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HLA Typing for Celiac Disease

  • Interpretive Guide
HLA Typing for Celiac Disease

Test Summary

HLA Typing for Celiac Disease


Clinical Use

  • Determine genetic susceptibility to celiac disease (CD)

  • Rule out CD diagnosis

Clinical Background

CD is caused by an immune response to gluten in genetically predisposed individuals. Although patients with CD may be asymptomatic, infants and young children commonly present with diarrhea, failure to thrive, and abdominal pain and distention. Older children and adolescents may exhibit extraintestinal symptoms including short stature, delayed puberty, anemia, and neurological symptoms caused by nutrient malabsorption. In up to 50% of adults with CD, the presenting symptom is diarrhea, which may be accompanied by abdominal pain or discomfort. Diagnosis is based on biopsy and histopathologic evaluation of the small intestine. Histopathologic characteristics such as partial to complete villous atrophy of the small intestine, crypt hyperplasia, and lymphocytic infiltration of the epithelium and lamina propria are essential to establish the diagnosis.1 Serologic assays such as tissue transglutaminase antibody (tTG; IgA) and endomysial antibody (EMA; IgA) may be used to select patients for biopsy and to support the diagnosis. Treatment is based on removing gluten from the diet.

Susceptibility to CD is linked to certain human leukocyte antigen (HLA) class II alleles, especially in the HLA-DQ region. HLA molecules are postulated to present gluten antigens to T-cells which in turn induce tissue damage.2 Approximately 95% of patients with CD have the HLA-DQ2 heterodimer encoded by the DQA1*05 and DQB1*02 alleles, while close to 5% have the HLA-DQ8 heterodimer encoded by the DQA1*03 and DQB1*0302 alleles.1 Rarely, patients will carry only one of the DQ2 alleles; ie, either DQA1*05 or DQB1*02.3 The HLA-DQ alleles are also found in 48% to 65% of first-degree relatives of patients with CD and up to 73% of patients with insulin-dependent diabetes mellitus; thus, these individuals are at increased risk of developing CD.1 Other high-risk groups include those with autoimmune thyroiditis; Down, Turner, or Williams syndrome; selective IgA deficiency; or individuals with symptoms of unexplained iron deficiency anemia or premature-onset osteoporosis.1,4

Since 25% to 40% of the United States population has either DQ2 or DQ8, the presence of either heterodimer is not diagnostic of CD.1 Thus, the primary use of HLA-DQ typing is to rule out CD and genetic susceptibility for CD. Such typing is particularly relevant when pathology of the small intestine is equivocal, serological testing is consistent with CD but villous atrophy is absent, a gluten-free diet is being considered in the absence of biopsy-proven CD, and a first-degree relative has been diagnosed with CD.5 Determining genetic susceptibility can avoid unnecessary small intestine biopsy, continual serologic testing, and initiation of a gluten-free diet, especially in individuals in high-risk groups.1,4

Individuals Suitable for Testing

  • Individuals at increased risk of CD

  • Symptomatic individuals in whom the diagnosis of CD is uncertain


  • Polymerase chain reaction (PCR) amplification of extracted DNA followed by hybridization with sequence-specific oligonucleotide probes.

  • Results reported: positive or negative for HLA-DQ2 and -DQ8; specific DQA1 and DQB1 variants detected (to determine zygosity); patient-specific interpretation

Interpretive Information

Negative results for both HLA-DQ2 and HLA-DQ8 virtually exclude the diagnosis of CD and indicate an extremely low risk for subsequent development of the disease (95% negative predictive value).4,5 In rare cases, however, when DQ2 and DQ8 heterodimers are negative, the presence of 1 of the DQ2 alleles (eg, either DQA1*05 or DQB1*02) is consistent with a diagnosis of CD.3

A positive DQ2 or DQ8 result, in conjunction with equivocal histopathology and/or serology test results, is consistent with a CD diagnosis.5 Positive results, however, are not diagnostic as 25% to 40% of the U.S. population have positive results. In high-risk individuals, positive DQ2 or DQ8 results reflect an increased likelihood for development of CD, and periodic screening should be considered.6

DQB1*0201 results may reflect the severity of disease. Although data are conflicting, homozygosity for this allele has been associated with having more severe villous atrophy, a slower rate of villous recovery once a gluten-free diet has been instituted, and developing CD at a younger age.7


  1. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1981-2002.

  2. Sollid LM. Coeliac disease: A complex inflammatory disorder. Nat Rev Immunol. 2002;2:647-655.

  3. Karell K, Louka AS, Moodie SJ, et al. HLA types in celiac disease patients not carrying the DQA1*05–DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol. 2003;64:469-477.

  4. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40:1-19.

  5. Kaukinen K, Partanen J, Mäki M, et al. HLA-DQ typing in the diagnosis of celiac disease. Am J Gastroenterol. 2002;97:695-699.

  6. Karinen H, Kärkkäinen P, Pihlajamäki J, et al. HLA genotyping is useful in the evaluation of the risk for coeliac disease in the 1st-degree relatives of patients with coeliac disease. Scand J Gastroenterol. 2006;41:1299-1304.

  7. Karinen H, Kärkkäinen P, Pihlajamäki J, et al. Gene dose effect of the DQB1*0201 allele contributes to severity of coeliac disease. Scand J Gastroenterol. 2006;41:191-199.

Content reviewed 12/2012
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