Celiac disease risk stratification based on HLA-DQ heterodimer (HLA-DQA1 ~ DQB1) typing in a large cohort of adults with suspected celiac disease.

BACKGROUNDS

Patients with celiac disease (CeD) carry the major histocompatibility complex class II, HLA-DQ2 or DQ8 haplotype; the absence of these haplotypes excludes a diagnosis of CeD. While the most common and highest risk HLA haplotypes in CeD have been established, the risk profiles of the less common and equivocal HLA haplotypes need further refinement. The aim of this study was to use a large national patient cohort to further stratify the risk gradient of HLA-DQ haplotypes.

METHODS

The study cohort included 24,339 adult patients with suspected CeD and immunoglobulin (Ig)A sufficiency (total IgA ≥ 70 mg/dL) whose samples were assessed at Mayo Clinic Laboratories for HLA-DQ genotyping, total IgA, and tissue transglutaminase (tTG)-IgA. Data from a subset of the patients who had duodenal biopsies were analyzed to determine the risk gradient of CeD. Logistic regression models were used to evaluate the risk gradient and to calculate odds ratios (ORs) for being positive to CeD serology according to different HLA-DQ2 and DQ8 heterodimers.

RESULTS

Of the 24,339 patients, 55% (n = 13,456) expressed HLA-DQ2 or DQ8 heterodimers. Compared with patients who had non-permissive HLA-DQ heterodimers, patients who had HLA-DQ2 homozygosity (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, or HLA-DQ2.2/DQ2.2) showed increased odds for tTG-IgA positivity (OR = 96.9; 95% CI, 58.3-147.9). Interestingly, the odds for patients who were compound heterozygous for HLA-DQ2.5 and HLA-DQ8 were similar to those for HLA-DQ2.5 heterozygotes. However, a single HLA-DQ2.2 haplotype (without HLA-DQ8, DQ2.2 heterozygous) was not associated with tTG-IgA positivity. These findings were confirmed in a subset of patients (n = 738) who had duodenal biopsies performed in addition to CeD serologic testing.

DISCUSSION

This large national reference laboratory cohort study demonstrated that HLA-DQ2.2 heterozygous is not associated with positive tTG-IgA serology, suggesting the reclassification of this haplotype as non-permissive for CeD.