Immunogenetics

, Volume 62, Issue 2, pp 101–107

Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects

  • Matthew W. Klinker
  • Jennifer J. Schiller
  • Victoria L. Magnuson
  • Tao Wang
  • Joel Basken
  • Kerry Veth
  • Kaela I. Pearce
  • Leena Kinnunen
  • Valma Harjutsalo
  • Xujing Wang
  • Jaakko Tuomilehto
  • Cinzia Sarti
  • Soumitra Ghosh
Brief Communication

DOI: 10.1007/s00251-009-0417-4

Cite this article as:
Klinker, M.W., Schiller, J.J., Magnuson, V.L. et al. Immunogenetics (2010) 62: 101. doi:10.1007/s00251-009-0417-4

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.

Keywords

Type 1 diabetesIL2RAAge at diagnosisGeneticsCase/control studiesAutoimmune diseases

Supplementary material

251_2009_417_MOESM1_ESM.doc (64 kb)
Supplementary material(DOC 64 kb)

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Matthew W. Klinker
    • 1
    • 2
    • 3
  • Jennifer J. Schiller
    • 1
    • 2
    • 3
  • Victoria L. Magnuson
    • 1
    • 2
    • 3
  • Tao Wang
    • 2
    • 4
  • Joel Basken
    • 1
    • 2
    • 3
  • Kerry Veth
    • 1
    • 2
    • 3
  • Kaela I. Pearce
    • 1
    • 2
    • 3
  • Leena Kinnunen
    • 5
  • Valma Harjutsalo
    • 5
    • 6
    • 7
  • Xujing Wang
    • 8
  • Jaakko Tuomilehto
    • 5
    • 9
    • 10
  • Cinzia Sarti
    • 5
  • Soumitra Ghosh
    • 1
    • 2
    • 3
    • 11
  1. 1.Max McGee National Research Center for Juvenile Diabetes, Department of PediatricsMedical College of WisconsinMilwaukeeUSA
  2. 2.Human and Molecular Genetics CenterMedical College of WisconsinMilwaukeeUSA
  3. 3.Children’s Research InstituteChildren’s Hospital of WisconsinMilwaukeeUSA
  4. 4.Division of Biostatistics, Department of Population HealthMedical College of WisconsinMilwaukeeUSA
  5. 5.National Public Health InstituteHelsinkiFinland
  6. 6.Folkhälsan Institute of GeneticsFolkhälsan Research Centre, Biomedicum HelsinkiHelsinkiFinland
  7. 7.Division of Nephrology, Department of MedicineHelsinki University Central HospitalHelsinkiFinland
  8. 8.Department of PhysicsUniversity of AlabamaBirminghamUSA
  9. 9.Department of Public HealthHelsinkiFinland
  10. 10.South Ostrobothnia Central HospitalSeinäjokiFinland
  11. 11.Medical College of WisconsinMilwaukeeUSA