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Genetic Control of Alternative Splicing in the TAP2 Gene

Possible Implication in the Genetics of Type 1 Diabetes

¹ Endocrine Genetics Laboratory, The McGill University Health Center (Montreal Children’s Hospital), Montréal, Quebec, Canada
² McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada
³ Department of Pediatrics, The McGill University Health Center (Montreal Children’s Hospital), Montréal, Quebec, Canada

Address correspondence and reprint requests to Constantin Polychronakos, MD, The McGill University Health Center (Montreal Children’s Hospital), 2300 Tupper, Montréal, QC, Canada, H3H 1P3. E-mail: constantin.polychronakos{at}mcgill.ca

Abbreviations: AI, allelic imbalance; gDNA, genomic DNA; LD, linkage disequilibrium; nsSNP, nonsynonymous single-nucleotide polymorphism; SNP, single-nucleotide polymorphism

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 x 10^–4), while isoform NM_018833 is derived almost exclusively from chromosomes carrying A (AG = 18.1 ± 5.6, P = 2.04 x 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.

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