(D INSTITIlT PASTEUR/ELSEVIER Paris 1991
Res. Immunol. 1991, 142, 483
Genetic analysis of a complex, multifactorial disease, autoimmune type 1 (insulin-dependent) diabetes J . A . T o d d (1), T . J . A i t m a n 0), R . J . Cornall (l), S. G h o s h (l), j . Hall (1), C . M . H e a r n e (1), A. Knight (2), j . Love (l), M . A . McAleer (1), J.B. Prins 0), M. L a t h r o p (3) L. Peterson (4) and L. Wicker (a) a) Nuffieid2Departmen t o f Surgery_. John Radcliffe Hospital, Headington, O x f o r d OX3 9 D U (UK), t ) Clinical Research wentre W a t f o r d Rd., Harrow, Middlesex H A 1 3 U J (UK), ~) CEPH, 27 rue Juliette Dodu, Paris, and ¢4) Merck, Sharpe & Dohme, Rahway, N J 07605 (USA)
Susceptibility to the autoimmune disease, type 1 diabetes, is determined by genetic factors and the environment. Two genes within the human MHC class II region, HLA-DQAI (Todd et al., 1989, 1990) and HLA-DQBI (Todd et ai., 1987; Horn et ai., 1988; Todd, 1990) have been correlated with susceptibility to the observed T-cell-dependent pancreatic beta cell destruction. Their murine homologues, I-Aa and I-A[3, are linked to disease susceptibility in the spontaneously diabetic mouse strain, NOD (Wicker et al., 1987). NOD mice transgenic for I-Aa and I-A~ genes from H-2 haplotypes that encode resistance to diabetes show that these genes and sequence variation within them directly influence disease development (Miyazaki et al., 1990; Slattery et al., 1990; Lund et aL, 1990), Both the human (Risch, 1987) and mouse diseases (Prochazka et al., 1987) are polygenic. Presumably, at least one of these other, non-MHC genes affects the immune system and many interact with MHC class II genes. Our current aims are to identify these non-MHC genes in the human and mouse to understand the aetiology of type 1 diabetes. As a first step, we have collected a large number of multiplex human families with disease (Bain et al., 1990) and also analysed a large backcross between NOD and the diabetes-resistant strain, BI0. To look for NOD non-MHC genes, we first characterized a new collection of genetic markers (Love et a!., 1990). These are called microsatellites or dinucleotide repeats, which are common in the mouse (and human) genomes and show considerable allelic variation between inbred strains. For a given locus which has a dinucleotide repeat in its sequence, the number of repeats can vary, giving rise to size variations that can be easily assayed using the polymerase chain reaction and agarose gel elec-
trophoresis. Currently, we have about 60 microsatellites that are variant between NOD and B 10 and give about 80 °7o coverage of the genome. Using these markers, we have found linkage of murine diabetes to at least four different chromosomes. Two of these genes lie in areas of the mouse genome that are homologous with the human genome and provide candidate regions to begin the hunt for human susceptibility genes (Todd et al., 1991). Key-words: 1~/1[ L I f " • 1Vll 1~,.,,
Diabetes,
Autoimmune
disease,
I~A[ . . . . . l¥11kJU,~.
References
Bain, S.C., Todd, J.A. & Barnett, A.H. (I990), Autoimmunity, 7, 83-85. Horn, G.T., Bugawan, T.L., Long, C.M. & Erlich, H.A. (1988), Proc. nat. Acad. Sci. (Wash.), 85, 6012-6016. Love, J.M., Knight, A.M., McAleer, A.M. & Todd, J.A. (1990), Nucl. Acids Res., 18, 4123-4130. Lund, T. et al. (1990), Nature (Lond.), 345, 727-729. Miyazaki, T. et al. (1990), Nature (Lond.), 345,722-724. Prochazka, M., Leiter, E.H., Serreze, D.V. & Coleman, D.L. (1987), Science, 237, 286-289. Risch, N. (1987), Amer. J. Hum. Genet., 40, 1-14. Slattery, R.M. et al. (1990), Nature (Lond.), 345,724-726. Todd, J.A. (1990), lmmunoL Today, 11, 122-129. Todd, J.A., Bell, J.l. & McDevitt, H.O. (1987), Nature (Lond.), 329, 599-604. Todd, J.A., Fukui, Y., Kitagawa, T. & Sasazuki, T. (1990), Proc. nat. Acad. Sci. (Wash.), 87, 1094-1098. Todd, J.A., Mijovic, C., Fletcher, J., Jenkins, D., Bradwell, A.R. & Barnett, A.H. (1989), Nature (Lond.), 338, 587-589. Todd, J.A. et al. (1991), Nature (Lond.), 351, .'42-547. Wicker, L.S., Miller, B.J., Coker, L.Z. et al. (1987), J. exp. Med., 165, 1639-1654.
Res. Immunol. 1991, 142, 483
Genetic analysis of a complex, multifactorial disease, autoimmune type 1 (insulin-dependent) diabetes J . A . T o d d (1), T . J . A i t m a n 0), R . J . Cornall (l), S. G h o s h (l), j . Hall (1), C . M . H e a r n e (1), A. Knight (2), j . Love (l), M . A . McAleer (1), J.B. Prins 0), M. L a t h r o p (3) L. Peterson (4) and L. Wicker (a) a) Nuffieid2Departmen t o f Surgery_. John Radcliffe Hospital, Headington, O x f o r d OX3 9 D U (UK), t ) Clinical Research wentre W a t f o r d Rd., Harrow, Middlesex H A 1 3 U J (UK), ~) CEPH, 27 rue Juliette Dodu, Paris, and ¢4) Merck, Sharpe & Dohme, Rahway, N J 07605 (USA)
Susceptibility to the autoimmune disease, type 1 diabetes, is determined by genetic factors and the environment. Two genes within the human MHC class II region, HLA-DQAI (Todd et al., 1989, 1990) and HLA-DQBI (Todd et ai., 1987; Horn et ai., 1988; Todd, 1990) have been correlated with susceptibility to the observed T-cell-dependent pancreatic beta cell destruction. Their murine homologues, I-Aa and I-A[3, are linked to disease susceptibility in the spontaneously diabetic mouse strain, NOD (Wicker et al., 1987). NOD mice transgenic for I-Aa and I-A~ genes from H-2 haplotypes that encode resistance to diabetes show that these genes and sequence variation within them directly influence disease development (Miyazaki et al., 1990; Slattery et al., 1990; Lund et aL, 1990), Both the human (Risch, 1987) and mouse diseases (Prochazka et al., 1987) are polygenic. Presumably, at least one of these other, non-MHC genes affects the immune system and many interact with MHC class II genes. Our current aims are to identify these non-MHC genes in the human and mouse to understand the aetiology of type 1 diabetes. As a first step, we have collected a large number of multiplex human families with disease (Bain et al., 1990) and also analysed a large backcross between NOD and the diabetes-resistant strain, BI0. To look for NOD non-MHC genes, we first characterized a new collection of genetic markers (Love et a!., 1990). These are called microsatellites or dinucleotide repeats, which are common in the mouse (and human) genomes and show considerable allelic variation between inbred strains. For a given locus which has a dinucleotide repeat in its sequence, the number of repeats can vary, giving rise to size variations that can be easily assayed using the polymerase chain reaction and agarose gel elec-
trophoresis. Currently, we have about 60 microsatellites that are variant between NOD and B 10 and give about 80 °7o coverage of the genome. Using these markers, we have found linkage of murine diabetes to at least four different chromosomes. Two of these genes lie in areas of the mouse genome that are homologous with the human genome and provide candidate regions to begin the hunt for human susceptibility genes (Todd et al., 1991). Key-words: 1~/1[ L I f " • 1Vll 1~,.,,
Diabetes,
Autoimmune
disease,
I~A[ . . . . . l¥11kJU,~.
References
Bain, S.C., Todd, J.A. & Barnett, A.H. (I990), Autoimmunity, 7, 83-85. Horn, G.T., Bugawan, T.L., Long, C.M. & Erlich, H.A. (1988), Proc. nat. Acad. Sci. (Wash.), 85, 6012-6016. Love, J.M., Knight, A.M., McAleer, A.M. & Todd, J.A. (1990), Nucl. Acids Res., 18, 4123-4130. Lund, T. et al. (1990), Nature (Lond.), 345, 727-729. Miyazaki, T. et al. (1990), Nature (Lond.), 345,722-724. Prochazka, M., Leiter, E.H., Serreze, D.V. & Coleman, D.L. (1987), Science, 237, 286-289. Risch, N. (1987), Amer. J. Hum. Genet., 40, 1-14. Slattery, R.M. et al. (1990), Nature (Lond.), 345,724-726. Todd, J.A. (1990), lmmunoL Today, 11, 122-129. Todd, J.A., Bell, J.l. & McDevitt, H.O. (1987), Nature (Lond.), 329, 599-604. Todd, J.A., Fukui, Y., Kitagawa, T. & Sasazuki, T. (1990), Proc. nat. Acad. Sci. (Wash.), 87, 1094-1098. Todd, J.A., Mijovic, C., Fletcher, J., Jenkins, D., Bradwell, A.R. & Barnett, A.H. (1989), Nature (Lond.), 338, 587-589. Todd, J.A. et al. (1991), Nature (Lond.), 351, .'42-547. Wicker, L.S., Miller, B.J., Coker, L.Z. et al. (1987), J. exp. Med., 165, 1639-1654.
