Identification of the transcription factor ARNTL2 as a candidate gene for the type 1 diabetes locus Idd6

The Idd6 murine type 1 diabetes locus has been shown to control diabetes by regulating the protective activity of the peripheral immune system, as demonstrated by diabetes transfer assays using splenocytes. The analysis of three novel subcongenic (NOD.C3H nonobese. C3H) diabetes strains has confirmed the presence of at least two diabetes-related genes within the 5.8 Mb Idd6 interval with the disease protection conferred by splenocyte co-transfer being located to the 700 kb Idd6.3 subregion. This subinterval contains the circadian rhythm-related transcription factor Arntl2 (Bmal2), a homologue of the type 2 diabetes-associated ARNT (HIF1beta) gene. Arntl2 exhibited a six-fold upregulation in spleens of the NOD.C3H 6.VIII congenic strain compared with the NOD control strain, strain-specific splice variants and a large number of polymorphisms in both coding and non-coding regions. Arntl2 upregulation was not associated with changes in the expression levels of other circadian genes in the spleen, but did correlate with the upregulation of the ARNT-binding motif containing Pla2g4a gene, which has recently been described as being protective for the progression of insulitis and autoimmune diabetes in the NOD mouse via regulation of the tumour necrosis factor-alpha pathway. Our studies strongly suggest that the HIFbeta-homologous Arntl2 gene is involved in the control of type 1 diabetes.