Genetic Control of Alternative Splicing in theTAP2Gene

Abstract

The transporter 2, ATP-binding cassette, subfamily B (TAP2) is involved in the transport of antigenic peptides to HLA molecules. Coding TAP2 polymorphisms shows a strong association with type 1 diabetes, but it is not clear whether this association may be entirely due to linkage disequilibrium with HLA DR and DQ. Functionally, rat Tap2 nonsynonymous single-nucleotide polymorphisms (nsSNPs) confer differential selectivity for antigenic peptides, but this was not shown to be the case for human TAP2 nsSNPs. In the human, differential peptide selectivity is rather conferred by two splicing isoforms with alternative carboxy terminals. Here, we tested the hypothesis that alleles at the coding SNPs favor different splicing isoforms, thus determining peptide selectivity indirectly. This may be the basis for independent contribution to the type 1 diabetes association. In RNA from heterozygous lymphoblastoid lines, we measured the relative abundance of each SNP haplotype in each isoform. In isoform NM_000544, the G (Ala) allele at 665 Thr>Ala (rs241447) is more than twice as abundant as A (Thr) (GA ‫؍‬ 2.2 ؎ 0.4, P ‫؍‬ 1.5 ؋ 10 ؊4 ), while isoform NM_018833 is derived almost exclusively from chromosomes carrying A (AG ‫؍‬ 18.1 ؎ 5.6, P ‫؍‬ 2.04 ؋ 10 ؊7 ). In 889 Canadian children with type 1 diabetes, differential transmission of parental TAP2 alleles persisted (P ‫؍‬ 0.011) when analysis was confined to chromosomes carrying only DQ*02 alleles, which mark a conserved DR-DQ haplotype, thus eliminating most of the variation at DR-DQ. Thus, we present evidence of TAP2 association with type 1 diabetes that is independent of HLA DR-DQ and describe a plausible functional mechanism based on allele dependence of splicing into isoforms known to have differential peptide selectivities. Diabetes 56: 270 -275, 2007

Tandem RNA Chimeras Contribute to Transcriptome Diversity in Human Population and Are Associated with Intronic Genetic Variants

“…Introns have increasing attention from the scientific community for their role in pre-mRNA splicing [47]. Reassuringly, two of the variants were already reported to play an important role in alternative splicing [48]. Thus, our results show that variants affecting splicing contribute to the RNA chimera origin.…”

The association between type 1 diabetes and the ITPR3 gene polymorphism due to linkage disequilibrium with HLA class II

“…The age-of-onset effect of rs2296336 in T1D patients was tested by the Mann-Whitney test. The genotypes of HLA-DQB1 were obtained by sequencing of the HLA-DQB1 exon 2 based on the reported method 6 with a small modification as described in our previous study 7 in a subset of 794 families. At the polymorphic site in the intron 1/exon 2 primer, a degenerate sense primer spanning the intron 1/exon 2 border, 5 0 -ATTCCYCGCAGAGGATTTCG-3 0 , was used.…”

Genetic Studies of IgA Nephropathy: What Have We Learned from Genome-Wide Association Studies

“…PSMB8 codes for an immunoproteasome involved in processing class I MHC peptides, and its expression is increased in peripheral blood mononuclear cells of some IgAN patients [17]. TAP1 and TAP2 code for proteins that are involved in the transport of peptides from the cytoplasm to the endoplasmic reticulum where they can be loaded onto MHC molecules; they have also been associated with ankylosing spondylitis [18], type I DM [19], and celiac disease [20]. In the replication of the second IgAN GWAS, four of the original five loci were replicated.…”