Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

A Gyllenberg, Samina Asad, F Piehl, Maria Swanberg, L Padyukov, B Van Yserloo, E A Rutledge, B McNeney, J Graham, Marju Orho-Melander, E. Lindholm, C. Graff, C Forsell, K Åkesson, Mona Landin-Olsson, G. Forsander, S.A. Ivarsson, H. Larsson, B. Lindblad, J LudvigssonC Marcus, Åke Lernmark, L Alfredsson, Kristina Åkesson, I Kockum, Annelie Carlsson

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Abstract

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.
Original languageEnglish
Pages (from-to)632-640
Number of pages9
JournalGenes and Immunity
Volume13
Issue number8
DOIs
Publication statusPublished - 2012

Subject classification (UKÄ)

  • Basic Medicine

Free keywords

  • age
  • association
  • autoimmunity
  • CIITA
  • type 1 diabetes (T1D)
  • major histocompatibility antigen class 2
  • transactivator protein
  • adolescent
  • adult
  • age distribution
  • article
  • controlled study
  • female
  • genetic association
  • genetic risk
  • genetic variability
  • genotype
  • human
  • human tissue
  • insulin dependent diabetes mellitus
  • major clinical study
  • male
  • priority journal
  • Sweden

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