This allele also confers defective IFN-gamma response in NK cells on a C57BL/6 genetic background (J:85823).
Mapping and Phenotype information for this QTL, its variants and associated markers
123 polymorphic markers were screened in a backcross population of NOD/Lt x (B10.NOD-H2<g7> x NOD/Lt)F1 animals to identify QTLs associated with susceptibility to insulin dependent (type 1) diabetes. 106 diabetic backcross animals and 190 non-diabetic backcross animals were used in this study. Parental strain NOD/Lt spontaneously develops type 1 diabetes whereas parental strain B10.NOD-H2<g7> is resistant.
Three novel diabetes susceptibility QTLs were identified. Idd7 mapped to 4.5 cM on mouse Chromosome 7 near D7Nds6, Idd8 mapped to 2.5 cM on mouse Chromosome 14 near D14Nds1, and Idd10 mapped to 45 cM on mouse chromosome 3 near D3Nds7, D3Nds11, and D3Nds8. Idd7 and Idd8 are associated with insulitis and diabetes susceptibility. Homozygosity for NOD/Lt-derived alleles confers resistance to diabetes at Idd7 and Idd8 indicating a dominant susceptible effect of the C57BL/10-derived allele. Idd10 also shows linkage to insulitis and diabetes susceptibility.
Several previously identified QTLs were detected in this study:
Idd3 mapped to 28 cM on mouse Chromosome 3 near D3Nds1 in linkage to diabetes susceptibility and insulitis. Sequence analysis of candidate gene Il2 revealed several amino acid difference between NOD/Lt and C57BL/10.
Idd4 mapped to 43.8 cM on mouse Chromosome 11 near D11Nds1 in linkage to diabetes susceptibility.
Idd5 mapped to 19.5 cM on mouse Chromosome 1 near D1Nds6 in linkage to diabetes susceptibility and insulitis.
Idd6 mapped to 71.2 cM on mouse Chromosome 6 near D6Mit14 in linkage to diabetes susceptibility.
Previous studies have shown linkage between the Idd6 locus and apoptosis resistance in immature thymocytes after gamma-irradiation. Idd6 locus also appears to be linked to apoptosis resistance after dexamethazone treatment. To confirm this observation linkage analysis was performed on 72 dexamethazone-treated female animals from a (C57BL/6 x NOD)F2 intercross. Peak association to dexamethazone-induced thymocyte depletion mapped to the Idd6 locus with LOD=6.5 between D6Mit14 (71.2 cM) and D6Mit15 (74 cM) on mouse Chromosome 6. Linkage to apoptosis resistance occurs in the same region with LOD=3.5. NOD-derived alleles at Idd6 confer resistance to apoptosis resistance in a dominant manner. This locus explains 34% of the phenotypic variation.
Construction of a congenic line by introgression of a C57BL/6-derived locus containing Idd6 on an NOD genetic background rescues the apoptosis phenotype. The Idd6 congenic interval controlling dexamethazone-induced apoptosis resistance of immature thymocytes was localized to a 3 cM region between D6Mit340 (72 cM) and D6Mit304 (75 cM). The natural killer complex, Nkcl at 57 cM is a possible candidate for Idd6. Two previously identified insulin-dependent diabetes QTLs, Idd19 (60.5 cM) and Idd20 (37.7 cM), also map to mouse Chromosome 6.
A congenic strain called NOD.B6-Klrb1c was created by introgression of a C57BL/6JOrl-derived donor region containing the Idd6 locus and Klrb1c onto a NOD/Necker genetic background. The congenic region spans 10 cM on mouse Chromosome 6 from D6Mit254 (60.55 cM) to D6Mit14 (71.2 cM). At backcross generation 10 (BC10) the animals were intercrossed to establish a homozygous congenic line. Homozygous congenic animals display decreased incidence of insulin dependent diabetes. The C57BL/6JOrl-derived congenic region was observed to confer dominant resistance to diabetes in both male and female animals. Potential candidate genes for Idd6 are Tnfrsf1a (60.55 cM) and Nkcl (57 cM).
C3H/HeJ alleles at Idd6 (insulin dependent diabetes susceptibility 6) on mouse Chromosome 6 confer protection against diabetes mellitus on a NOD genetic background as previously observed in the congenic line NOD.C3H-Idd6. In the current study authors observe a significant decrease in invariant natural killer (iNKT) cell frequency and numbers in spleen, liver and thymus of NOD.C3H-Idd6 congenics compared to NOD and C3H/HeJ parental strains. In NOD.C3H-Idd6 congenic animals, CD4+ iNTK cell numbers were at30%-50% of the levels seen in NOD animals, and at 20%-25% of the levels seen in C3H/HeJ animals. The pancreas of NOD.C3H-Idd6 congenic mice displayed reduced iNKT cell proportions compared to NOD mice. IL-4 and IFN-gamma secretion following induced cytokine production were also reduced in NOD.C3H-Idd6 animals compared to NOD mice.
Subcongenic lines were analyzed to localize the interval responsible for reduced iNKT cell frequency. Subcongenic lines NOD.C3H-Idd6a and NOD.C3H-Idd6c displayed similar iNKT cell frequencies compared to NOD inbred mice. However, NOD.C3H-Idd6b showed low iNKT cell number and low CD4+/double negative iNKT cell ratios similar to that observed in NOD.C3H-Idd6 congenic animals. Authors conclude the Idd6b locus [from approximately 70cM (D6Mit13) to 73.4 cM (D6Mit294)] influences diabetes resistance as well as iNKT cell population frequencies.
Female animals from a (C57BL/6 x NOD)F2 cross were screened for markers near Idd (insulin dependent diabetes) susceptibility loci to determine if any previously identified diabetes QTLs were associated with impaired thymocyte proliferation. Parental strain NOD exhibits slower thymocyte proliferation compared to C57BL/6 (thymocyte recovery in NOD is only 71% of C57BL/6). Markers on mouse Chromosome 6 near Idd6 showed linkage to this trait with a maximum LOD score of 5.36 at D6Mit15. NOD-derived alleles appear to confer dominantly inherited thymocyte proliferation impairment with reduced penetrance at Idd6.