Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles.
OBJECTIVE
Susceptibility to celiac disease (CD) is related to HLA-DQ2 and DQ8 alleles and the heterodimers they encode. The objective of this study was to stratify risk for CD on the basis of HLA-DQ genotype.


METHODS
DNA from 10,191 subjects who are at risk for CD was analyzed for HLA-DQ haplotypes. Individuals with CD were identified as those who tested positive for anti-endomysial immunoglobulin A (EMA+) in an immunofluorescence assay.


RESULTS
Samples homozygous for DQ2.5 (HLA-DQA1 05-DQB1 02) or DQ2.2/DQ2.5 (HLA-DQA1 05-DQB1 02 and HLA-DQA1 0201-DQB1 02) comprised 5.38% of the total; 28.28% of these were EMA+ (95% confidence interval [CI], 24.55-32.26). Of the samples that were DQ2.5 heterozygous (HLA-DQA1 05-DQB1 02); 9.09% were EMA+ (95% CI, 7.82-10.51). Among samples in which HLA-DQ8 (HLA-DQA1 03-DQB1 0302) was detected, 8.42% of homozygotes (95% CI, 3.71-15.92) and 2.11% of heterozygotes (95% CI, 1.43-3.00) were EMA+. Samples with DQ2.2/DQ8 or DQ2.5/DQ8 comprised 5.08% of the total, and 11.78% of these were EMA+ (95% CI, 9.13-14.87). HLA-DQ2 and HLA-DQ8 were absent in 4283 samples (42.03% of the total); 0.16% of these samples were EMA+ (95% CI, 0.07-0.34).


CONCLUSIONS
High-resolution, sequence-specific oligonucleotide probe typing with 35 DQA1-specific and 37 DQB1-specific probes of DNA from more than 10,000 subjects was used to stratify risk of CD in an at-risk U.S. population. DQ2 homozygosity (DQ2.5/DQ2.2+2.5) increased risk for CD, estimated by the rate of EMA positivity, compared with the entire sample population and other DQ genotypes. These data suggest a quantitative relationship between the type/proportion of DQ heterodimers and the risk of CD and identify potential immunotherapeutic targets.
Pietzak
Michelle M
MM
Department of Pediatrics, Women's and Children's Hospital, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA. pietzak@usc.edu
Schofield
Timothy C
TC
McGinniss
Matthew J
MJ
Nakamura
Robert M
RM
D000483:Alleles; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D002446:Celiac Disease / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006683:HLA-DQ Antigens / Q000032:analysis / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015345:Oligonucleotide Probes; D012307:Risk Factors; D014481:United States
D001323:Autoantibodies; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D015345:Oligonucleotide Probes