Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus

Abstract

Objective. Rheumatoid arthritis (RA) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-DRB1 effect could be detected and to determine its likely location.Methods. We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with RA that had at least 1 affected offspring and used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs).Results. Unconditioned TDTs revealed overtransmission of shared epitope alleles (P ‫؍‬ 2.12 ؋ 10 ؊5 ) and an allele of the HLA-B-associated transcript 1 (BAT1) gene in the telomeric class III region (P ‫؍‬ 0.009). Using a DRB1-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P ‫؍‬ 0.004), BAT1 (P ‫؍‬ 0.003), and PG8 (P ‫؍‬ 0.003). Conclusion.At least 1 additional non-DRB1 susceptibility locus for RA exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes.

Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases

“…Apart from the three TNF family members, the functions of the other proteins are poorly defined, although some evidence for an immune-related role exists for AIF1, 16 LST1 17 and NCR3. 18 Two recent Japanese studies have suggested NFKBIL1 as a susceptibility gene for RA; 14,19 however, this has not been replicated in our British family study 12 or in a Spanish case-control study. 20 The identification of these non-HLA-DR-associated MHC susceptibility genes will require more powerful genetic analyses using dense marker sets and large cohorts.…”

“…This haplotype bears the LST1*2 allele shown to be overtransmitted to RA cases in our family study 12 and also carries HLA-DRB1*15, the allele responsible for the serological DR2 specificity. This specificity is associated particularly with susceptibility to lupus nephritis, 30 and there is considerable evidence from human studies 31 and animal models 32 that this may be mediated by low production of TNF in association with DR2-carrying haplotypes.…”

“…11 We examined transmission of DRB1 alleles and 13 telomeric SNPs in 164 British RA families and found overtransmission of two SNPs in the telomeric class III region and another in the centromeric class I region. 12 Two large Japanese case-control studies have used highthroughput genotyping technology and reported up to three additional genetic effects telomeric of DRB1. 13,14 Another British study compared haplotypes across the class III region in DRB1*0404-matched cases and controls and detected two RA-associated haplotypes in a 126 kb region surrounding the TNF locus.…”

Association of tumor necrosis factor α polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort

“…The TNFA gene is located within the class III region of the MHC. The strong linkage disequilibrium among the Ͼ200 genes of the MHC has made it challenging to delineate the specific contribution of individual MHC genes to the pathogenesis of RA (19)(20)(21). Increased production of TNF␣ has been demonstrated in DR3ϩ and DR4ϩ individuals as compared with DR2ϩ individuals, suggesting genetic variation in levels of TNF␣ production (22).…”

HLA-DPB1-COL11A2 and three additional xMHC loci are independently associated with RA in a UK cohort

“…[8][9][10][11][12][13] More recently, dense single-nucleotide polymorphism (SNP)-mapping studies have identified several loci conferring RA susceptibility independently of HLA-DRB1 risk alleles using novel statistical approaches to avoid confounding. [14][15][16] Validation in independent data sets is particularly important to confirm new RA loci in the MHC.…”