Rajashree Mishra1,2, Mikael Åkerlund3, Diana L Cousminer1,4, Emma Ahlqvist3, Jonathan P Bradfield5, Alessandra Chesi1, Kenyaita M Hodge1, Vanessa C Guy1, David J Brillon6, Richard E Pratley7, Michael R Rickels8, Adrian Vella9, Fernando Ovalle10, Ronald I Harris11, Olle Melander3, Stephen Varvel12, Hakon Hakonarson5,13, Phillippe Froguel14,15, John T Lonsdale16, Didac Mauricio17, Nanette C Schloot18, Kamlesh Khunti19, Carla J Greenbaum20, Knud B Yderstræde21, Tiinamaija Tuomi22,23,24, Benjamin F Voight4,8,25,26, Stanley Schwartz27, Bernhard O Boehm28,29, Leif Groop3,24, Richard David Leslie30, Struan F A Grant31,4,5,8,13. 1. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA. 2. Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 3. Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden. 4. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 5. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA. 6. Weill Cornell Medical College, New York City, NY. 7. Translational Research Institute for Metabolism and Diabetes, Florida Hospital, FL. 8. Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 9. Mayo Clinic, Rochester, MN. 10. University of Alabama at Birmingham, Birmingham, AL. 11. Geisinger Health System, Danville, PA. 12. Health Diagnostic Laboratory, Inc., Richmond, VA. 13. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 14. CNRS 8199, Université Lille Nord de France, Pasteur Institute, Lille, France. 15. Department of Genomics of Common Disease, Imperial College London, London, U.K. 16. National Disease Research Interchange, Philadelphia, PA. 17. Hospital de la Santa Creu i Sant Pau, CIBERDEM, Barcelona, Spain. 18. German Diabetes Center, Düsseldorf, German. 19. Diabetes Research Centre, University of Leicester, Leicester, U.K. 20. Benaroya Research Institute, Seattle, WA. 21. Odense University Hospital, Odense, Denmark. 22. Department of Endocrinology, Helsinki University Hospital, Helsinki, Finland. 23. Folkhälsan Research Centre, Helsinki, Finland, and Research Programs Unit, Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland. 24. Institute for Molecular Medicine Finland, Helsinki, Finland. 25. Department of Systems, Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 26. Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 27. Main Line Health System, Wynnewood, PA. 28. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, and Imperial College London, London, U.K. 29. Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany. 30. Department of Immunobiology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K. 31. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA grants@email.chop.edu.
Abstract
OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.
OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.
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