Evidence of association with type 1 diabetes in the SLC11A1 gene region

• Main Authors: Walker Neil M (Author), Stevens Helen E (Author), Nutland Sarah (Author), Howson Joanna MM (Author), Downes Kate (Author), Yang Jennie HM (Author), Todd John A (Author)
• Format: Book
• Published: BMC, 2011-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1186/1471-2350-12-59; 1471-2350
• Keywords: Internal medicine; RC31-1245; Genetics; QH426-470
• Source: BMC Medical Genetics, Vol 12, Iss 1, p 59 (2011)

<p>Abstract</p> <p>Background</p> <p>Linkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse <it>Idd </it>(insulin dependent diabetes) loci, including <it>Slc11a1 </it>(formerly known as <it>Nramp1</it>). Genetic variants in the orthologous region encompassing <it>SLC11A1 </it>in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform.</p> <p>Methods</p> <p>Nine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C→T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered <it>P </it>≤ 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and <it>SLC11A1 </it>expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR).</p> <p>Results</p> <p>Using the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (<it>P </it>= 1.55 × 10^-6). There was also some evidence of association at rs4674297 (<it>P </it>= 1.57 × 10^-4). No evidence of disease association was obtained at any of the loci using the family collections (<it>P</it>_TDT≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and <it>SLC11A1 </it>expression overall or with splice isoform expression.</p> <p>Conclusion</p> <p>We conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in <it>SLC11A1 </it>expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages.</p>