Promoter polymorphism of SLC11A1 (formerly NRAMP1) confers susceptibility to autoimmune type 1 diabetes mellitus in Japanese

Abstract

Defective function of antigen-presenting cells has been postulated to be one of the non-HLA-linked susceptibility factors for type 1 diabetes mellitus, though the underlying genetic factors remain unclear. SLC11A1 (formerly NRAMP1), a divalent cation transporter, plays a crucial role in macrophage activation. We performed a case-control study in 224 healthy and 95 type 1 diabetic Japanese subjects, examining the length polymorphisms in the promoter region (-377 to -222) of SLC11A1, which may influence transcriptional activity. Alleles designated 2, 3, and 7 have been identified in Japanese subjects. The frequency of allele 7 was significantly higher in subjects with type 1 diabetes (9.47%) than in the healthy controls (4.46%). The difference is more marked in the subpopulation of Japanese subjects with type 1 diabetes; diabetic subjects with at least one protective HLA class II allele and those without any susceptibility HLA class II haplotypes, DR4-DQ4 or DR9-DQ9, had a much higher allele 7 frequency than controls. These findings suggest that the novel promoter polymorphism of SLC11A1 influences the susceptibility to type 1 diabetes in Japanese subjects.

Ramp-ing up allergies: Nramp1 (Slc11a1), macrophages and the hygiene hypothesis

“…Polymorphisms in the genomic region of human NRAMP1 are associated with the risk of atopy in BCG-vaccinated children [23]. Moreover, the Nramp1 gene is involved in several other diseases of deregulated immunity: a polymorphism in the promoter region of NRAMP1 has been associated with inflammatory bowel disease [24], rheumatoid arthritis [25], multiple sclerosis [26] and type 1 diabetes mellitus [27].…”

Natural resistance-associated macrophage protein 1 gene polymorphisms in rheumatoid arthritis

“…Several studies demonstrated NRAMP1 to be related to susceptibility to RA [11][12][13]. The associations of NRAMP1 with other immune-mediated diseases, including juvenile rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and Crohn's disease have also been demonstrated [14][15][16][17][18][19]. NRAMP1 was also associated with behavioral and immune response to stress [20].…”

RNA-Binding Protein HuR Is Required for Stabilization of SLC11A1 mRNA and SLC11A1 Protein Expression

“…It seems clear that SLC11A1 polymorphisms are associated with susceptibility to infectious and autoimmune diseases in human (7,40,53). In the promoter region of SLC11A1, seven different alleles (alleles 1 to 7) of the polymorphism containing a functional Z-DNA-forming repeat have been reported for different populations.…”