Enterovirus RNA in longitudinal blood samples and risk of islet autoimmunity in children with a high genetic risk of type 1 diabetes: the MIDIA study
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Only a few longitudinal molecular studies of enterovirus and islet autoimmunity have been reported, and positive results seem to be limited to Finland. We aimed to investigate an association between enterovirus RNA in blood and islet autoimmunity in the MIDIA study from Norway, a country which largely shares environmental and economic features with Finland.
We analysed serial blood samples collected at ages 3, 6, and 9 months and then annually from 45 children who developed confirmed positivity for at least two autoantibodies (against insulin, GAD65 and IA-2) and 92 matched controls, all from a cohort of children with a single high-risk HLA-DQ-DR genotype. Enterovirus was tested in RNA extracted from frozen blood cell pellets, using real-time RT-PCR with stringent performance control.
Out of 807 blood samples, 72 (8.9%) were positive for enterovirus. There was no association between enterovirus RNA and islet autoimmunity in samples obtained strictly before (7.6% cases, 10.0% controls, OR 0.75 [95% CI 0.36, 1.57]), or strictly after the first detection of islet autoantibodies (10.5% case, 5.8% controls, OR 2.00 [95% CI 0.64, 6.27]). However, there was a tendency towards a higher frequency of enterovirus detection in the first islet autoantibody-positive sample (15.8%) compared with the corresponding time point in matched controls (3.2%, OR 8.7 [95% CI 0.97, 77]). Neither of these results was changed by adjusting for potential confounders, restricting to various time intervals or employing various definitions of enterovirus positivity.
Positivity for enterovirus RNA in blood did not predict the later induction of islet autoantibodies, but enterovirus tended to be detected more often at the islet autoantibody seroconversion stage.
KeywordsAutoimmunity Enterovirus Infancy Longitudinal Study RNA RT-PCR Virus-associated aetiology
Diabetes Autoimmunity Study in the Young
We thank the public healthcare nurses for their recruitment efforts for the MIDIA study and the follow-up of high-risk children, and the staff at the Biobank Department at the Norwegian Institute of Public Health. In particular, we would like to express our gratitude to all of the parents for their efforts in handling their children’s type 1 diabetes risk, for allowing samples to be taken from their children and for completing questionnaires.
This study and the MIDIA project were funded by the Norwegian Organization for Health and Rehabilitation (2008/0182), the Ministry of Health of the Czech Republic (IGA MZ 11465–5), the Research Council of Norway (grants 135893/330, 155300/320, 156477/730, 205086/F20 and 166515/V50), the Norwegian Diabetes Association, the Academy of Finland (grant to HH) and the Project for the Conceptual Development of Research Organisation 00064203 (University Hospital Motol, Prague, Czech Republic). OC’s sabbatical at HH’s laboratory in 2012 was supported by an ISPAD Research Fellowship.
Duality of interest
HH is a minor shareholder (<5%) of Vactech Ltd., which develops picornavirus vaccines. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.
KSR and LCS conceived and designed the study. OC, LK, SO and HH collected data (performed or supervised the enterovirus testing), PAT collected data (tested islet autoantibodies), and TR managed the databases. LCS, GT, EW, TR and OC analysed and interpreted data. All authors drafted the manuscript and/or revised it for important intellectual content, and have approved the final version.
LCS is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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