Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major Histocompatibility Complex
- Theresa A. Aly12,
- Erin E. Baschal12,
- Mohamed M. Jahromi1,
- Maria S. Fernando1,
- Sunanda R. Babu1,
- Tasha E. Fingerlin23,
- Adam Kretowski14,
- Henry A. Erlich5,
- Pamela R. Fain12,
- Marian J. Rewers13 and
- George S. Eisenbarth12
- 1Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
- 2Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
- 3Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
- 4Medical Academy of Bialystok, Bialystok, Poland
- 5Roche Molecular Systems, Alameda, California
- Address correspondence and reprint requests to George S. Eisenbarth, MD, PhD, Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Mail Stop B140, P.O. Box 6511, Aurora, CO 80045-6511. E-mail: george.eisenbarth{at}uchsc.edu
Abstract
OBJECTIVE—HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both major histocompatibility complex (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 single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium.
RESULTS—We found evidence for an association with type 1A diabetes (rs1233478, P = 1.6 × 10−23, 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, P = 1.4 × 10−12) 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.
- AFBAC, affected family-based control
- DAISY, Diabetes Autoimmunity Study in the Young
- HBDI, Human Biological Data Interchange
- MHC, major histocompatibility complex
- SNP, single nucleotide polymorphism
- T1DGC, Type 1 Diabetes Genetics Consortium
Footnotes
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T.A.A. and E.E.B. contributed equally to this work.
Published ahead of print at http://diabetes.diabetesjournals.org on 7 December 2007. DOI: 10.2337/db07-0900.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0900.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
See accompanying commentary, p. 527.
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- Accepted November 21, 2007.
- Received July 3, 2007.
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