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

Abstract

BackgroundLinkage 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 Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 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.MethodsNine 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 P ≤ 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 SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR).ResultsUsing the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 × 10-6). There was also some evidence of association at rs4674297 (P = 1.57 × 10-4). No evidence of disease association was obtained at any of the loci using the family collections (PTDT ≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression.ConclusionWe 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 SLC11A1 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.

Genetic Interactions among Idd3, Idd5.1, Idd5.2, and Idd5.3 Protective Loci in the Nonobese Diabetic Mouse Model of Type 1 Diabetes

“…In humans, SLC11A1 is associated with T1D and rheumatoid arthritis (11, 36, 37). SLC11A1 is a divalent cation transporter expressed on the membrane of late endosomes and lysosomes in macrophages and DCs, and expression of the WT SLC11A1 confers resistance to intracellular pathogens by promoting phagocytosis and rapid acidification of phago/lysosomes (38–44).…”

Characterization of chicken natural resistance-associated macrophage protein encoding genes (Nramp1 and Nramp2) and association with salmonellosis resistance

“…A 4-bp deletion polymorphism in the 3ꞌ-UTR is related to the incidence of post-transplant lymphoproliferative disease after liver transplantation (Barshes et al, 2006). Some polymorphisms were further identified to be associated with type 1 diabetes (T1D) (Yang et al, 2011). The association between D543N polymorphism and tuberculosis is sex-and age-dependent in Chinese (Leung et al, 2007).…”

Type 1 Diabetes Therapy Beyond T Cell Targeting: Monocytes, B Cells, and Innate Lymphocytes

“…Although associations with a variety of immune-mediated diseases have been reported, a recent study did not observe changes in SLC11A1 expression at the RNA level in whole blood samples from patients with T1D. However, the study did not exclude the possibility that genetic effects of polymorphisms in the gene may be seen in purified monocyte or macrophage populations [21]. In rats, Heinig and colleagues have identified an interferon regulatory factor 7 (IRF7)-driven inflammatory gene network (IDIN) [22].…”