study of transcriptional effects in cis at the ifih1 locus研究转录的影响在独联体ifih1轨迹.pdfVIP

Study of Transcriptional Effects in Cis at the IFIH1 Locus 1,2 1 1,2,3 Hana Zouk , Luc Marchand , Constantin Polychronakos * 1 Endocrine Genetics Laboratory, McGill University Health Center, Montreal Children’s Hospital Research Institute, McGill University, Montreal, Quebec, Canada, 2 Department of Human Genetics, McGill University, Montreal, Quebec, Canada, 3 Department of Paediatrics, McGill University Health Centre, Montreal, Quebec, Canada Abstract Background: The Thr allele at the non-synonymous single-nucleotide polymorphism (nsSNP) Thr946Ala in the IFIH1 gene confers risk for Type 1 diabetes (T1D). The SNP is embedded in a 236 kb linkage disequilibrium (LD) block that includes four genes: IFIH1, GCA, FAP and KCNH7. The absence of common nsSNPs in the other genes makes the IFIH1 SNP the strongest functional candidate, but it could be merely a marker of association, due to LD with a variant regulating expression levels of IFIH1 or neighboring genes. Methodology/Principal Findings: We investigated the effect of the T1D-associated variation on mRNA transcript expression of these genes. Heterozygous mRNA from lymphoblastoid cell lines (LCLs), pancreas and thymus was examined by allelic expression imbalance, to detect effects in cis on mRNA expression. Using single-nucleotide primer extension, we found no difference between mRNA transcripts in 9 LCLs, 6 pancreas and 13 thymus samples, suggesting that GCA and FAP are not involved. On the other hand, KCNH7 was not expressed at a detectable level in all tissues examined. Moreover, the association of the Thr946Ala SNP with T1D is not due to modulation of IFIH1 expression in organs involved in the disease, pointing to the IFIH1 nsSNP as the causal variant. Conclusions/Significance