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.
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.
Authors: Erin E Baschal; Suparna A Sarkar; Theresa A Boyle; Janet C Siebert; Jean M Jasinski; Katharine R Grabek; Taylor K Armstrong; Sunanda R Babu; Pamela R Fain; Andrea K Steck; Marian J Rewers; George S Eisenbarth Journal: J Diabetes Date: 2011-09 Impact factor: 4.006
Authors: E E Baschal; T A Aly; J M Jasinski; A K Steck; K N Johnson; J A Noble; H A Erlich; G S Eisenbarth Journal: Diabetes Obes Metab Date: 2009-02 Impact factor: 6.577
Authors: Lisa F Barcellos; Suzanne L May; Patricia P Ramsay; Hong L Quach; Julie A Lane; Joanne Nititham; Janelle A Noble; Kimberly E Taylor; Diana L Quach; Sharon A Chung; Jennifer A Kelly; Kathy L Moser; Timothy W Behrens; Michael F Seldin; Glenys Thomson; John B Harley; Patrick M Gaffney; Lindsey A Criswell Journal: PLoS Genet Date: 2009-10-23 Impact factor: 5.917