Faculty Collaboration Database

Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects. Immunogenetics 2010 Feb;62(2):101-7

Date

12/25/2009

Pubmed ID

20033399

DOI

10.1007/s00251-009-0417-4

Scopus ID

2-s2.0-76249129135 (requires institutional sign-in at Scopus site)   27 Citations

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 x 10(-9); OR (95%CI) = 1.50 (1.27-1.78), p = 3.98 x 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.

Author List

Klinker MW, Schiller JJ, Magnuson VL, Wang T, Basken J, Veth K, Pearce KI, Kinnunen L, Harjutsalo V, Wang X, Tuomilehto J, Sarti C, Ghosh S

Author

Tao Wang PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Age of Onset
Diabetes Mellitus, Type 1
Finland
Genetic Predisposition to Disease
Humans
Interleukin-2 Receptor alpha Subunit
Middle Aged
Polymorphism, Single Nucleotide
Young Adult