Is it still possible to have celiac disease if you don't carry the HLA-DQ2 or HLA-DQ8 (Human Leukocyte Antigen) genes?

Celiac Disease Without HLA-DQ2/DQ8 Genes

It is extremely rare to have celiac disease without carrying either the HLA-DQ2 or HLA-DQ8 genes, with less than 1% of celiac disease patients lacking these genetic markers. 1

Genetic Testing in Celiac Disease Diagnosis

HLA typing plays a crucial role in celiac disease diagnosis due to its exceptionally high negative predictive value:

• HLA-DQ2 and HLA-DQ8 presence: Found in >95% of celiac disease patients 2, 3
• Absence of both markers: Makes celiac disease highly unlikely (negative predictive value approaching 100%) 2
• Clinical utility: Most valuable when results are negative, effectively ruling out celiac disease 1, 2

Rare Exceptions to Consider

While extremely uncommon, there are documented cases of celiac disease in patients who test negative for the traditional HLA-DQ2 and HLA-DQ8 markers:

• Some patients may carry only "half" of the HLA-DQ2.5 heterodimer (either in cis or trans configuration) 4
• HLA-DQ2.2 (DQA102:01, DQB102:02) has been identified in approximately 5.8% of celiac patients who lack the traditional markers 5
• Complete allele assessment should include HLA-DQ2.5, HLA-DQ8, HLA-DQ2.2, and HLA-DQ7.5 for accurate interpretation 2

Diagnostic Algorithm When HLA Status is Negative

If a patient has symptoms suggestive of celiac disease but tests negative for HLA-DQ2 and HLA-DQ8:

1. Verify complete HLA testing: Ensure testing included all relevant alleles (DQ2.5, DQ8, DQ2.2, DQ7.5) 2
2. Review laboratory reporting: Different labs may report results differently; check for half heterodimers 2
3. Consider alternative diagnoses: When HLA testing is truly negative, investigate other causes of enteropathy 2:
   • Infectious causes (giardiasis, tropical sprue, Whipple's disease)
   • Immune-mediated conditions
   • Medication-induced enteropathy
   • Inflammatory conditions (Crohn's disease, collagenous sprue)

Clinical Implications and Recommendations

• HLA typing should be used to rule out celiac disease with high confidence when negative 1
• HLA typing is particularly valuable in:
  • Patients with suspected celiac disease who fail to respond to a gluten-free diet 1
  • Individuals who started a gluten-free diet without proper diagnostic confirmation 1, 2
  • Evaluating high-risk individuals (first-degree relatives) to minimize future testing 1
• A positive HLA test alone cannot confirm celiac disease due to its low positive predictive value (many people without celiac disease carry these genes) 1

Common Pitfalls to Avoid

• Incomplete HLA testing: Ensure testing includes all relevant alleles, not just DQ2 and DQ8
• Misinterpreting positive results: Remember that 20-40% of the general population carries HLA-DQ2 or HLA-DQ8 without having celiac disease 1
• Relying solely on HLA testing: Diagnosis should still incorporate serology (tTG-IgA, EMA-IgA) and duodenal biopsies when appropriate 1, 2
• Overlooking rare variants: The small percentage of celiac patients without traditional HLA markers may carry other genetic variants like HLA-DQ2.2 5

In conclusion, while theoretically possible, celiac disease without HLA-DQ2 or HLA-DQ8 is extremely rare and should prompt thorough verification of testing methodology and consideration of alternative diagnoses.