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

摘要

OBJECTTVE-HLA-DRB1~*03-DQB1~* 0201/~*04-DQB1~*0302 (DB3/4-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 (rsl233478, 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.