HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Online-Only Appendix All Versions of this Article: db07-0900v1 57/3/770    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Aly, T. A. Articles by Eisenbarth, G. S. PubMed PubMed Citation Articles by Aly, T. A. Articles by Eisenbarth, G. S. Related Collections Related Article Social Bookmarking                What's this?

Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major Histocompatibility Complex

¹ Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
² Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
³ Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
⁴ Medical Academy of Bialystok, Bialystok, Poland
⁵ Roche 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

Abbreviations: 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

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 x 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 x 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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article:

HLA on Chromosome 6: The Story Gets Longer and Longer

Leslie J. Raffel, Janelle A. Noble, and Jerome I. Rotter
Diabetes 2008 57: 527-528. [Extract] [Full Text] [PDF]