Age Dependent Variation of Genotypes in MHCII Transactivator gene (CIITA) in Controls and Association to Type 1 Diabetes Short title: Age dependent variation in CIITA

Genes and Immunity. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Access to the published version may require subscription. Sweden Study Group and the Better Diabetes Diagnosis Study group are listed in supplementary material. 4 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 families. Here we analyze five Swedish type 1 diabetes 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 type 1 diabetes. Unexpectedly we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, p=4x10-5 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 type 1 diabetes 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 type 1 diabetes 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.