Celiac disease is caused by a combination of genetic and nongenetic factors. In celiac disease, the human leukocyte antigen (HLA) class II genes HLA-DQ2 and DQ8 are shown to be the strongest and best-characterized genetic susceptibilities, and they are encoded by approximately 30% of the general population.1 However, only approximately 1% of the population is diagnosed with celiac disease, which indicates additional factors may be involved in the progression of this complex genetic disorder.1
HLA genetic testing is commercially and academically available to evaluate celiac disease and identify this condition in family members who may be at risk. The current method of HLA genetic testing for celiac disease has a low positive predictive value. Therefore, clinicians are encouraged to gain an understanding about when HLA genetic testing should be ordered, the type of test that should be ordered, and how to interpret results.
General Features of HLA
The genes encoding HLA molecules are found in the major histocompatibility complex (MHC) on chromosome 6. Each HLA locus has many known alleles, and new alleles are continuously being characterized. The HLA loci in celiac disease are in the class II region at the DQ locus, and HLA-DQA1 and DQB1 loci code for α- and β-chain proteins that associate as heterodimers on the surface of antigen-presenting cells. These protein heterodimers are known as HLA-DQ molecules.
The process of determining which alleles or proteins are present in a patient is referred to as “HLA typing.” To determine a class II HLA heterodimer, both loci encoding for that particular heterodimer must be typed (in the instance of celiac disease, DQA1 and DQB1 for the DQ protein). Most laboratories type HLA using molecular techniques and use molecular nomenclature.
There can be up to 4 different heterodimers in a patient, as every person encodes 2 alleles of each of the DQA1 and DQB1 loci. A heterodimer encoded by alleles on the same chromosome is cis-encoded, whereas a heterodimer formed from alleles on opposite chromosomes is trans-encoded. Compatible heterodimers that are cis- or trans-encoded will express functional molecules. Therefore, contemporary testing for celiac disease usually types the DQA1 and DQB1 loci directly.
HLA-DQ2 and DQ8 are found to play important roles in the development of celiac disease. HLA-DQ2 and DQ8 can uniquely present specific gluten-derived peptides, compared with other HLA types that cannot. Inflammation is triggered by a pathogenic process in which antigen-presenting cells present deamidated gluten that binds to HLA-DQ2 or DQ8. However, this pathogenic process is inactive in most patients encoding DQ2 or DQ8, as approximately 3% of patients positive in DQ2 or DQ8 develop celiac disease.1
Researchers state that the genetics of HLA types that contribute to celiac disease are complex, as the risk for celiac disease is determined by the number and configuration of the DQA1 and DQB1 alleles. The component parts of HLA genetics and how they combine to increase the risk for celiac disease are highlighted below.
· HLA-DQ2.5: This variant of the DQ2 molecule is encoded by approximately 90% of patients with celiac disease. HLA-DQ2.5 is encoded by the DQB1*02 and DQA1*05 alleles. The DQ2.5 heterodimer can be cis-encoded or trans-encoded.
· HLA-DQ8: The DQ8 protein is present in approximately 20% of patients with celiac disease. The HLA-DQ8 heterodimer is encoded by the DQB1*03:02 and DQA1*03 alleles.
· HLA-DQ2.2: This heterodimer is present in 35% of patients with celiac disease. The DQA chain of this heterodimer is encoded by a DQA1*02 allele, instead of a DQA1*05 allele. Otherwise, HLA-DQ2.2 is found to be similar to the DQ2.5 heterodimer.
When to Order HLA Genetic Testing
Researchers state there are many clinical scenarios in which HLA genetic testing should be considered. For instance, HLA testing can be used to exclude celiac disease in patients experiencing symptoms after beginning a gluten-free diet or to identify patients who may be at risk for celiac disease due to having a family history.
Guidelines from the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommend that high-risk groups undergo HLA testing due to its high negative predictive value.1 Researchers say HLA testing may also be clinically useful for patients who test negative for HLA-DQ2 or DQ8 since no follow up would be required.
Conversely, the 2013 guidelines from the American College of Gastroenterology do not recommend routine HLA testing of relatives due to the high likelihood of these patients encoding HLA susceptibility, which currently stands at >80%.1 At this time, researchers recommend that clinicians determine whether the benefits of HLA testing on first-degree relatives outweigh the costs, given that present guidelines advise against this protocol.
What HLA Test to Order
Many commercial and academic laboratories in the United States perform HLA testing using blood or cheek swab samples. Researchers advise clinicians to inform patients to consult with their health insurance providers prior to testing to confirm the test cost. Researchers also advise clinicians to order full HLA-DQA1 and DQB1 typing to confirm celiac disease. Patients who undergo HLA typing need only to be tested once in their lifetime, since this test is genetic and patients’ genetic status will not change over time or be affected by gluten intake.
Interpreting HLA Test Results
Considering both the DQA1 and DQB1 are typed in HLA genetic testing, clinicians will receive results that indicate whether HLA-DQ2 or DQ8 are absent or present. In cases where neither of these alleles are detected, clinicians may rule out celiac disease, as patients who do not encode these alleles may not be at risk for the disease. In cases where a patient is typed positive for DQ2 or DQ8, researchers say clinicians must keep in mind that this means the patient is permissive for celiac disease, and is capable of developing or having the disease.
The risk for celiac disease in patients who are positive for DQ2 or DQ8 can be determined based on which molecules are encoded. DQ2.5 is most highly associated with celiac disease, while DQ8 and DQ2.2 are associated with a lower risk. However, a patient who encodes any 2 of these molecules may be more likely to develop celiac disease. In addition, patients with 2 copies of DQ2.5 are shown to have more severe symptoms of celiac disease.1
Researchers state that in all cases when patients are positive for DQ2 or DQ8, a diagnosis of celiac disease requires other clinical correlates, including a positive serology with or without abnormal duodenal biopsy, which must be performed while the patient is eating a diet that contains gluten.
In conclusion, researchers advise clinicians to consider 3 important guidelines when performing HLA testing for celiac disease. First, clinicians must ensure the laboratory is typing and reporting both the DQA1 and DQB1 loci in molecular nomenclature. Second, clinicians should look for a positive result of either DQ2.5 or DQ2.2, or DQ8. Third, clinicians should understand that celiac disease can be ruled out in the absence of both DQ2 and DQ8, and that the presence of DQ2 or DQ8 may indicate a risk, but cannot be used to conclusively diagnose celiac disease.
Brown NK, Guandalini S, Semrad C, Kupfer SS. A clinician’s guide to celiac disease HLA genetics [published online July 4, 2019]. Am J Gastroenterol. doi: 10.14309/ajg.0000000000000310.