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

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 ¼ 4 Â 10 À 5 and rs3087456, P ¼ 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 ¼ 0.006, P ¼ 0.007). We also detect association to T1D for both markers, rs11074932 (P ¼ 0.004) and rs3087456 (P ¼ 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.

Genome-wide Analysis in Brazilians Reveals Highly Differentiated Native American Genome Regions

“…CIITA has been implicated in immune function through association with autoimmune diseases or very recently with leprosy (Liu et al 2015). The gene complex including CIITA and neighboring DEXI/CLEC16A has been shown to be associated with multiple autoimmune diseases (Bronson et al 2011; Gyllenberg et al 2012, 2014; Leikfoss et al 2015). DOCK2 is predominantly expressed in hematopoietic cells, regulates migration and activation of neutrophils through Rac activation (Nishikimi et al 2013) and is associated with early-onset invasive infections (Dobbs et al 2015).…”

Functions of NOD-Like Receptors in Human Diseases

“…GWAS and patient exome sequencing studies have linked SNPs in CIITA to celiac disease (238, 239), susceptibility to myocardial infarction (240), rheumatoid arthritis (240–242), multiple sclerosis (240, 242), primary adrenal insufficiency (243), SLE (244), and type 1 diabetes (245, 246), although these results have not always been replicated in subsequent studies (247–249). Gyllenberg et al suggested that age-dependent variation in the gene encoding CIITA could be responsible for false associations in GWAS (250).…”

Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases

“…41 Chromosomal translocation of CIITA has been linked to primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. 42 Genetic variations in the CIITA gene have also been associated with several autoimmune disorders in humans, including RA, 13,15,16 MS, 13,17,18 myocardial infarction, 13 T1D, 19 coeliac disease 20 and systemic lupus erythematosus. 20,21 Different SNPs have been associated with these diseases, including rs3087456 in the type III promoter of CIITA, an intronic SNP rs8048002, and rs4774, which is a missense mutation resulting in an amino acid change from glycine to alanine.…”

“…13 It was later shown in the congenic strains in rats that the C2ta polymorphisms alter susceptibility to experimental autoimmune encephalomyelitis (EAE), a chronic relapsing model of MS. 14 The experimental findings in rats prompted further investigation of C2TA in humans and it was demonstrated that a single nucleotide polymorphism in the 5 0 flanking region of type III promoter of C2TA is associated with susceptibility to RA, MS and myocardial infarction. 13 C2TA disease association has since then been shown in different patient cohorts in not only RA 15,16 and MS, 17,18 but also T1D, 19 coeliac disease 20 and systemic lupus erythematosus, 21,22 although disease associations could not be reproduced in some populations. [23][24][25] In this study, we generated a C2ta congenic mouse strain to investigate the effect of an allelic variant of C2ta promoter on MHC-II expression in different antigen-presenting cells (APCs).…”

“…The experimental findings in rats prompted further investigation of C2TA in humans and it was demonstrated that a single nucleotide polymorphism in the 5′ flanking region of type III promoter of C2TA is associated with susceptibility to RA, MS and myocardial infarction . C2TA disease association has since then been shown in different patient cohorts in not only RA and MS, but also T1D, coeliac disease and systemic lupus erythematosus, although disease associations could not be reproduced in some populations …”