NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans.

A genome scan for B10-derived loci that reduce the frequency of diabetes and insulitis in NOD mice demonstrated a large region (34 cM) of linkage on the proximal end of chromosome 1. This locus was designated Idd5 and encompassed candidate genes including Il1r1, Il1r2, Stat1, Stat4, Nramp1, and Bcl2. In the current study, we have confirmed the existence of Idd5 by developing a series of congenic mouse strains that are resistant to diabetes and determined that Idd5 is actually two genes located within a 9.4-cM interval. Idd5.1 is in the proximal 1.5-cM portion of the interval and contains the candidates Casp8, Cflar (FLIP), Cd28, and Cd152 (CTLA4). Idd5.1 overlaps the orthologous CTLA4/IDDM12 locus in humans. Idd5.2 is in the distal 5.1-cM portion of the 9.4-cM interval and contains the candidates Nramp1, which has a functional polymorphism between NOD and B10, and Cmkar2 (CXCR2, interleukin [IL]-8 receptor alpha). Candidate genes eliminated by this analysis include Il1r1, Ilr2, Zap70, Orch5, Stat1, Stat4, Bcl2, Cmkar4 (CXCR4), and Il10. On its own, the Idd5 locus provides a significant amount of protection from diabetes (50% reduction from parental frequency) and when combined with another resistance locus (Idd3 on chromosome 3), provides nearly complete protection from diabetes and insulitis.

[1]  D. Clayton,et al.  Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35. , 1996, Journal of medical genetics.

[2]  E. N. Miller,et al.  Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA. , 1997, Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[3]  J. Todd,et al.  The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. , 1996, Human molecular genetics.

[4]  J. Todd,et al.  Congenic mapping of the insulin-dependent diabetes (Idd) gene, Idd10, localizes two genes mediating the Idd10 effect and eliminates the candidate Fcgr1. , 1997, Journal of immunology.

[5]  Maria R. Davis,et al.  A first-generation whole genome-radiation hybrid map spanning the mouse genome. , 1997, Genome research.

[6]  P. Bedossa,et al.  Genetic analysis of immune dysfunction in non‐obese diabetic (NOD) mice: Mapping of a susceptibility locus close to the Bcl‐2 gene correlates with increased resistance of NOD T cells to apoptosis induction , 1994, European journal of immunology.

[7]  D. Malo,et al.  Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. , 1994, Genomics.

[8]  M. Olivier,et al.  TNF-alpha and IL-10 modulate the induction of apoptosis by virulent Mycobacterium tuberculosis in murine macrophages. , 1999, Journal of immunology.

[9]  J. Todd,et al.  Mapping of the IDDM Locus Idd3 to a 0.35-cM Interval Containing the Interleukin-2 Gene , 1997, Diabetes.

[10]  T. Yanagawa,et al.  CTLA-4 gene polymorphism associated with Graves' disease in a Caucasian population. , 1995, The Journal of clinical endocrinology and metabolism.

[11]  J. Todd,et al.  Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/lty/Bcg genes on chromosome 1 , 1991, Nature.

[12]  P. Bedossa,et al.  Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice , 1991, Nature.

[13]  J. Todd,et al.  Polygenic control of autoimmune diabetes in nonobese diabetic mice , 1993, Nature Genetics.

[14]  L. Abel,et al.  Susceptibility to leprosy is linked to the human NRAMP1 gene. , 1998, The Journal of infectious diseases.

[15]  J. Todd,et al.  Congenic mapping of the type 1 diabetes locus, Idd3, to a 780-kb region of mouse chromosome 3: identification of a candidate segment of ancestral DNA by haplotype mapping. , 2000, Genome research.

[16]  J. Todd,et al.  Genetic analysis of chromosome 2 in type 1 diabetes: analysis of putative loci IDDM7, IDDM12, and IDDM13 and candidate genes NRAMP1 and IA-2 and the interleukin-1 gene cluster. IMDIAB Group. , 1998, Diabetes.

[17]  D. Malo,et al.  Natural resistance to infection with intracellular parasites: Isolation of a candidate for Bcg , 1993, Cell.

[18]  M. Bergman,et al.  Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Todd,et al.  Resistance alleles at two non-major histocompatibility complex-linked insulin-dependent diabetes loci on chromosome 3, Idd3 and Idd10, protect nonobese diabetic mice from diabetes , 1994, The Journal of experimental medicine.

[20]  D. Radzioch,et al.  Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette-Guérin involves class II transactivator and depends on the Nramp1 gene. , 1999, Journal of immunology.