What is the difference between human leukocyte antigen DQ2 (HLA‑DQ2) and human leukocyte antigen DQ2.5 (HLA‑DQ2.5); are they the same?

HLA-DQ2 vs. HLA-DQ2.5: Understanding the Distinction

HLA-DQ2 and HLA-DQ2.5 are NOT the same thing—HLA-DQ2 is a broad serologic family that includes multiple distinct molecular subtypes, while HLA-DQ2.5 refers specifically to the heterodimer formed by DQA105:01 and DQB102:01 alleles, which is the primary disease-associated variant in celiac disease. 1

The HLA-DQ2 Family: Multiple Molecular Variants

The term "HLA-DQ2" encompasses several distinct molecular heterodimers that differ in their disease associations and functional properties:

HLA-DQ2.5 (The Primary Disease-Associated Variant)

• HLA-DQ2.5 is composed of the specific allele pair DQA105:01 and DQB102:01, and this is the variant strongly associated with celiac disease 1, 2
• Over 90% of celiac disease patients carry the complete DQ2.5 heterodimer, making it the dominant genetic risk factor 1
• HLA-DQ2.5 can be inherited in two configurations: in cis (both alleles on the same chromosome, typically the DR3 haplotype) or in trans (alleles on opposite chromosomes, usually DR5 and DR7 haplotypes) 1, 2
• HLA-DQ2.5 presents a large repertoire of gluten peptides to T cells, which explains its strong disease association 2

HLA-DQ2.2 (A Distinct, Lower-Risk Variant)

• HLA-DQ2.2 is formed by DQA102:01 and DQB102:02, which differs from DQ2.5 by a single polymorphic residue (Phe22α instead of Tyr22α) 1, 3
• HLA-DQ2.2 can only present a limited subset of gluten peptides compared to DQ2.5, specifically requiring epitopes with serine at the P3 position 2, 3
• A single HLA-DQ2.2 haplotype alone (heterozygous without DQ2.5 or DQ8) is NOT associated with positive celiac serology and should be reclassified as non-permissive for celiac disease 4
• However, HLA-DQ2.2 homozygosity or compound heterozygosity with DQ2.5 does confer disease risk, with odds ratios for positive serology of 96.9 when homozygous 1, 4, 5

Critical Clinical Implications

Why the Distinction Matters for Diagnosis

• Commercial laboratories often report only "DQ2-positive" or "DQ2-negative" without specifying whether the patient carries DQ2.5, DQ2.2, or other variants, which can lead to misclassification of disease risk 1
• Clinicians must request that laboratories report every allele tested (DQA1 and DQB1 separately) rather than accepting summary results 1
• The negative predictive value exceeds 99% only when both DQ2.5 AND DQ8 are absent—a generic "DQ2-negative" result may miss trans-configured DQ2.5 or other permissive combinations 1, 6

Gene Dosage Effects and Risk Stratification

• Highest risk: Homozygous DQ2.5 (two copies in cis) 1, 2
• High risk: Heterozygous DQ2.5 in cis, DQ2.5 formed in trans, or DQ2.5/DQ2.2 compound heterozygosity 1, 4
• Moderate risk: DQ8 (DQA103 + DQB10302) or DQ2.2 homozygosity 1, 4
• Minimal to no risk: Single DQ2.2 heterozygous without other permissive alleles 4

Additional Complexity: Trans Dimers and Half-Heterodimers

• In HLA-DQ2.5/2.2 compound heterozygotes, trans dimers can form (DQA105:01 from one chromosome pairing with DQB102:02 from the other), which have properties identical to DQ2.5 dimers and confer disease risk 2
• DQA105 alone can be disease-permissive if paired with DQB10301 (forming DQ7.5), DQB1*0202 (forming variant DQ2.2), or when DQ8 alleles are present 1

Common Pitfalls to Avoid

• Never accept a laboratory report stating only "HLA-DQ2 positive" without verification of the specific alleles—this could represent DQ2.5 (high risk), DQ2.2 heterozygous alone (minimal risk), or other combinations 1
• Do not assume that "HLA-DQ2 negative" excludes celiac disease unless you have confirmed that DQ2.5 (both in cis and trans configurations), DQ2.2, DQ7.5, and DQ8 have all been specifically tested and excluded 1
• Recognize that HLA-DQ molecules are heterodimers composed of both alpha (DQA1) and beta (DQB1) chains encoded by different genetic loci—both chains must be considered together 7
• In transplantation contexts, failure to account for both DQA and DQB chains as paired heterodimers leads to inequitable access and misrepresentation of sensitization levels 7

Practical Algorithm for Interpretation

When reviewing HLA results for celiac disease risk assessment:

1. Verify the laboratory reported specific alleles (DQA1 and DQB1) rather than just serologic designations 1
2. Check specifically for DQ2.5: DQA105:01 + DQB102:01 (in cis or trans) 1
3. Check for DQ8: DQA103 + DQB10302 1
4. Check for DQ2.2: DQA102:01 + DQB102:02 (only significant if homozygous or with DQ2.5) 1, 4
5. Check for DQ7.5: DQA105 + DQB10301 (disease-permissive) 1
6. If DQA105 is present without DQB102, verify whether DQB1*0301, *0202, or DQ8 alleles are present before declaring low risk 1