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Diabetes Care 27:285-286, 2004
© 2004 by the American Diabetes Association, Inc.

Letters: Observations

Increased Prevalence of Enteroviral RNA in Blood Spots From Newborn Children Who Later Developed Type 1 Diabetes

A population-based case-control study

Gisela G. Dahlquist, MD, PHD1, Jenny Forsberg, MS1, Lars Hagenfeldt, MD, PHD2,{dagger}, Jens Boman, MD3 and Per Juto, MD, PHD3

1 Department of Clinical Sciences-Paediatrics, Umeå University, Umeå, Sweden
2 Centre of Inherited Metabolic Diseases, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
3 Department of Virology, Umeå University, Umeå, Sweden

Address correspondence to Professor Gisela Dahlquist, Umeå University, Department of Clinical Sciences-Paediatrics, SE-901 87 Umeå, Sweden. E-mail: gisela.dahlquist{at}pediatri.umu.se

Virus infections during fetal life may lead to persistent infections due to unresponsiveness of the immature immune system and by different mechanisms inducing autoimmunity in the ß-cell (1). In a previous study, we found group-reacting antibodies to enterovirus more frequently increased in serum at delivery in a cohort of mothers whose children later developed diabetes than in control subjects (2). It has been argued that mothers of later diabetic children might have increased immune responses to certain viruses (3). Therefore, detection of the virus nucleic acid would be important to confirm.

Enteroviral infections typically occur as epidemics with a short viremic phase; therefore, they are detectable for only a short time in peripheral blood (4). Consequently, large series of blood or serum samples would be necessary. Since 1973, blood spots routinely taken on days 2–4 of life for analysis of inherited metabolic diseases in all newborns in Sweden are stored in a biobank. From this biobank, we collected blood spots from 600 children in the Swedish childhood diabetes register who were born during the years 1986–1995 and who had diabetes onset before 1996. For each case, a control sample was included from a child born on the same date and not found in the Swedish childhood diabetes register, and the control sample was stored adjacent to the case filter.

Nested enterovirus PCR was performed essentially according to Puig et al. (5). To exclude the possibility of false-positivity due to contamination, we excluded all case-control pairs with double positivity and each step of RNA extraction and analysis included positive and negative controls. All case-control pairs were analyzed in the same run. As references, representatives of the most common congenital viral infections were chosen for analysis: CMV (6) and parvo B19 virus (7). A total of 542 pairs of samples were valid and analyzed for enterovirus RNA.

Twenty-seven diabetic cases were RNA positive, as compared with 14 control subjects (odds ratio 1.98 [95% CI 1.04-3.77], two-tailed P = 0.04). Due to limited material, typing of enteroviral RNA by sequencing was not possible . For CMV and parvo B19 viruses, no differences were shown between cases and references in samples of 208 and 180 pairs, respectively.

The findings support the hypothesis that early enteroviral infections may play a role in the pathogenesis of type 1 diabetes. In our previous study of maternal sera, the etiological fraction of enteroviral infection in pregnancy (4) was calculated at 27%. Thus, early fetal or neonatal infections may explain a fraction of childhood diabetes cases.

Acknowledgments

This study was supported by grants from the Swedish Research Council (Medicine) (project no. 07531), the Swedish Diabetes Association, and the Västerbotten County Council.

Footnotes

{dagger} Deceased, summer 2003. Back

References

  1. Jun HS, Yoon JW: The role of viruses in type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals. Diabetologia 44:271–285, 2001[Medline]
  2. Dahlquist GG, Ivarsson S, Lindberg B, Forsgren M: Maternal enteroviral infection during pregnancy as a risk factor for childhood IDDM: a population-based case-control study. Diabetes 44:408–413, 1995[Abstract]
  3. Graves PM, Norris JM, Pallansch MA, Gerling IC, Rewers M: The role of enteroviral infections in the development of IDDM. Diabetes 46:161–168, 1997[Abstract]
  4. Cherry JP: Enteroviruses: polioviruses, coxsackieviruses, echoviruses and enteroviruses. In Textbook of Pediatric Infectious Diseases. Vol. 2, 3rd ed. Feigin RD, Cherry JD, Eds. Philadelphia, PA, WB Saunders, 1992, p. 1705–1753
  5. Puig M, Jofre J, Lucena F, Alland A, Wadell G, Girones R: Detection of adenoviruses and enteroviruses in polluted waters by nested PCR amplification. Appl Environment Microbiol 60:2963–2970, 1994[Abstract/Free Full Text]
  6. Brytting M, Sundqvist VA, Stålhandske P, Linde A, Wahren B: Cytomegalovirus DNA detection of an immediate early protein gene with nested primer oligonucleotides. J Virol Methods 32:127–138, 1991[Medline]
  7. Lundqvist A, Tolfvenstam T, Bostic J, Söderlund M, Broliden K: Clinical and laboratory findings in immunocompetent patients with persistent parvovirus B 19 DNA in bone marrow. Scand J Infect Dis 31:11–16, 1999[Medline]

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