MHC2TA promoter polymorphism (-168*G/A, rs3087456) is not associated with susceptibility to rheumatoid arthritis in British Caucasian rheumatoid arthritis patients

Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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“…However, the initial disease associations were modest and subsequent studies have been conflicting. [49][50][51][52][53] …”

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confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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“…[6][7][8]10,14,17 These geographical subgroups also showed clear negative results in our meta-analysis of rs3087456. To our knowledge, no genomewide association study has demonstrated association with the CIITA locus, however, many of the commonly used SNP arrays do not include either of the rs3087456 or rs8048002 SNPs.…”

Section: Discussionmentioning

confidence: 67%

“…This has been proposed for a single-nucleotide polymorphism (SNP) in the CIITA promoter, rs3087456 A4G (-168 A/G), which has been reported associated with a number of autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune Addison's disease (AAD). [2][3][4][5] However, other association results for rs3087456 have been conflicting, 3,[6][7][8][9][10][11][12][13][14] and a recent meta-analysis in RA found no significant association with rs3087456. 15 A possible explanation for this could be that rs3087456 is only an imperfect marker for a real aetiological variant in the vicinity.…”

Section: Introductionmentioning

confidence: 99%

CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations

et al. 2012

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“…22 Previous studies have reported positive, 19,20 but also negative, 23,24 results regarding association of CIITA to different autoimmune diseases.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2012

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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.

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MHC2TA promoter polymorphism (-168*G/A, rs3087456) is not associated with susceptibility to rheumatoid arthritis in British Caucasian rheumatoid arthritis patients

Cited by 20 publications

References 12 publications

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations

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

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