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© 2001 by the American Diabetes Association, Inc.
Suggestive Evidence for Association of Human Chromosome 18q12-q21 and Its Orthologue on Rat and Mouse Chromosome 18 With Several Autoimmune Diseases
From the Wellcome Trust Centre for Molecular Mechanisms in Disease (T.R.M., H.J.C., I.A.E., R.Ba., J.A.T.), University of Cambridge, Cambridge, U.K.; the Department of Biochemistry (T.R.M.), University of Otago, Dunedin, New Zealand; the University of Cambridge Neurology Unit (F.Co., S.B., S.S., A.C.), Addenbrooke's Hospital, Cambridge, U.K.; the Clinica Pediatrica (F.Cu.) and Chair of Neurophysiopathology (M.G.M.), University of Cagliari, Cagliari, Italy; the Wellcome Trust Centre for Human Genetics (T.R.M., P.A.D., P.W., J.S., S.L.), University of Oxford, Oxford, U.K.; Department of Genetics and Pathology (J.J., R.H.), Biomedical Center, Uppsala University, Uppsala, Sweden; the Department of Immunology (A.N.T., D.H.K.), the Scripps Research Institute, La Jolla, California; the Department of Epidemiology and Health Promotion (J.T., E.T.-W.), National Public Health Institute, Helsinki, Finland; Istituto Clinica Medica II (R.Bu.), University of Rome `La Sapienza, Rome, Italy; the Institute of Transplantation Immunology (D.E.U.), the National Hospital, Oslo, Norway; the Department of Population Health Sciences (K.S.R.), National Institute of Public Health, Oslo, Norway; the Clinic of Nutrition and Metabolic Diseases (C.I.-T.), Bucharest, Romania; the Institute of Child Health (J.P.S.), University of Bristol, Royal Hospital for Sick Children, Bristol, U.K.; Steno Diabetes Center (F.P., J.N.), Gentofte, Denmark; the Department of Medicine (C.O.J.), University of Southern California School of Medicine, Los Angeles, California; Montreal Children's Hospital (C.P.), Montréal, Québec, Canada; and the Department of Medicine (S.C.B.), University of Birmingham, Birmingham Heartlands Hospital, Birmingham, U.K.
Address correspondence reprint requests to Tony R. Merriman, PhD, Department of Biochemistry, University of Otago, Box 56, Dunedin, New Zealand. E-mail: tony.merriman{at}stonebow.otago.ac.nz .
Some immune system disorders, such as type 1 diabetes, multiple sclerosis
(MS), and rheumatoid arthritis (RA), share common features: the presence of
autoantibodies and self-reactive T-cells, and a genetic association with the
major histocompatibility complex. We have previously published evidence, from
1,708 families, for linkage and association of a haplotype of three markers in
the D18S487 region of chromosome 18q21 with type 1 diabetes. Here,
the three markers were typed in an independent set of 627 families and,
although there was evidence for linkage (maximum logarithm of odds score [MLS]
= 1.2; P = 0.02), no association was detected. Further linkage
analysis revealed suggestive evidence for linkage of chromosome 18q21 to type
1 diabetes in 882 multiplex families (MLS = 2.2; 
s = 1.2; P =
0.001), and by meta-analysis the orthologous region (also on chromosome 18) is
linked to diabetes in rodents (P = 9 x 10-4). By
meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous
region show positive evidence for linkage to an autoimmune phenotype
(P = 0.004 and 2 x 10-8, respectively, empirical
P = 0.01 and 2 x 10-4, respectively). In the
diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in
colorectal carcinoma (DCC), was tested for association with human autoimmunity
in 3,380 families with type 1 diabetes, MS, and RA. A haplotype
("2-10") of two newly characterized microsatellite markers within
DCC showed evidence for association with autoimmunity (P = 5
x 10-6). Collectively, these data suggest that a locus (or
loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune
diseases and that this association might be conserved between species.
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