossRef
23.
go back to reference Frezza D, Giambra V, Tolusso B, De Santis M, Bosello S, Vettori S, et al. Polymorphism of immunoglobulin enhancer element HS1, 2A: allele* 2 associates with systemic sclerosis. Comparison with HLA-DR and DQ allele frequency. Annals of the rheumatic diseases. 2007;66(9):1210–5.CrossRef Frezza D, Giambra V, Tolusso B, De Santis M, Bosello S, Vettori S, et al. Polymorphism of immunoglobulin enhancer element HS1, 2A: allele* 2 associates with systemic sclerosis. Comparison with HLA-DR and DQ allele frequency. Annals of the rheumatic diseases. 2007;66(9):1210–5.CrossRef
24.
go back to reference Kawasaki ES. Sample preparation from blood, cells, and other fluids. PCR protocols: a guide to methods and applications. 1990;1. Kawasaki ES. Sample preparation from blood, cells, and other fluids. PCR protocols: a guide to methods and applications. 1990;1.
25.
go back to reference Dorman JS, Bunker CH. HLA-DQ locus of the human leukocyte antigen complex and type 1 diabetes mellitus: a HuGE review. Epidemiol Rev. 2000;22(2):218–27.CrossRef Dorman JS, Bunker CH. HLA-DQ locus of the human leukocyte antigen complex and type 1 diabetes mellitus: a HuGE review. Epidemiol Rev. 2000;22(2):218–27.CrossRef
26.
go back to reference Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39(7):857–64.CrossRef Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39(7):857–64.CrossRef
27.
go back to reference Plagnol V, Howson JM, Smyth DJ, Walker N, Hafler JP, Wallace C, et al. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet. 2011;7(8):e1002216.CrossRef Plagnol V, Howson JM, Smyth DJ, Walker N, Hafler JP, Wallace C, et al. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet. 2011;7(8):e1002216.CrossRef
28.
go back to reference Walter MA, Chambers CA, Zimmerman B, Cox DW. A multigene deletion in the immunoglobulin heavy chain region in a highly atopic individual. Hum Genet. 1990;85(6):643–7.CrossRef Walter MA, Chambers CA, Zimmerman B, Cox DW. A multigene deletion in the immunoglobulin heavy chain region in a highly atopic individual. Hum Genet. 1990;85(6):643–7.CrossRef
29.
go back to reference Avnir Y, Watson CT, Glanville J, Peterson EC, Tallarico AS, Bennett AS, et al. IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity. Sci Rep. 2016;6(1):1–13.CrossRef Avnir Y, Watson CT, Glanville J, Peterson EC, Tallarico AS, Bennett AS, et al. IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity. Sci Rep. 2016;6(1):1–13.CrossRef
30.
go back to reference Liu L, Lucas AH. IGH V3–23* 01 and its allele V3–23* 03 differ in their capacity to form the canonical human antibody combining site specific for the capsular polysaccharide of Haemophilus influenzae type b. Immunogenetics. 2003;55(5):336–8.CrossRef Liu L, Lucas AH. IGH V3–23* 01 and its allele V3–23* 03 differ in their capacity to form the canonical human antibody combining site specific for the capsular polysaccharide of Haemophilus influenzae type b. Immunogenetics. 2003;55(5):336–8.CrossRef
31.
go back to reference Chang C-J, Chen C-H, Chen B-M, Su Y-C, Chen Y-T, Hershfield MS, et al. A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol. Nat Commun. 2017;8(1):1–7.CrossRef Chang C-J, Chen C-H, Chen B-M, Su Y-C, Chen Y-T, Hershfield MS, et al. A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol. Nat Commun. 2017;8(1):1–7.CrossRef
32.
go back to reference Tang S-J. The R-Operon: a model of repetitive DNA-organized transcriptional compartmentation of eukaryotic chromosomes for coordinated gene expression. Genes. 2016;7(4):16.CrossRef Tang S-J. The R-Operon: a model of repetitive DNA-organized transcriptional compartmentation of eukaryotic chromosomes for coordinated gene expression. Genes. 2016;7(4):16.CrossRef
33.
go back to reference Choi NM, Feeney AJ. CTCF and ncRNA regulate the three-dimensional structure of antigen receptor loci to facilitate V (D) J recombination. Front Immunol. 2014;5:49.CrossRef Choi NM, Feeney AJ. CTCF and ncRNA regulate the three-dimensional structure of antigen receptor loci to facilitate V (D) J recombination. Front Immunol. 2014;5:49.CrossRef
Metadata
Title
Association of IGHM polymorphisms with susceptibility to type 1 diabetes
Authors
Zouidi Ferjeni
Fakhfakh Raouia
O. Abida
C. Penha-Gonçalves
H. Masmoudi
Publication date
20-01-2022
Publisher
Springer US
Keyword
Type 1 Diabetes
Published in
Immunologic Research / Issue 3/2022
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-021-09252-x

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