Suggestive Evidence for Association of Human Chromosome 18q12-q21 and Its Orthologue on Rat and Mouse Chromosome 18 With Several Autoimmune Diseases

  1. Tony R. Merriman,
  2. Heather J. Cordell,
  3. Iain A. Eaves,
  4. Patrick A. Danoy,
  5. Francesca Coraddu,
  6. Rachael Barber,
  7. Francesco Cucca,
  8. Simon Broadley,
  9. Stephen Sawcer,
  10. Alastair Compston,
  11. Paul Wordsworth,
  12. Jane Shatford,
  13. Steve Laval,
  14. Johan Jirholt,
  15. Rikard Holmdahl,
  16. Argyrios N. Theofilopoulos,
  17. Dwight H. Kono,
  18. Jaakko Tuomilehto,
  19. Eva Tuomilehto-Wolf,
  20. Raffaella Buzzetti,
  21. Maria Giovanna Marrosu,
  22. Dag E. Undlien,
  23. Kjersti S. Rønningen,
  24. C. Ionesco-Tirgoviste,
  25. Julian P. Shield,
  26. Fleming Pociot,
  27. Jorn Nerup,
  28. Chaim O. Jacob,
  29. Constantin Polychronakos,
  30. Steve C. Bain and
  31. John A. Todd
  1. 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.
  1. 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 .

Abstract

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; λs = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 × 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 × 10-8, respectively, empirical P = 0.01 and 2 × 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 × 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.

Footnotes

  • J.A.T. was a paid consultant of Merck Research Laboratories, which provided grants to his laboratory to conduct studies on the genetics of type 1 diabetes.

  • DCC, deleted in colorectal carcinoma; df, degrees of freedom; EAE, experimental allergic encephalomyelitis; GSMA, genome search meta-analysis; JDFI, Juvenile Diabetes Foundation International; MAS, maximal arthritis score; MHC, major histocompatibility complex; MLS, maximum logarithm-of-odds score; MS, multiple sclerosis; PCR, polymerase chain reaction; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TDT, transmission disequilibrium test; Tsp, TDT-based statistic.

    • Accepted September 8, 2000.
    • Received April 6, 2000.
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  1. doi: 10.2337/diabetes.50.1.184 Diabetes January 2001 vol. 50 no. 1 184-194
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