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

Abstract

The telomeric class III region of the major histocompatibility complex is gene dense, but apart from the three tumour necrosis factor (TNF) superfamily members (TNF, lymphotoxin alpha and lymphotoxin beta) little is known of the expression and function of the majority of the genes. Recent genetic studies in autoimmune diseases, particularly rheumatoid arthritis (RA), have suggested a human leukocyte antigen (HLA)-DR-independent disease effect in this region. To gain further insights into these associations, we used lipopolysaccharide-stimulated human macrophages to examine inducible mRNA expression and genotype-phenotype relationships for genes in this region. Following stimulation in addition to the expected induction of TNF mRNA, a 14-fold increase of ATP6V1G2 at 18 h (Po0.001) was seen, whereas B-associated transcript (BAT)2 (Po0.001) and leucocyte-specific transcript (LST)1 (Po0.001) were both downregulated. By genotyping single-nucleotide polymorphisms spanning a 70 kb interval centred on the TNF locus, we constructed haplotypes and determined associated expression profiles for 10 genes in the cluster using quantitative real-time polymerase chain reaction. Overexpression of BAT1 mRNA was associated with carriers of a haplotype containing the LST1 marker transmitted to RA cases in a family study and also DRB1*15 associated with susceptibility to nephritis in systemic lupus erythematosus. The implications of our findings for the understanding of genetic associations with disease susceptibility in this region are discussed.

The interferon induced with helicase domain 1 A946T polymorphism is not associated with rheumatoid arthritis

“…The synthesis of cDNA and the gene expression analysis were performed in 200 RA cases and in 200 healthy controls as described previously [15]. The sequences of the primers were 5'-CAGTGTGCTAGCCTGTTC-3' (sense) and 5'-TCCTTGAATTCTGGGGTC-3' (antisense).…”

“…The sequences of the primers were 5'-CAGTGTGCTAGCCTGTTC-3' (sense) and 5'-TCCTTGAATTCTGGGGTC-3' (antisense). The levels of IFIH1 mRNA in each sample were normalised using the housekeeping gene GAPDH as described previously [15]. …”

Extended LTA, TNF, LST1 and HLA Gene Haplotypes and Their Association with Rubella Vaccine-Induced Immunity

“…Because of their linkage to HLA class I and II genes, it has been suggested that TNF and/or LTA (and LST1) may contribute to combinations or haplotypes of allelic variants that differ in composition and occurrence, and may contribute to the etiology of HLA-associated infectious diseases and immunity [5], [8], [9]. Studies have associated specific single nucleotide polymorphisms (SNPs) in either the TNF or LTA locus, along with HLA-B and/or HLA-DRB1 loci, with severe dengue virus infection, malaria, and susceptibility to autoimmune diseases [5], [6], [10]; however, extended LTA, TNF, LST1, and class I and class II HLA haplotype associations with rubella vaccine-induced immune responses have not been examined.…”

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

“…Moreover, the 50-kb interval between these SNPs also contains both tumor necrosis factor (TNF) and lymphotoxin α (LTA), each of which are strong candidate genes. Notably, differences in macrophage expression of these class III genes after stimulation reportedly associate with different LST1 haplotypes (53). Of the three SNPs, only rs2071596 has a high predicted regulatory function (RegulomeDB score = 2b indicating TF binding + any TF binding motif + DNase Footprint + DNase peak).…”