Abstract
The onset of type 1 diabetes can occur at any age, with as many as half of all cases diagnosed after age 15. Despite this wide distribution in age at diagnosis, most genetic studies focus on cases diagnosed in childhood or during early adulthood. To better understand the genetics of late-onset type 1 diabetes, we collected a Finnish case/control cohort with all cases diagnosed between ages 15 and 40. We genotyped 591 probands and 1,538 control subjects at regions well established as susceptibility loci in early onset type 1 diabetes. These loci were then tested for disease association and age-at-diagnosis effects. Using logistic regression, we found that single-nucleotide polymorphisms (SNPs) at the INS, PTPN22, and IFIH1 loci were associated with late-onset disease (OR (95%CI) = 0.57(0.47–0.69), p = 2.77 × 10−9; OR (95%CI) = 1.50 (1.27–1.78), p = 3.98 × 10−6; and OR (95%CI) = 0.81(0.71–0.93), p = 0.0028, respectively). In contrast, a disease association was not detected for two SNPs at the IL2RA locus (rs11594656 and rs41295061). Despite this, we did find an independent age-at-diagnosis effect for each IL2RA SNP using a multivariate Cox proportional hazards model (p = 0.003, 0.002, respectively). Taken together, polymorphisms at the IL2RA locus were a major determinant of age at diagnosis in our cohort with an effect at par with the HLA-DQ2/DQ8 genotype as measured by hazard ratios. These findings suggest that the IL2RA locus controls both the susceptibility to disease and its time of occurrence. Thus, we believe the IL2/IL2R axis represents a potential therapeutic target for delaying the onset of disease.
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Acknowledgments
We acknowledge the support of the Juvenile Diabetes Research Foundation (Grant 9-2001-1012), the Children’s Research Institute (Children’s Hospital Of Wisconsin), the National Institute of Diabetes and Digestive and Kidney Disease (Grant RO1DK080100), and the Human and Molecular Genetics Center (Medical College of Wisconsin). We also thank Timo T. Valle for assisting in the organization of the project, William A. Hagopian and Eva Tuomilehto-Wolf for sharing their expertise in HLA typing, Ernest Luczkowski, Joanne Rovensky, Natalya Zinkevich, and Azza Malik for genotyping work, Ramin Alemzadeh for facilitating the recruitment of a comparative sample in Wisconsin, John Blimke for maintaining our genotype database, and Jin Zhang, Mateusz Serafin, and John A. Todd for critical review of the manuscript. Lastly, we wish to express our sincere gratitude to all study participants for their generosity and enthusiastic support of our work.
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Klinker, M.W., Schiller, J.J., Magnuson, V.L. et al. Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects. Immunogenetics 62, 101–107 (2010). https://doi.org/10.1007/s00251-009-0417-4
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DOI: https://doi.org/10.1007/s00251-009-0417-4