Analysis of SNPs Identifies Major Type 1A Diabetes Locus Telomeric of the MHC

  1. Theresa A. Aly, MD, PhD1,,2,
  2. Erin E. Baschal, BA1,,2,
  3. Mohamed M. Jahromi, PhD1,
  4. Maria S. Fernando, BS1,
  5. Sunanda R. Babu, PhD1,
  6. Tasha E. Fingerlin, PhD2,,3,
  7. Adam Kretowski, MD1,,4,
  8. Henry A Erlich, PhD5,
  9. Pamela R. Fain, PhD1,,2,
  10. Marian J. Rewers, MD, PhD1,,3 and
  11. George S. Eisenbarth, MD, PhD (George.Eisenbarth{at}UCHSC.edu)1,,2
  1. 1Barbara Davis Center for Childhood Diabetes and
  2. 2Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045 USA
  3. 3Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045 USA
  4. 4Medical Academy of Bialystok, Poland
  5. 5Roche Molecular Systems, Alameda, CA 94710, USA

    Abstract

    Objective: HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both MHC haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-by-descent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes.

    Research Design and Methods: We completed an extensive SNP analysis of the extended MHC in 237 families with type 1A diabetes from the United States and 1,240 families from the Type 1 Diabetes Genetics Consortium.

    Results: We found evidence for an association with type 1A diabetes (rs1233478, p=1.6x10−23, allelic odds ratio=2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the “8.1 haplotype.” The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, p1.4x10−12), and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B and HLA-A (p=0.01).

    Conclusions: Polymorphisms in the region of the UBD/MAS1L genes are associated with type 1A diabetes independent of HLA class II and I alleles.

    Footnotes

      • Received July 3, 2007.
      • Accepted November 21, 2007.

    This Article

    1. Published online before print December 7, 2007, doi: 10.2337/db07-0900
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