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


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.
Aly
Theresa A
TA
Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045-6511, USA.
Baschal
Erin E
EE
Jahromi
Mohamed M
MM
Fernando
Maria S
MS
Babu
Sunanda R
SR
Fingerlin
Tasha E
TE
Kretowski
Adam
A
Erlich
Henry A
HA
Fain
Pamela R
PR
Rewers
Marian J
MJ
Eisenbarth
George S
GS
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016615:Telomere