Promoter Polymorphism of SLC11A1 (formerly NRAMP1) Confers Susceptibility to Autoimmune Type 1 Diabetes Mellitus in Japanese

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.