The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes.
OBJECTIVE
The goal of this study was to develop and implement methodology that would aid in the analysis of extended high-density single nucleotide polymorphism (SNP) major histocompatibility complex (MHC) haplotypes combined with human leucocyte antigen (HLA) alleles in relation to type 1 diabetes risk.


METHODS
High-density SNP genotype data (2918 SNPs) across the MHC from the Type 1 Diabetes Genetics Consortium (1240 families), in addition to HLA data, were processed into haplotypes using PedCheck and Merlin, and extended DR3 haplotypes were analysed.


RESULTS
With this large dense set of SNPs, the conservation of DR3-B8-A1 (8.1) haplotypes spanned the MHC (>/=99% SNP identity). Forty-seven individuals homozygous for the 8.1 haplotype also shared the same homozygous genotype at four 'sentinel' SNPs (rs2157678 'T', rs3130380 'A', rs3094628 'C' and rs3130352 'T'). Conservation extended from HLA-DQB1 to the telomeric end of the SNP panels (3.4 Mb total). In addition, we found that the 8.1 haplotype is associated with lower risk than other DR3 haplotypes by both haplotypic and genotypic analyses [haplotype: p = 0.009, odds ratio (OR) = 0.65; genotype: p = 6.3 x 10(-5), OR = 0.27]. The 8.1 haplotype (from genotypic analyses) is associated with lower risk than the high-risk DR3-B18-A30 haplotype (p = 0.01, OR = 0.23), but the DR3-B18-A30 haplotype did not differ from other non-8.1 DR3 haplotypes relative to diabetes association.


CONCLUSIONS
The 8.1 haplotype demonstrates extreme conservation (>3.4 Mb) and is associated with significantly lower risk for type 1 diabetes than other DR3 haplotypes.
Baschal
E E
EE
Barbara Davis Center for Childhood Diabetes, Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA. george.eisenbarth@UCHSC.edu
Aly
T A
TA
Jasinski
J M
JM
Steck
A K
AK
Johnson
K N
KN
Noble
J A
JA
Erlich
H A
HA
Eisenbarth
G S
GS
D017124:Conserved Sequence; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
D015803:HLA-DR3 Antigen