TY - JOUR
T1 - Replication and further characterization of a Type 1 diabetes-associated locus at the telomeric end of the major histocompatibility complex
AU - Baschal, Erin E.
AU - Sarkar, Suparna A.
AU - Boyle, Theresa A.
AU - Siebert, Janet C.
AU - Jasinski, Jean M.
AU - Grabek, Katharine R.
AU - Armstrong, Taylor K.
AU - Babu, Sunanda R.
AU - Fain, Pamela R.
AU - Steck, Andrea K.
AU - Rewers, Marian J.
AU - Eisenbarth, George S.
PY - 2011/9
Y1 - 2011/9
N2 - Background: We recently reported an association between Type 1 diabetes and the telomeric major histocompatibility complex (MHC) single nucleotide polymorphism (SNP) rs1233478. As further families have been analyzed in the Type 1 Diabetes Genetics Consortium (T1DGC), we tested replication of the association and, with more data, analyzed haplotypic associations. Methods: An additional 2717 case and 1315 control chromosomes have been analyzed from the T1DGC, with human leukocyte antigen (HLA) typing and data for 2837 SNPs across the MHC region. Results: We confirmed the association of rs1233478 (new data only: P=2.2E-5, OR=1.4). We also found two additional SNPs nearby that were significantly associated with Type 1 diabetes (new data only rs3131020: P=8.3E-9, OR=0.65; rs1592410: P=2.2E-8, OR=1.5). For studies of Type 1 diabetes in the MHC region, it is critical to account for linkage disequilibrium with the HLA genes. Logistic regression analysis of these new data indicated that the effects of rs3131020 and rs1592410 on Type 1 diabetes risk are independent of HLA alleles (rs3131020: P=2.3E-3, OR=0.73; rs1592410: P=2.1E-3, OR=1.4). Haplotypes of 12 SNPs (including the three highly significant SNPs) stratify diabetes risk (high risk, protective, and neutral), with high-risk haplotypes limited to approximately 20000bp in length. The 20000-bp region is telomeric of the UBD gene and contains LOC729653, a hypothetical gene. Conclusions: We believe that polymorphisms of the telomeric MHC locus LOC729653 may confer risk for Type 1 diabetes.
AB - Background: We recently reported an association between Type 1 diabetes and the telomeric major histocompatibility complex (MHC) single nucleotide polymorphism (SNP) rs1233478. As further families have been analyzed in the Type 1 Diabetes Genetics Consortium (T1DGC), we tested replication of the association and, with more data, analyzed haplotypic associations. Methods: An additional 2717 case and 1315 control chromosomes have been analyzed from the T1DGC, with human leukocyte antigen (HLA) typing and data for 2837 SNPs across the MHC region. Results: We confirmed the association of rs1233478 (new data only: P=2.2E-5, OR=1.4). We also found two additional SNPs nearby that were significantly associated with Type 1 diabetes (new data only rs3131020: P=8.3E-9, OR=0.65; rs1592410: P=2.2E-8, OR=1.5). For studies of Type 1 diabetes in the MHC region, it is critical to account for linkage disequilibrium with the HLA genes. Logistic regression analysis of these new data indicated that the effects of rs3131020 and rs1592410 on Type 1 diabetes risk are independent of HLA alleles (rs3131020: P=2.3E-3, OR=0.73; rs1592410: P=2.1E-3, OR=1.4). Haplotypes of 12 SNPs (including the three highly significant SNPs) stratify diabetes risk (high risk, protective, and neutral), with high-risk haplotypes limited to approximately 20000bp in length. The 20000-bp region is telomeric of the UBD gene and contains LOC729653, a hypothetical gene. Conclusions: We believe that polymorphisms of the telomeric MHC locus LOC729653 may confer risk for Type 1 diabetes.
KW - Genetic association studies
KW - Major histocompatibility complex
KW - Type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=80051815907&partnerID=8YFLogxK
U2 - 10.1111/j.1753-0407.2011.00131.x
DO - 10.1111/j.1753-0407.2011.00131.x
M3 - Article
C2 - 21631897
AN - SCOPUS:80051815907
SN - 1753-0393
VL - 3
SP - 238
EP - 247
JO - Journal of Diabetes
JF - Journal of Diabetes
IS - 3
ER -