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Celiac.com 02/03/2024 - Celiac disease is a complex condition influenced by a combination of genetic and environmental factors. Genetic testing, along with other diagnostic tools, helps in assessing the risk of celiac disease. Consultation with a healthcare professional is crucial for accurate diagnosis and management. Understanding celiac disease requires unraveling the complex genetic puzzle that underlies this autoimmune condition. Within the human genome, certain genes stand out as key players, influencing susceptibility and shaping the landscape of celiac disease. There are both common and uncommon genes that are related to celiac disease and gluten sensitivity, and here we will explore both. Common Genes Associated with Celiac Disease The number of genes associated with celiac disease is more than two, but there are two main genes that are commonly tested for celiac disease susceptibility. These genes are HLA-DQ2 and HLA-DQ8. HLA-DQ2: The majority of individuals with celiac disease (about 90-95%) carry the HLA-DQ2 gene. HLA-DQ8: Around 5-10% of individuals with celiac disease have the HLA-DQ8 gene. It's important to note that the presence of these genes doesn't guarantee the development of celiac disease. Additionally, the absence of HLA-DQ2 and HLA-DQ8 doesn't rule out the possibility of celiac disease, as there are cases of individuals with celiac disease who lack these genes, and there are less common genes that have been found to be related to the disease. Uncommon Genes Associated with Celiac Disease While HLA-DQ2 and HLA-DQ8 are the primary genes associated with celiac disease, other genetic factors may contribute to its development. Within the realm of celiac disease, the genetic narrative extends beyond the well-known HLA-DQ2 and HLA-DQ8 genes to the uncommon genes that contribute to the disease. While not as prevalent as their more recognized counterparts, several uncommon genes have also been found to be a factor in triggering celiac disease in some individuals. Non-HLA Genes Identified as Potential Risk Factors for Celiac Disease HLA-DQ2.5 Subtypes: Within the HLA-DQ2 category, specific subtypes such as HLA-DQ2.2 have been linked to celiac disease risk. HLA-DQ7: Although less common than HLA-DQ2 and HLA-DQ8, HLA-DQ7 has been identified as a potential risk factor. HLA-DQ4: While individuals with HLA-DQ4 are at lower risk compared to those with HLA-DQ2 or HLA-DQ8, this gene may still play a role in susceptibility. Other Non-HLA Genes: Genome-wide association studies (GWAS) have identified several non-HLA genes associated with celiac disease, including IL2 and IL21. Genes Related to Non-Celiac Gluten Sensitivity Intriguingly, the genetic landscape we traverse in celiac disease extends its influence beyond the boundaries of this autoimmune condition. Emerging research suggests a potential link between certain celiac-associated genes and non-celiac gluten sensitivity (NCGS). While NCGS lacks the autoimmune component seen in celiac disease, the overlap in genetic markers hints at shared mechanisms. Individuals with NCGS may also carry genetic variations that contribute to their sensitivity to gluten. Unraveling these connections broadens our understanding of gluten-related disorders and opens avenues for investigating the spectrum of gluten-related conditions. The intricate interplay of genetics in both celiac disease and non-celiac gluten sensitivity invites further exploration into the nuances of gluten-induced immune responses, paving the way for more comprehensive insights into gluten-related health issues. Summary In summary, while HLA-DQ2 and HLA-DQ8 are significant markers for celiac disease susceptibility, having these genes is not a definitive diagnosis, and not having them doesn't rule out the possibility of celiac disease. Other genetic and environmental factors contribute to the development of celiac disease. A diagnosis typically involves a combination of genetic testing, serological tests, and, in some cases, a biopsy of the small intestine. As we decipher the genetic blueprint, it becomes evident that celiac disease is not a one-size-fits-all scenario. The interplay of diverse genetic factors illuminates the variability in how the disease manifests and underscores the importance of individualized approaches to diagnosis and management. Additional Resources: NIH - Gene Reviews Celiac disease: From genetics to epigenetics Celiac Disease Genetics: Current Concepts and Practical Applications Journal of Medical Genetics - Genetics of Celiac Disease The genetics of celiac disease: A comprehensive review of clinical implications -
Celiac.com 01/31/2022 - As intestinal permeability and innate immune system activation emerge as possible pathophysiological mechanisms in non-celiac gluten sensitivity (NCGS), a number of researchers have become interested in markers for gut integrity and inflammation. The idea being that thesis markers might help to reveal pathological changes that occur with non-celiac gluten sensitivity. A team of researchers recently set out to assess relevant biomarkers in non-celiac gluten sensitivity by analyzing serum levels of gut integrity and permeability markers, pro-inflammatory cytokines and antigliadin IgG in patients with suspected non-celiac gluten sensitivity on a gluten-free diet, and compare them to serum levels in patients with irritable bowel syndrome (IBS) and healthy controls (HC). The research team included Hanna Fjeldheim Dale, Julianne CH Johannessen, Ingeborg Brønstad, and Gülen Arslan Lied. They are variously affiliated with the Centre for Nutrition, Department of Clinical Medicine, University of Bergen, Bergen, Norway; the Division of Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway; and the National Centre of Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway. Their team analyzed serum samples collected from twenty patients with suspected non-celiac gluten sensitivity patients on a gluten-free diet, twenty with IBS, and twenty healthy sex and age matched control subjects. The team used IBS severity scoring system (IBS-SSS) to assess gastrointestinal symptom severity. Compared to heathy control subjects, suspected non-celiac gluten sensitivity and IBS patients had higher IBS-SSS scores. Their analysis showed no significant differences in serum levels of any of the gut integrity and permeability markers, cytokines or antigliadin IgG antibodies between the three groups. However, they did see positive correlations between claudin-1 and i-FABP, and between claudin-1 and antigliadin IgG antibodies. The team's assessment showed no differences in serum levels of gut integrity and permeability markers, pro-inflammatory cytokines or antigliadin IgG antibodies among patients with suspected non-celiac gluten sensitivity patients on a gluten-free diet, IBS and healthy control subjects. The findings suggest that these biomarkers do not offer a way to spot possible pathophysiological mechanisms in non-celiac gluten sensitivity. Stay tuned for more on this and related stories. Read more at DovePress.com. -
Dig Dis Sci 1999;44:2344-2349. Celiac.com 04/10/2000 - Dr. Carme Farre, of Hospital Sant Joan de Deu, in Barcelona, Spain, and his multi-center colleagues, report in the November issue of Digestive Diseases and Sciences that both serologic markers and the human lymphocyte antigen class II extended DQ2 (HLA-DQ2) haplotype are useful markers for screening first-degree relatives of patients with celiac disease for the disorder. These markers are more reliable predictors of celiac disease than other clinical features, which are absent from one third of relatives of people with celiac disease. The researchers examined the usefulness of serologic markers, HLA-DQ2 haplotype, and clinical features common to celiac disease in the diagnosis of the disorder in 675 first-degree relatives of celiac disease patients. The diagnosis was confirmed by intestinal biopsy. Their results showed that 5.5% of the subjects were diagnosed with celiac disease, which is significantly higher than what was observed in the general public in a previous study. Serum IgA-class anti-endomysium antibodies (IgA-AEA) and IgA-class anti-gliadin antibodies (IgA-AGA) were observed in 5.8% and 1.9% of the relatives, respectively. According to the researchers: Our results show that IgA-AEA is the most useful marker, since all but one IgA-AEA-positive relative showed histological findings of [celiac disease]. Further, the measurement of IgA-AGA would have missed 66% of the affected relatives. The researchers also concluded that the HLA-DQ2 haplotype also appeared to be a more useful indicator to determine which first-degree relatives had an increased genetic susceptibility to celiac disease, because the marker was detected in 93% of first-degree relatives found to have celiac disease, and 18% of those without it. The four most common clinical symptoms for celiac disease, diarrhea, anemia, food intolerance and growth retardation, were not found in one third of the relatives of patients with celiac disease. The researchers conclude: Although the definitive diagnosis of [celiac disease] relies upon the intestinal biopsy, it should be preceded by a noninvasive, inexpensive and easy-to-perform screening technique. Their findings indicate that using blood serum IgA-AEA measurements is a useful screening tool for noninvasive screening, and HLA-DQ2 assessment may delineate a very high risk population with a particular genetic susceptibility to [celiac disease].
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Celiac.com 10/15/2014 - A team of researchers recently set out to assess the benefits of a gluten-free diet for people whose blood screens show markers for celiac disease, but who show no physical symptoms. Specifically, they investigated whether screen-detected and apparently asymptomatic adults with endomysial antibodies (EmA) benefit from a gluten-free diet. The research team included K. Kurppa, A. Paavola, P. Collin, H. Sievänen, K. Laurila, H. Huhtala, P. Saavalainen, M. Mäki, and K. Kaukinen. They are variously associated with the Tampere Center for Child Health Research, the Tampere School of Health Sciences of the University of Tampere and Tampere University Hospital, the Department of Gastroenterology and Alimentary Tract Surgery at Tampere University Hospital and School of Medicine, University of Tampere, the UKK Institute in Tampere, Finland, the Research Program Unit of the Immunobiology and Haartman Institute at the Department of Medical Genetics of the University of Helsinki in Helsinki, Finland, and the Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland and Seinäjoki Central Hospital, Seinäjoki, Finland. For their study, they conducted a prospective trial of 3031 individuals at risk for celiac disease based on screens for EmA. They found 40 of 148 seropositive individuals who fulfilled inclusion criteria. They randomly assigned the 40 patients to groups receiving either a gluten-free diet, or a gluten-containing diet. They then evaluated ratios of small-bowel mucosal villous height:crypt depth, serology and laboratory test results, gastrointestinal symptom scores, physiologic well-being, perception of health by a visual analog scale, bone mineral density, and body composition at baseline and after 1 year. From that point on, they switched the group on the gluten-containing diet to a gluten-free diet, evaluated them a third time. Patients in the first gluten-free diet group remained on that diet. After 1 year on the gluten-free diet, the mean mucosal villous height:crypt depth values increased (P < .001), levels of celiac-associated antibodies decreased (P < .003), and gastrointestinal symptoms improved compared to patients on gluten-containing diets (P = .003). The gluten-free diet group showed less indigestion (P = .006), reflux (P = .05), and anxiety (P = .025), and better overall health, based on the visual analog scale (P = .017), compared gluten-containing diet group. Only social function scores improved more in the gluten-containing diet group than in the gluten-free diet group (P = .031). There were no differences between groups in terms of lab test results, bone mineral density, or body composition. Most measured parameters improved when patients in the gluten-containing diet group were placed on gluten-free diets. No subjects considered their experience to be negative and most expected to continue eating gluten-free. The results show that a gluten-free diet benefits asymptomatic EmA-positive patients, and show the benefits of actively screening patients at risk for celiac disease. Source: Gastroenterology. 2014 Sep;147(3):610-617.e1. doi: 10.1053/j.gastro.2014.05.003.
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10/05/2009 - Pregnant women with celiac disease suffer early pregnancy loss more often than women without celiac disease. A team of Italian researchers recently set out to look at a possible role of genetic pro-thrombotic variants in early pregnancy loss in women with celiac disease. The research team was made up of C. Ciacci, R. Tortora, O. Scudiero, R. Di Fiore, F. Salvatore, and G. Castaldo. The team looked at 39 women with celiac disease, who had experienced at least two early pregnancy losses within the first 3 months of pregnancy, a control group of 72 celiac women with a history of one or more normal pregnancies with no pregnancy loss. Each of the women were enrolled in the study immediately upon diagnosis for celiac disease, whereupon, the researchers obtained a clinical history obtained from each woman. The researchers then screened leukocyte DNA for factor V Leiden (mutation G1691A), factor V R2 (H1299R), factor II (G20210A), methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), beta-fibrinogen (−455 G>A), PAI-1 alleles 4G/5G, factor XIII (V34L), and HPA-1 (L33P). Women with pregnancy losses were notably older (p = 0.002) among the celiacs than in controls. Of the gene variants examined, the allelic frequency of 4G variant of PAI-1, and the frequency of mutant genotypes were significantly more frequent in the group of celiac women with early pregnancy loss (p = 0.00003 and 0.028, respectively). Interestingly, the beta-fibrinogen −455 G>A genotype distribution differs substantially between the two groups, though frequency of the variant allele remains the same. The control group showed more frequent variant genotypes (p = 0.009). Based on these data, the research team believes the 4G variant of the PAI-I gene may predispose some celiac women who carry the gene to early pregnancy loss, though they note that their data should be confirmed on larger populations. Digestive and Liver DiseaseVolume 41, Issue 10, October 2009, Pages 717-720
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T-bet and pSTAT-1: New Genetic Markers for Celiac Disease?
Jefferson Adams posted an article in Latest Research
Celiac.com 01/18/2013 - Up-regulation of T-bet and phosphorylated signal transducers and activators of transcription (pSTAT)1 are key transcription factors for the development of T helper type 1 (Th1) cells, and have been found in the mucosa of patients with untreated celiac disease. A team of researchers recently set out to determine if T-bet and pSTAT-1 expression in PBMC from celiac disease patients might offer new genetic markers of disease activity. The research team included G. Frisullo, V. Nociti, R. Iorio, A.K. Patanella, D. Plantone, A. Bianco, A. Marti, G. Cammarota, P.A. Tonali, A.P. Batocchi. They are affiliated with the Department of Neurosciences at Catholic University in Rome, Italy. For their study, the team used transcription factor analysis to determine whether T-bet and pSTAT1 expressions are up-regulated in the peripheral blood of celiac disease patients, and if they correlate with disease activity. They used flow cytometry to analyse T-bet, pSTAT1 and pSTAT3 expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes from peripheral blood of 15 untreated and 15 treated celiac disease patients and 30 controls. They also conducted a longitudinal study of five celiac patients before and after treatment with a gluten-free diet. For their evaluation, the team used enzyme-linked immunosorbent assay (ELISA), interferon (FN)-gamma, interleukin (IL)-17 and IL-10 production by peripheral blood mononuclear cell (PBMC) cultures. They found that T-bet expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes and IFN-gamma production by PBMC was higher in untreated than in treated celiac disease patients and control subjects. They also found that pSTAT1 expression was higher in CD4(+)T cells, B cells and monocytes from untreated celiac disease patients than from treated patients and control subjects. Compared with treated celiac disease patients and control subjects, untreated patients showed increased pSTAT3 only in monocytes. They confirmed their results using data obtained from the longitudinal evaluation of transcription factors. From their results, they conclude that flow cytometric analysis of pSTAT1 and T-bet protein expression in peripheral blood mononuclear cells could be useful and sensible markers in the follow-up of celiac disease patients to evaluate disease activity and response to dietary treatment. Source: Clin Exp Immunol. 2009 Oct;158(1):106-14. doi: 10.1111/j.1365-2249.2009.03999.x. -
Celiac.com 08/25/2010 - The revolution in genetic studies continues to drive discoveries about the genetic triggers for celiac disease. In recent developments, a genome-wide association study (GWAS) has nearly doubled the number of single-nucleotide polymorphisms (SNPs) associated with celiac disease from 14 to 27, most of which contain genes related to immune functions. Doctors have known for some time now that people with genetic markers DQ2 and DQ8 are more susceptible to celiac disease than those without those gene markers. This fact points to the importance of histocompatibility complex presentation of gluten antigens to immune cells. In 2007, a landmark study established 14 celiac-associated SNPs. Recently, a team of researchers conducted a comprehensive follow-up to that study. The study team included P. C. Dubois, G. Trynka, and L. Franke. The resulting GWAS used six times more genetic samples than the 2007 study, including five European case-control data sets comprised of 4,533 celiac disease patients and 10,750 controls. In all, the team tested nearly 300,000 genes. Based on low P values (P < 5 × 10-8) and biological likelihood of candidate SNPs being related to immune function, the team selected a total of 131 single-nucleotide polymorphisms (SNPs) for replication in an independent cohort of 4918 cases and 5684 controls. Their data identify 13 additional regions associated with celiac disease. To determine the trigger gene for each potential locus, the team used three complementary, objective methods. They first used a computerized algorithm, known as GRAIL, that searches PubMed for specific terms related to various gene features. They next employed what is called expression quantitative trait locus mapping, which isolates variations that may influence the expression of the gene, rather than its protein structure and function. Lastly, they looked for co-expression of gene clusters in suspect candidate genes relative to known susceptibility loci. Each of these methods shed additional light on the association between suspect SNPs and celiac disease susceptibility. However, the authors of the study go out of their way to note that, ultimately, the authors categorized loci and predicted causal genes using their "own knowledge of celiac disease pathogenesis.” This fact, they point out, emphasizes the crucial role played by knowledgable scientists exercising their insights to reap the most benefit from ‘objective’ advanced genomic data mining technologies. This study involved genetic assessment in a very large cohort, replication in a similarly large cohort, and multiple independent approaches at refining candidate SNPs. As a result, the number of known loci of celiac disease susceptibility genes has increased from 14 to 27. Their findings also identify several new pathways of celiac disease pathogenesis that merit further investigation. The study team also notes that these findings only account for 20% of the variance in celiac disease heritability. This, they say, points to a need for additional studies regarding genetic triggers for celiac disease. Source: Nature Genetics 42, 295 - 302 (2010). doi:10.1038/ng.543 -
Celiac.com 10/28/2009 - Celiac disease is a T cell-mediated autoimmune disease, and a number of clinicians have described up-regulation of T-bet and phosphorylated signal transducers and activators of transcription (pSTAT)1, both of which are key transcription factors for the development of T helper type 1 (Th1) cells, in the mucosa of patients with untreated celiac disease. A team of researchers recently used transcription factor analysis to examine whether celiac patients up-regulate T-bet and pSTAT1 expressions in peripheral blood and whether such up-regulation may be associated with celiac disease activity. The research team was made up of G. Frisullo, V. Nociti, R. Iorio, A. K. Patanella, D. Plantone, A. Bianco, A. Marti, G. Cammarota, P. A. Tonali, and A. P. Batocchi of the Department of Neurosciences at the Catholic University in Rome, Italy. The team used flow cytometry to analyze T-bet, pSTAT1 and pSTAT3 expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes from peripheral blood of 15 untreated and 15 treated celiac disease patients and 30 controls, and longitudinally in five celiac patients before and after dietary treatment. The team measured the results using enzyme-linked immunosorbent assay (ELISA), interferon (FN)-gamma, interleukin (IL)-17 and IL-10 production by peripheral blood mononuclear cell (PBMC) cultures. Patients with untreated celiac disease showed higher T-bet expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes and IFN-gamma production by PBMC, than either treated celiac patients or control subjects. CD4(+)T cells, B cells and monocytes from untreated celiac patients showed higher pSTAT1 expression than either treated celiac patients or controls. Only in monocytes from untreated patients showed increased pSTAT3 compared with treated celiac patients and controls. Data from longitudinal evaluation of transcription factors corroborated these findings. Flow cytometric analysis of pSTAT1 and T-bet protein expression in peripheral blood mononuclear cells could be useful and sensible markers in the follow-up of celiac disease patients to evaluate disease activity and response to dietary treatment. Being able to spot celiac disease early is key to achieving optimal outcomes for celiac patients. The development of simple, reliable, low-cost tests is key to that effort. Stay tuned for more developments regarding celiac disease testing, screening and diagnosis. Source: Clinical & Experimental Immunology, Volume 158 Issue 1, Pages 106 - 114
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Celiac.com 10/28/2004 - The following study demonstrates a connection between the length of time a celiac is exposed to gluten and the prevalence of anti-islet cell antibodies. This study supports many others that have shown that celiac patients are at high risk of developing insulin-dependent diabetes mellitus, which is a condition that has a long pre-diabetic period. It would be interesting to conduct a similar study on non-celiacs to determine if gluten has the same effect, which, if demonstrated, would mean that gluten has toxic, disease-causing properties in other people in addition to those with celiac disease. Rev Med Chil. 2004 Aug;132(8):979-84. BACKGROUND: Celiac patients are at high risk of developing insulin-dependent diabetes mellitus, a condition that has a long pre-diabetic period. During this lapse, anti-islet cell antibodies serve as markers for future disease. This may be related with the duration of the exposure to gluten. AIM: To test the hypothesis that long term adherence to a gluten free diet decreases the frequency of risk markers for insulin dependent diabetes mellitus during adolescence and early adulthood. PATIENTS AND METHODS: 158 celiac patients were classified as: G1, (n=30 patients) studied at the time of diagnosis; G2 (n=97 patients) exposed to gluten as a result of non compliance with the gluten free diet and, G3 (n=31 patients) who had maintained a long term, strict gluten free diet. Isotype IgG anti-islet cell antibodies were detected by indirect immunofluorescence using monkey pancreas, results were reported in Juvenile Diabetes Foundation (JDF) units. RESULTS: Celiac patients exposed to a gluten containing diet had a significantly higher prevalence of anti-islet cell antibodies than those who had been exposed only briefly (p CONCLUSIONS: Celiac patients long exposed to gluten have a significantly higher prevalence of anti-islet cell antibodies than those exposed for a short period. This fact supports the hypothesis that the development of these antibodies is associated with the length of the exposure to gluten. Verbeke S, Cruchet S, Gotteland M, Rios G, Hunter B, Chavez E, Brunser O, Araya M. Unidad de Gastroenterologia, Division de Nutricion Humana, Instituto de Nutricion y Tecnologia de los Alimentos, Universidad de Chile, Macul 5540, Santiago, Chile.
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Bardella MT, Minoli G, Radaelli F, Quatrini M, Bianchi PA, Conte D Gastrointest Endosc. 2000 Jun;51(6):714-716 Background: Loss or reduction of duodenal folds, scalloping of Kerkring folds and a micronodular or mosaic duodenal mucosal pattern have been described in celiac disease (celiac disease), endoscopic findings that are considered reliable in the diagnosis of this disorder. However, most data have been obtained in patients with suspected or certain disease. We assessed the accuracy of the above markers in diagnosing celiac disease in patients with non-ulcer dyspepsia. Methods: In this prospective study, in 705 consecutive dyspeptic patients (284 men, 421 women, mean age 51 +/- SD 15.8 years) duodenal biopsies were obtained only in the presence of typical endoscopic markers, whereas in another 517 (207 men, 310 women, mean age 49.9 +/- SD 16 years) duodenal biopsies were done irrespective of macroscopic findings. celiac disease was diagnosed histologically and on the basis of positive antiendomysium antibody. Results: Endoscopic markers were found in 4 patients of the first group but celiac disease was ruled out. In the second group 5 patients had an endoscopic pattern that was consistent and celiac disease was diagnosed in 3, whereas 3 others with normal endoscopic findings were eventually diagnosed as having celiac disease. Endoscopic markers had a sensitivity of 50% and a specificity of 99.6% (95% CI [11.8, 88.2 and 98.6, 99.9], respectively) with positive and negative predictive values of 60% and 99.4%, respectively. Conclusion: The accuracy of endoscopic markers in the diagnosis of celiac disease must be reevaluated in relation to the characteristics of the population studied.
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By Vijay Kumar, PhD., IMMCO Diagnostics, Inc. - IMMTEST@AOL.COM The genetic markers associated with celiac disease are: HLA DQalpha *0501 HLA DQbeta *0201 More than 90% of patients with celiac disease have these markers. Negative tests for these markers in conjunction with negative serum antibody tests suggest an absence of celiac disease. However, positive tests for the genetic markers do not necessarily mean that the patient has celiac disease. In conclusion, genetic markers can be used as a test to exclude celiac disease as a diagnosis.
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