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High prevalence of humoral autoimmunity in first-degree relatives of Mexican type 1 diabetes patients

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Abstract

Aims

To assess the prevalence of autoantibodies (Aab) to insulin (IAA), glutamic acid decarboxylase 65 (GADA) and insulinoma antigen 2 (IA-2A), as well as human leukocyte antigen (HLA) class II alleles, in first degree relatives (FDR) of Mexican patients with type 1 diabetes (T1D), and to explore whether these parameters mirror the low incidence of T1D in the Mexican population.

Methods

Aab titers were determined by ELISA in 425 FDR, 234 siblings, 40 offspring and 151 parents of 197 patients with T1D. Typing of HLA-DR and -DQ alleles was performed in 41 Aab-positive FDR using polymerase chain reaction with allele-specific oligotyping.

Results

Seventy FDR (16.47%) tested positive for Aab. The siblings (19.2%) and the offspring (25%) had significantly higher prevalence of Aab than the parents (9.9%). GADA was the most frequent Aab. Almost half of the Aab-positive FDR had two different Aab (45.7%), and none tested positive for three Aab. The highest prevalence of Aab was found among women in the 15–29 years age group. Moreover, the positivity for two Aab was significantly more frequent among females. A considerable number of FDR (48.8%) carried the susceptible HLA-DR3, -DR4, -DQB1*0201 or -DQB1*0302 alleles, but almost none had the high risk genotype HLA-DR3/DR4.

Conclusions

FDR of Mexican T1D patients have high prevalence of islet Aab, comparable to countries with the highest incidence of T1D. However, Aab positivity does not seem to be associated with HLA risk genotypes, which may have an impact on the low incidence of T1D in Mexico.

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References

  1. Eisenbarth GS (1986) Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314:1360–1368

    Article  CAS  Google Scholar 

  2. Gale EAM (2002) The rise of childhood type 1 diabetes in the 20th century. Diabetes 51:3353–3361

    Article  CAS  Google Scholar 

  3. DIAMOND Project Group (2006) Incidence and trends of childhood type 1 diabetes worldwide 1990–1999. Diabet Med 23:857–866

    Article  Google Scholar 

  4. Foulis AK, McGill M, Farquharson MA (1991)) Insulitis in type 1 (insulin-dependent) diabetes mellitus in man—macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol 165:97–103

    Article  CAS  Google Scholar 

  5. Ferraro A, Socci C, Stabilini A et al (2011) Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes 60:2903–2913

    Article  CAS  Google Scholar 

  6. Pinkse GG, Tysma OH, Bergen CA, Kester MG, Ossendorp F, van Veelen PA et al (2005) Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Proc Natl Acad Sci U S A 102:18425–18430

    Article  CAS  Google Scholar 

  7. Schloot NC, Roep BO, Wegmann D et al (1997) Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects. Diabetologia 40:564–572

    Article  CAS  Google Scholar 

  8. Atkinson MA, Kaufman DL, Campbell L, Gibbs KA, Shah SC, Bu DF et al (1992) Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet 339:458–459

    Article  CAS  Google Scholar 

  9. Hawkes CJ, Schloot NC, Marks J, Willemen SJ, Drijfhout JW, Mayer EK et al (2000) T-cell lines reactive to an immunodominant epitope of the tyrosine phosphatase-like autoantigen IA-2 in type 1 diabetes. Diabetes 49:356–366

    Article  CAS  Google Scholar 

  10. Bluestone JA, Herold K, Eisenbarth G (2010) Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464:1293–1300

    Article  CAS  Google Scholar 

  11. Pociot F, Lernmark A (2016) Genetic risk factors for type 1 diabetes. Lancet 387:2331–2339

    Article  CAS  Google Scholar 

  12. Beyerlein A, Donnachie E, Jergens S, Ziegler AG (2016) Infections in early life and development of type 1 diabetes. JAMA 315:1899–1901

    Article  Google Scholar 

  13. Knip M, Virtanen SM, Akerblom HK (2010) Infant feeding and the risk of type1 diabetes. Am J Clin Nutr 91:1506S–1513S

    Article  Google Scholar 

  14. Knip M, Siljander H, Ilonen J, Simell O, Veijola R (2016) Role of humoral beta-cell autoimmunity in type 1 diabetes. Pediatr Diabetes 17:17–24

    Article  CAS  Google Scholar 

  15. Bingley PJ (2010) Clinical applications of diabetes antibody testing. J Clin Endocrinol Metab 95:25–33

    Article  CAS  Google Scholar 

  16. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A et al (2013) Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309:2473–2479

    Article  CAS  Google Scholar 

  17. Bruno G, Maule M, Biggeri A, Ledda A, Mannu C, Merletti F et al (2013) More than 20 years of registration of type 1 diabetes in Sardinian children: temporal variations of incidence with age, period of diagnosis, and year of birth. Diabetes 62:3542–3546

    Article  CAS  Google Scholar 

  18. Harjutsalo V, Sund R, Knip M, Groop PH (2013) Incidence of type 1 diabetes in Finland. JAMA 310:427–428

    Article  CAS  Google Scholar 

  19. Joner G, Søvik O (1991) The incidence of type 1 (insulin-dependent) diabetes mellitus 15–29 years in Norway 1978–1982. Diabetologia 34:271–274

    Article  CAS  Google Scholar 

  20. Kyvik KO, Nystrom L, Gorus F, Songini M, Oestman J, Castell C et al (2004) The epidemiology of type 1 diabetes mellitus is not the same in young adults as in children. Diabetologia 47:377–384

    Article  CAS  Google Scholar 

  21. Lawrence JM, Imperatore G, Dabelea D, Mayer-Davis EJ, Linder B, Saydah S et al (2014) Trends in incidence of type 1 diabetes among non-Hispanic white youth in the US, 2002–2009. Diabetes 63:3938–3945

    Article  CAS  Google Scholar 

  22. Diaz-Valencia PA, Bougnères P, Valleron AJ (2015) Global epidemiology of type 1 diabetes in young adults and adults: a systematic review. BMC Public Health 15:255

    Article  Google Scholar 

  23. http://http://www.epidemiologia.salud.gob.mx/anuario/html/anuarios.html. Accessed May 2018

  24. Gómez-Díaz RA, Nishimura-Meguro E, Garrido-Magaña E, Lizárraga-Paulin L, Aguilar Herrera BE, Bekker-Méndez C et al (2016) HLA risk haplotype: Insulin deficiency in pediatric type 1 diabetes. Rev Invest Clin 68:128–136

    PubMed  Google Scholar 

  25. Fourlanos S, Varney MD, Tait BD, Morahan G, Honeyman MC, Colman PG et al (2008) The rising incidence of type 1diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 31:1546–1549

    Article  Google Scholar 

  26. Gorodezky C, Alaez C, Murguía A, Rodríguez A, Balladares S, Vazquez M et al (2006) HLA and autoimmune diseases: Type 1 diabetes (T1D) as an example. Autoimmun Rev 5:187–194

    Article  CAS  Google Scholar 

  27. Erlich HA, Zeidler A, Chang J, Shaw S, Raffel LJ, Klitz W et al (1993) HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families. Nat Genet 3:358–364

    Article  CAS  Google Scholar 

  28. Kukko M, Toivonen A, Kupila A, Korhonen S, Keskinen P, Veijola R et al (2006) Familial clustering of beta-cell autoimmunity in initially non-diabetic children. Diabetes Metab Res Rev 22:53–58

    Article  CAS  Google Scholar 

  29. Incani M, Serafini C, Satta C, Perra L, Scano F, Frongia P et al (2017) High prevalence of diabetes-specific autoimmunity in first-degree relatives of Sardinian patients with type 1 diabetes. Diabetes Metab Res Rev 33:e2864

    Article  Google Scholar 

  30. Siljander HT, Veijola R, Reunanen A, Virtanen SM, Akerblom HK, Knip M (2007) Prediction of type 1 diabetes among siblings of affected children and in the general population. Diabetologia 50:2272–2275

    Article  CAS  Google Scholar 

  31. Yu L, Cuthbertson DD, Eisenbarth GS, Krischer JP (2002) Diabetes Prevention Trial 1: prevalence of GAD and ICA512 (IA-2) autoantibodies by relationship to proband. Ann N Y Acad Sci 958:254–258

    Article  CAS  Google Scholar 

  32. Ito T, Nakamura K, Umeda E, Kaino Y, Hirai H, Kida K et al (2001) Familial predisposition of type 1 diabetes mellitus in Japan, a country with low incidence. Japan Diabetes Society Data Committee for Childhood Diabetes. J Pediatrics Endocrinol Metab 14:589–595

    Article  Google Scholar 

  33. Weng J, Zhou Z, Guo L, Zhu D, Ji L, Luo X et al (2018) Incidence of type 1 diabetes in China, 2010-13: population based study. BMJ 360:j5295

    Article  Google Scholar 

  34. Wang JP, Zhou ZG, Lin J, Huang G, Zhang C, Yang L et al (2007) Islet autoantibodies are associated with HLA-DQ genotypes in Han Chinese patients with type 1 diabetes and their relatives. Tissue Antigens 70:369–375

    Article  CAS  Google Scholar 

  35. Zeidler A, Raffel LJ, Costin G, Shaw SJ, Buchanan TA, Noble J et al (2001) Autoantibodies and human leucocyte antigen class II in first-degree family members of Mexican-American type 1 diabetic patients. J Clin Endocrinol Metab 86:4957–4962

    Article  CAS  Google Scholar 

  36. Becerril Ángeles M, García Lara SE, González Bárcena D, Ibarra Olmos MA, Torres Ambriz P, Angeles Garay U (2010) Autoantibodies in GAD65 in Mexican adults with diabetes types 1 and 2 and their siblings. Rev Alerg Mex 57:190–195

    PubMed  Google Scholar 

  37. Krischer JP, Liu X, Lernmark Å, Hagopian WA, Rewers MJ, She JX et al (2017) The influence of type 1 diabetes genetic susceptibility regions, age, sex, and family history on the progression from multiple autoantibodies to type 1 diabetes: a TEDDY Study Report. Diabetes 66:3122–3129

    Article  CAS  Google Scholar 

  38. Tuomilehto J (2013) The emerging global epidemic of type 1 diabetes. Curr Diabetes Rep 13:795–804

    Article  CAS  Google Scholar 

  39. Songini M, Mannu C, Targhetta C, Bruno G (2017) Type 1 diabetes in Sardinia: facts and hypotheses in the context of worldwide epidemiological data. Acta Diabetol 54:9–17

    Article  CAS  Google Scholar 

  40. Karvonen M, Pitkäniemi M, Pitkäniemi J, Kohtamäki K, Tajima N, Tuomilehto J et al (1997) Sex-difference in the incidence of insulin-dependent diabetes mellitus (IDDM). An analysis of the recent epidemiological data. Diab Metab Rev 13:275–291

    Article  CAS  Google Scholar 

  41. Mrena S, Savola K, Kulmala P, Akerblom HK, Knip M (1999) Staging of preclinical type 1 diabetes in siblings of affected children. Childhood diabetes in Finland Study Group. Pediatrics 104:925–930

    Article  CAS  Google Scholar 

  42. Barquera R, Zúñiga J, Hernández-Díaz R, Acuña-Alonzo V, Montoya-Gama K, Moscoso J et al (2008) HLA class I and class II haplotypes in admixed families from several regions of Mexico. Mol Immunol 45:1171–1178

    Article  CAS  Google Scholar 

  43. Niechciał E, Rogowicz-Frontczak A, Piłaciński S, Fichna M, Skowrońska B, Fichna P et al (2018) Autoantibodies against zinc transporter 8 are related to age and metabolic state in patients with newly diagnosed autoimmune diabetes. Acta Diabetol 55:287–294

    Article  Google Scholar 

  44. Rodríguez-Ventura AL, Yamamoto-Furusho JK, Coyote N, Dorantes LM, Ruiz-Morales JA, Vargas-Alarcón G et al (2007) HLA-DRB1*08 allele may help to distinguish between type 1 diabetes mellitus and type 2 diabetes mellitus in Mexican children. Pediatr Diabetes 8:5–10

    Article  Google Scholar 

  45. Tosur M, Geyer SM, Rodriguez H et al (2018) Ethnic differences in progression of islet autoimmunity and type 1 diabetes in relatives at risk. Diabetologia. https://doi.org/10.1007/s00125-018-4660-9

    Article  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge the support of the relatives of T1D patients who participated in the study. We are grateful for the assistance of the Endocrinology Unit staff at the Hospital de Especialidades “Antonio Fraga Mouret” (IMSS) and of María Díaz Martínez (Hospital Regional “Licenciado Adolfo López Mateos”, ISSSTE) for her help in the performance of laboratory tests. We also thank Julio C. Ramírez for technical assistance, and Ms. Ninfa Arreola for her aid in the preparation of the manuscript, both from CINVESTAV-IPN.

Funding

This study was supported by a grant to C. Sánchez-Torres from Fondo Sectorial de Investigación en Salud y Seguridad Social (SS/IMSS/ISSSTE-CONACYT, no. 233290), Mexico.

Author information

Authors and Affiliations

  1. Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV-IPN), Av. I.P.N. 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico

    Norma C. Segovia-Gamboa & Carmen Sanchez-Torres

  2. Research Department, Hospital Regional “Licenciado Adolfo López Mateos”, ISSSTE, Av. Universidad 1321, Florida, 01030, Mexico City, Mexico

    Martha E. Rodríguez-Arellano

  3. Endocrinology Department, Hospital de Especialidades “Antonio Fraga Mouret”, Centro Médico nacional “La Raza” (IMSS), Paseo de las Jacarandas S/N, Atzcapotzalco, 02990, Mexico City, Mexico

    Andrés Muñoz-Solís & Marisela Jiménez-Sánchez

  4. Pediatrics Department, Hospital Regional “Licenciado Adolfo López Mateos”, ISSSTE, Av. Universidad 1321, Florida, 01030, Mexico City, Mexico

    Jorge E. Retana-Jiménez

  5. Department of Internal Medicine, Ticoman General Hospital, Plan de San Luis S/N, La Purísima Ticoman, 07330, Mexico City, Mexico

    Germán Vargas-Ayala

  6. Division of Immunogenetics, Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Vasco de Quiroga 15, Tlalpan, 14080, Mexico City, Mexico

    Julio Granados

Authors
  1. Norma C. Segovia-Gamboa
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  8. Carmen Sanchez-Torres
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Contributions

MERA, AMS, GVA, and MJS recruited donors and performed laboratory test. NCSG and JERJ carried out autoantibody measurement. JG and MERA performed and analyzed the HLA typing assays. CST designed the study, analyzed the data, and wrote the manuscript.

Corresponding author

Correspondence to Carmen Sanchez-Torres.

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Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human and animal rights

The study was approved by the Bioethics Committee of CINVESTAV-IPN (017/2014), by the Ethics Committee of the Hospital Regional “Licenciado Adolfo López Mateos” (526.2016), and by the IMSS National Committee of Scientific Research (R-2015-785-044), and conducted in conformance with the Helsinki Declaration.

Statement of informed consent

Informed consent was obtained from each participant or from its parents/legal guardians (when applied) included in the study.

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Segovia-Gamboa, N.C., Rodríguez-Arellano, M.E., Muñoz-Solís, A. et al. High prevalence of humoral autoimmunity in first-degree relatives of Mexican type 1 diabetes patients. Acta Diabetol 55, 1275–1282 (2018). https://doi.org/10.1007/s00592-018-1241-9

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  • DOI: https://doi.org/10.1007/s00592-018-1241-9

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