Brief: First degree relatives of individuals with celiac disease are at elevated risk for developing a similarly severe gluten intolerance disorder. However, a quick screening test for the genetic alterations responsible for encoding gluten recognition immune receptors can rule out celiac disease risk in these individuals. Developed by Targeted Genomics, the DNA-based, non-invasive Gluten ID Test identifies the presence or absence of the HLA-DQ2/DQ8 genes responsible for encoding gluten recognition immune receptors. With the gluten ID test exclusively available through PacificDx, Gluten ID DNA testing provides prompt and valuable information to those who want to understand disease risks for themselves, their children and family members.
Background: Otherwise known as “celiac sprue”, celiac disease is a chronic, autoimmune disorder resulting from an aberrant inflammatory response in the gastrointestinal tract (GI) of susceptible individuals. The singular cause is the ingestion of foods containing gluten, a protein found in wheat, rye and barley. Although one of the common nutritional ingredients in food today, an insoluble fraction of gluten lingers in the gastrointestinal tract, triggering a significant immunogenic response in those predisposed for celiac disease.
Celiac disease (CD) is a multifactorial disease, triggered by both environmental factors and genetic predisposition. Environmentally, a segment of the gluten protein called gliadin is responsible for triggering an abnormal activation of the immune system. Inflammation produced by the autoimmune response damages and eventually flattens intestinal villi found throughout the small intestine. The resulting villous atrophy causes diarrhea, obstructs the gut’s ability to absorb nutrients and leads to a host of symptomology associated with CD, including an increased risk for developing certain gastrointestinal cancers in the small intestine and esophagus. Genetically, a predisposition has been identified that pertains to heritable genes, HLA-DQ2 and HLA-DQ8 that encode for specific immune cell receptors that recognize gluten proteins. These genes belong to the major histocompatibility complex (HLA) and provide instructions for making proteins with a critical functionality of distinguishing the body’s native proteins from a wide range of foreign invader proteins—like those from viruses or bacteria.
Burden of disease: As one of the most common genetically-based disorders in humans, CD is estimated to occur in 1 in 100 people worldwide—though many believe estimates are low due to an under-diagnosis based on positive serologic findings in people not previously diagnosed with CD. Diagnostic delays have been reported in people whose symptoms were present a dozen or so years before a diagnosis was recognized. Prevalence in the U.S. has been reported to have increased over recent decades though the reasons are not well-defined but may be related to changes in dietary gluten.
Clinical disease: Due to the wide spectrum of clinical manifestations and systems involvement, CD might be termed syndromic. Compared to other autoimmune diseases, it displays peculiar features in that total avoidance of gluten can stimulate complete recovery of intestinal muscosal damage and reverse disease progression and its associated ‘chronic’ dynamics. The disease can be present with and without gastrointestinal symptomology but can be associated with other conditions found in people affected by CD. These include genetic syndromes such as Down or Turner, autoimmune disorders associated with thyroid and liver disease and neurological disorders such as epilepsy. It has been reported that patients with Type I diabetes possess an increased risk for developing CD based on a shared genetic risk represented by the HLA complex—with a prevalence of up to 19% in patients with Type I diabetes. People diagnosed with CD experience four times the risk for developing small intestinal cancers and twice the risk for coronary artery disease (CAD).
Although initially thought to be a pediatric disease, the disease is markedly heterogeneous and independent of age, duration, extent of disease and presence of extra-intestinal co-morbidities. CD can occur at any age after the ingestion of foods containing gluten and can present differently, for which several forms or subtypes have been described—although, now, it is unclear if distinct subtypes truly exist or, if these represent progressive stages of disease. Two peaks of presentation have been noted—in children less than six years and adults between the ages of 40 and 60.
Undiagnosed, late diagnosis and/or untreated CD has been associated with serious health complications such as osteoporosis, enteropathy-associated intestinal T-cell lymphoma, collagenous sprue, refractory sprue, ulcerative jejunoileitis, non-Hodgkin lymphoma, small-bowel lymphoma, and reproductive disorders in both men and women. Other long-term health conditions have been reported such as iron deficiency anemia, chronic fatigue syndrome, brain fog, lactose intolerance, vitamin and mineral deficiencies, central and peripheral nervous system deficiencies, pancreatic insufficiency, gall bladder malfunction and other neurological manifestations.
Genetic diagnostic targets: Globally, the genetic frequency for the presence of CD risk-based HLA-genes DQ2 and DQ8 genes is 30%. DQ2 and DQ8 are HLA haplotype gene variants belonging to a group of MHC class II proteins, HLA-DQA1 and HLA-DQB1, respectively. Although these haplotypes may occur individually or together, their presence is the best-characterized risk factor for disseminating an aberrant immune response to gluten protein that results in the development of CD in about 3% of people. Over 90% of patients with CD express HLA-DQ2 and the remainder, HLA-DQ8, making these genes effective targets to pair with clinical signs and symptoms for a CD diagnoses.
Inheritance: While the exact inheritance pattern is unknown, CD tends to be familial among first and second degree relatives—parents, siblings, children, aunts, uncles, nephews, nieces, grandparents, grandchildren, half-siblings, and double cousins, with prevalence estimates ranging from 5-20%. The risk for transmitting combinations of DQ2 and DQ8 genes to future generations is much greater at 50-100%.
Non-celiac gluten sensitivity (NCGS): A condition defined by gastrointestinal symptomology that improves with a gluten-free diet, these individuals lack the characteristic diagnostic features of CD and render negative genetic testing results for biomarkers HLA-DQ2 and DQ8. Unlike CD, NCGS lesser understood and more challenging in that the condition may be the result of a combination of disorders that lead to symptoms associated with the environmental trigger (gluten) that is mismanaged the immune system.
Diagnostic testing
HLA-DQ2/DQ8 Genotyping: Genetic testing includes gluten susceptibility testing to determine the risk factor associated with the presence of the HLA-DQ2/DQ8 genes, particularly for those with familial history. Since nearly 100% of persons with CD express these genes, negative genetic testing may be used to rule out CD, particularly in cases where serologic and histologic testing returns equivocal results. Developed by Targeted Genomics, the Gluten ID Test employs DNA testing obtained by buccal cheek swabs to rule out the presence of the gluten-sensitivity genes with a 99% degree of confidence, HLA-DQ2/DQ8. The Gluten ID test kit is available to anyone wishing to understand their genetic susceptibility and transmission risks—though optimally, the test would be best ordered by the person’s primary care provider as additional diagnostics may be warranted.
In partnership with Targeted Genomics, the Gluten ID is exclusively available through PacificDx , a premier CLIA-certified molecular laboratory in Irvine California. For the patient, information on obtaining the test please visit Targeted Genomics.
Serological testing: Serological testing includes glutaminase IgA antibody (tTG IgA) combined or followed by an anti-endomysium IgA antibody, particularly in children over the age of 2. Total IgA levels are measured when CD-associated IgA deficiency is suspected. In such cases, tTG immunoglobulin G (IgG) and/or IgG deaminadated gliadin peptide (DGP) testing may also be pursued.
Biopsy: When serologic testing is positive, an endoscopic duodenal biopsy is pursued to determine histological findings and confirmation of CD based the presence of villous atrophy (Marsh criteria, grade 3 or higher). Biopsy may also be pursued when CD is strongly suspected in absence of positive serologic findings.
References
- Celiac Disease Foundation. Accessed Aug 2019.
- Experts Weigh-in on Celiac Disease in Research and Treatment in 2019. Accessed Aug 2019
- Celiac Disease Clinical Practice Guidelines (2019). European Society for the Study of Coeliac Disease (ESsCD) July 2019.
- Genetics Home Reference. National Institutes of Health Library.
- Chou R et al. (2017) Screening for celiac disease: a systematic review for the U.S. Preventive Services Task Force. AHRQ No. 14-05215-EF-1, 1-60.
- Parzanese I et al. (2017) Celiac disease: from pathology to treatments. World J Gastrointest Pathophysiol, 8(2):17-38.
- Abadie V et al. (2011) Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol, 29:493-525.