Enterovirus RNA in Blood is Linked to the Development of Type 1 Diabetes

Overview

Journal Diabetes

Specialty Endocrinology

Date 2010 Oct 15

PMID 20943747

Citations 89

Authors

Sami Oikarinen

Mika Martiskainen

Sisko Tauriainen

Heini Huhtala

Jorma Ilonen

Riitta Veijola

Olli Simell

Mikael Knip

Heikki Hyoty

Affiliations

Soon will be listed here.

Abstract

Objective: To assess whether the detection of enterovirus RNA in blood predicts the development of clinical type 1 diabetes in a prospective birth cohort study. Further, to study the role of enteroviruses in both the initiation of the process and the progression to type 1 diabetes.

Research Design And Methods: This was a nested case-control study where all case children (N = 38) have progressed to clinical type 1 diabetes. Nondiabetic control children (N = 140) were pairwise matched for sex, date of birth, hospital district, and HLA-DQ-conferred genetic susceptibility to type 1 diabetes. Serum samples, drawn at 3- to 12-month intervals, were screened for enterovirus RNA using RT-PCR.

Results: Enterovirus RNA-positive samples were more frequent among the case subjects than among the control subjects. A total of 5.1% of the samples (17 of 333) in the case group were enterovirus RNA-positive compared with 1.9% of the samples (19 of 993) in the control group (P < 0.01). The strongest risk for type 1 diabetes was related to enterovirus RNA positivity during the 6-month period preceding the first autoantibody-positive sample (odds ratio 7.7 [95% CI 1.9-31.5]). This risk effect was stronger in boys than in girls.

Conclusions: The present study supports the hypothesis that enteroviruses play a role in the pathogenesis of type 1 diabetes, especially in the initiation of the β-cell damaging process. The enterovirus-associated risk for type 1 diabetes may be stronger in boys than in girls.

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References

Dotta F, Censini S, van Halteren A, Marselli L, Masini M, Dionisi S . Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A. 2007; 104(12):5115-20. PMC: 1829272. DOI: 10.1073/pnas.0700442104. View

Tracy S, Drescher K, Jackson J, Kim K, Kono K . Enteroviruses, type 1 diabetes and hygiene: a complex relationship. Rev Med Virol. 2010; 20(2):106-16. PMC: 7169204. DOI: 10.1002/rmv.639. View

Hou J, Sheikh S, Martin D, Chatterjee N . Coxsackievirus B4 alters pancreatic glutamate decarboxylase expression in mice soon after infection. J Autoimmun. 1993; 6(5):529-42. DOI: 10.1006/jaut.1993.1044. View

Tauriainen S, Oikarinen S, Oikarinen M, Hyoty H . Enteroviruses in the pathogenesis of type 1 diabetes. Semin Immunopathol. 2010; 33(1):45-55. DOI: 10.1007/s00281-010-0207-y. View

Viskari H, Ludvigsson J, Uibo R, Salur L, Marciulionyte D, Hermann R . Relationship between the incidence of type 1 diabetes and enterovirus infections in different European populations: results from the EPIVIR project. J Med Virol. 2004; 72(4):610-7. DOI: 10.1002/jmv.20033. View

Schulte B, Bakkers J, Lanke K, Melchers W, Westerlaken C, Allebes W . Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection. Viral Immunol. 2010; 23(1):99-104. DOI: 10.1089/vim.2009.0072. View

Smyth D, Cooper J, Bailey R, Field S, Burren O, Smink L . A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet. 2006; 38(6):617-9. DOI: 10.1038/ng1800. View

Lonnrot M, Knip M, Marciulionyte D, Rahko J, Urbonaite B, MOORE W . Enterovirus antibodies in relation to islet cell antibodies in two populations with high and low incidence of type 1 diabetes. Diabetes Care. 1999; 22(12):2086-8. DOI: 10.2337/diacare.22.12.2086. View

Lonnrot M, Salminen K, Knip M, Savola K, Kulmala P, Leinikki P . Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group. J Med Virol. 2000; 61(2):214-20. View

10.

Graves P, Rotbart H, Nix W, Pallansch M, Erlich H, Norris J . Prospective study of enteroviral infections and development of beta-cell autoimmunity. Diabetes autoimmunity study in the young (DAISY). Diabetes Res Clin Pract. 2002; 59(1):51-61. DOI: 10.1016/s0168-8227(02)00198-5. View

11.

Richardson S, Willcox A, Bone A, Foulis A, Morgan N . The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia. 2009; 52(6):1143-51. DOI: 10.1007/s00125-009-1276-0. View

12.

Sadeharju K, Knip M, Virtanen S, Savilahti E, Tauriainen S, Koskela P . Maternal antibodies in breast milk protect the child from enterovirus infections. Pediatrics. 2007; 119(5):941-6. DOI: 10.1542/peds.2006-0780. View

13.

Oikarinen M, Tauriainen S, Honkanen T, Vuori K, Karhunen P, Vasama-Nolvi C . Analysis of pancreas tissue in a child positive for islet cell antibodies. Diabetologia. 2008; 51(10):1796-802. DOI: 10.1007/s00125-008-1107-8. View

14.

Lonnrot M, Sjoroos M, Salminen K, Maaronen M, Hyypia T, Hyoty H . Diagnosis of enterovirus and rhinovirus infections by RT-PCR and time-resolved fluorometry with lanthanide chelate labeled probes. J Med Virol. 1999; 59(3):378-84. View

15.

Oikarinen M, Tauriainen S, Honkanen T, Oikarinen S, Vuori K, Kaukinen K . Detection of enteroviruses in the intestine of type 1 diabetic patients. Clin Exp Immunol. 2007; 151(1):71-5. PMC: 2276929. DOI: 10.1111/j.1365-2249.2007.03529.x. View

16.

Kukko M, Kimpimaki T, Korhonen S, Kupila A, Simell S, Veijola R . Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population. J Clin Endocrinol Metab. 2005; 90(5):2712-7. DOI: 10.1210/jc.2004-1371. View

17.

Hermann R, Turpeinen H, Laine A, Veijola R, Knip M, Simell O . HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families. Tissue Antigens. 2003; 62(2):162-9. DOI: 10.1034/j.1399-0039.2003.00071.x. View

18.

Wagenknecht L, Roseman J, Herman W . Increased incidence of insulin-dependent diabetes mellitus following an epidemic of Coxsackievirus B5. Am J Epidemiol. 1991; 133(10):1024-31. DOI: 10.1093/oxfordjournals.aje.a115811. View

19.

Yin H, Berg A, Westman J, Hellerstrom C, Frisk G . Complete nucleotide sequence of a Coxsackievirus B-4 strain capable of establishing persistent infection in human pancreatic islet cells: effects on insulin release, proinsulin synthesis, and cell morphology. J Med Virol. 2002; 68(4):544-57. DOI: 10.1002/jmv.10236. View

20.

Salminen K, Sadeharju K, Lonnrot M, Vahasalo P, Kupila A, Korhonen S . Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study. J Med Virol. 2002; 69(1):91-8. DOI: 10.1002/jmv.10260. View