Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects.
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.
Klinker
Matthew W
MW
Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. mklinker@umich.edu
Schiller
Jennifer J
JJ
Magnuson
Victoria L
VL
Wang
Tao
T
Basken
Joel
J
Veth
Kerry
K
Pearce
Kaela I
KI
Kinnunen
Leena
L
Harjutsalo
Valma
V
Wang
Xujing
X
Tuomilehto
Jaakko
J
Sarti
Cinzia
C
Ghosh
Soumitra
S
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005387:Finland; D020022:Genetic Predisposition to Disease; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D053645:Interleukin-2 Receptor alpha Subunit