Analysis of single nucleotide polymorphisms identifies major type 1A diabetes locus telomeric of the major histocompatibility complex

OBJECTIVE-HLA-DRB1*03-DQBI*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 MEC 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 I 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/MASIL 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 aqjustment 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.