title: Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects.
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.
authors.affiliation: Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. mklinker@umich.edu
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Klinker
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Schiller
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Magnuson
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Joel
authors.initials: J
authors.lastname: Basken
authors.forename: Kerry
authors.initials: K
authors.lastname: Veth
authors.forename: Kaela I
authors.initials: KI
authors.lastname: Pearce
authors.forename: Leena
authors.initials: L
authors.lastname: Kinnunen
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.forename: Xujing
authors.initials: X
authors.lastname: Wang
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sarti
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
mesh_terms: 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
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit