DQ Haplotypes Research Articles

HLA-DQ2 and -DQ8 haplotypes frequency and diagnostic utility in celiac disease patients of Gaza strip, Palestine

PurposeCeliac disease (CD) diagnosis can be established by serological and small bowel biopsy (SBB), while absence of HLA-DQ2 and -DQ8 haplotypes excludes the disease. The present study aims at evaluating the diagnosis of a representative sample of pediatric and adult CD patients of Gaza strip in light of DQ2 and DQ8 haplotypes expression.MethodsUnrelated CD patients (n = 101) and matched healthy controls (n = 97) were genotyped for DQA1*05, DQB1*02 and DQB1*03:02 alleles by allele-specific real-time PCR. The diagnosis was re-evaluated according to the patient laboratory tests and HLA-DQ genotype.ResultsThe diagnosis of 35 patients who have been managed for CD could not be confirmed. Twenty-five of them were diagnosed upon their clinical presentation only. The remaining were either negative for serological and SBB tests or negative for HLA-DQ haplotypes. The HLA-DQ alleles were negative in 4 SBB and one Anti-EMA positive patients. The frequency of DQ2 and DQ8 haplotypes among the remaining 65 confirmed cases was 70.8 and 15.4%, respectively, compared to 17.5 and 27.8% in the controls. The DQB1*02 allele was the most common in the cases (84.6%) followed by DQA1*05 allele (80%) and DQB1*03:02 allele (20%). The DQA1*05 allele was commonest in the control group (54.6%) followed by DQB1*02 allele (42.3%) and DQB1*03:02 allele (28.9%).ConclusionsAbsence of HLA-DQ2 and HLA-DQ8 genotyping in the workup of patients may result in CD misdiagnosis, particularly in a setting with poor histopathological diagnostic capacity.

Community Family Member Screening Event for Diagnosis of Celiac Disease

Introduction: The prevalence of celiac disease (CeD) in first and second degree family members is estimated to be 7.5% and 2.3%, respectively (Singh P., et al. 2015). Family members are often unaware of their increased risk of CeD and best practices for identifying CeD in at-risk individuals are unknown. Methods: We conducted a community-wide screening event of first and second degree family members of patients diagnosed with CeD. Family members were recruited through patient and provider letters, patient telephone contacts, social media posts, email notices, television media, websites and physician encounters in the clinic setting. Eligibility was restricted to family members who were: ≥ 18 years of age, on a gluten-containing diet, not previously diagnosed with CeD, and not known to have an absence of the HLA-DQ2 or DQ8 haplotypes. Participants completed a questionnaire to assess eligibility, symptoms, comorbidities, health-related quality of life and family history. The event was held on a single day in a community-based, outpatient clinic location. Serology assessments included tTG-IgA, IgA and IgG Deamidated Gliadin Peptide (DGP). Serology results were characterized as positive (>10 U/mL for tTG-IgA antibodies), equivocal (tTG-IgA ≥7 and ≤10 U/mL or DGP ≥7 in the absence of elevated tTG), or negative (Phadia 250, Thermo Fisher Scientific, USA). Results: A total of 147 family members registered on-line for the event. Of these, 114 were confirmed as eligible and participated in the event. Overall, 5.2% of participants (n=6) had an abnormal serologic test. From these, two (1.8%; 95% CI 0.3%, 5.7%) participants were positive, and four (3.5%; 95% CI: 1.1%, 8.2%) participants tested equivocal. Of the four with an equivocal test result, all had a tTG-IgA result of < 2 U/mL. Of the tested cohort, 16 (14.9%) had previously tested negative for CeD, and of these, one patient tested equivocal (Table 1). Clinical and demographic characteristics between participants with abnormal vs. seronegative results were similar (Tables 1-2).Table: *TTG IGA >10 U/mL = positive (n=2); TTG IGA ≥7 and ≤10 U/mL, Deamidated Gliadin G ≥7, or Deamidated Gliadin A ≥7 = equivocal (n=4).Table: *TTG IGA >10 U/mL = positive (n=2); TTG IGA ≥7 and ≤10 U/mL, Deamidated Gliadin G ≥7, or Deaminated Gliadin A ≥7 = equivocal (n=4).Conclusion: On this one day event, 1.8% of participants (n=2) were identified to have a positive serologic test and 5.2% of participants (n=6) were identified as having an abnormal serologic test and may warrant further clinical evaluation. Family screening events may increase CeD diagnosis, however additional research is needed to determine which family members may be at increased risk.

New Insights into the Pathogenesis of Celiac Disease.

Celiac disease (CD) is an autoimmune and multisystem gluten-related disorder that causes symptoms involving the gastrointestinal tract and other organs. Pathogenesis of CD is only partially known. It had been established that ingestion of gluten proteins present in wheat and other cereals are necessary for the disease and develops in individuals genetically predisposed carrying the DQ2 or DQ8 human leukocyte antigen haplotypes. In this review, we had pay specific attention on the last discoveries regarding the three cellular components mainly involved in the development and maintenance of CD: T-cells, B-cells, and microbioma. All of them had been showed critical for the interaction between inflammatory immune response and gluten peptides. Although the mechanisms of interaction among overall these components are not yet fully understood, recent proteomics and molecular studies had shed some lights in the pathogenic role of tissue transglutaminase 2 in CD and in the alteration of the intestinal barrier function induced by host microbiota.

Coeliac disease: review of diagnosis and management.

Coeliac disease is an immune-mediated systemic disease triggered by exposure to gluten, and manifested by small intestinal enteropathy and gastrointestinal and extra-intestinal symptoms. Recent guidelines recommend a concerted use of clear definitions of the disease. In Australia, the most recent estimated prevalence is 1.2% in adult men (1:86) and 1.9% in adult women (1:52). Active case finding is appropriate to diagnose coeliac disease in high risk groups. Diagnosis of coeliac disease is important to prevent nutritional deficiency and long term risk of gastrointestinal malignancy. The diagnosis of coeliac disease depends on clinico-pathological correlation: history, presence of antitransglutaminase antibodies, and characteristic histological features on duodenal biopsy (when the patient is on a gluten-containing diet). Human leucocyte antigen class II haplotypes DQ2 or DQ8 are found in nearly all patients with coeliac disease, but are highly prevalent in the general population at large (56% in Australia) and testing can only exclude coeliac disease for individuals with non-permissive haplotypes. Adhering to a gluten free diet allows duodenal mucosal healing and alleviates symptoms. Patients should be followed up with a yearly review of dietary adherence and a health check. Non-coeliac gluten or wheat protein sensitivity is a syndrome characterised by both gastrointestinal and extra-intestinal symptoms related to the ingestion of gluten and possibly other wheat proteins in people who do not have coeliac disease or wheat allergy recognised by diagnostic tests.

The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes Is Independent of the HLA DR-DQ Genotype.

Introduction: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA) DR and DQ haplotypes in a cohort with early-onset (age < 5 years), long term type 1 diabetes (T1D) and explored their influence on clinical and laboratory parameters. Methods: Intermediate resolution HLA-DRB1, DQA1 and DQB1 typing was performed in 233 samples from the German Paediatric Diabetes Biobank and compared with a local control cohort of 19,544 cases. Clinical follow-up data of 195 patients (diabetes duration 14.2 ± 2.9 years) and residual C-peptide levels were compared between three HLA risk groups using multiple linear regression analysis. Results: Genetic variability was low, 44.6% (104/233) of early-onset T1D patients carried the highest-risk genotype HLA-DRB1*03:01-DQA1*05:01-DQB1*02:01/DRB1*04-DQA1*03:01-DQB1*03:02 (HLA-DRB1*04 denoting 04:01/02/04/05), and 231 of 233 individuals carried at least one of six risk haplotypes. Comparing clinical data between the highest (n = 83), moderate (n = 106) and low risk (n = 6) genotypes, we found no difference in age at diagnosis (mean age 2.8 ± 1.1 vs. 2.8 ± 1.2 vs. 3.2 ± 1.5 years), metabolic control, or frequency of associated autoimmune diseases between HLA risk groups (each p > 0.05). Residual C-peptide was detectable in 23.5% and C-peptide levels in the highest-risk group were comparable to levels in moderate to high risk genotypes. Conclusion: In this study, we saw no evidence for a different clinical course of early-onset T1D based on the HLA genotype within the first ten years after manifestation.

Celiac disease and its histopathology

Celiac disease is gluten induced enteropathy and is a chronic inflammatory disorder of the small intestine characterized by malabsorption. It is a common immune mediated disorder which is triggered by consumption of wheat (gluten). It occurs in genetically predisposed individuals (carriers of HLA-DQ2 and DQ8 haplotypes). It is characterized by inflammation of the small-intestinal mucosa and myriad gastrointestinal and systemic manifestations. A duodenal biopsy with positive serology is the gold standard for the diagnosis of Celiac disease. As there are changing presentation for Celiac disease, communication of pathologist and gastroenterologists is essential for appropriate interpretation of duodenal biopsy.

Limited role of HLA DQ2/8 genotyping in diagnosing coeliac disease.

The European guidelines for diagnosing coeliac disease in children were revised in 2012. These recommend that in symptomatic children, a diagnosis of coeliac disease can be made without small-bowel biopsies provided their anti-tissue transglutaminase (anti-tTG) titre is >10 times of upper-limit-of-normal (>10×ULN) and anti-endomysial antibody is positive. In order to firm up the diagnosis in these children with very high anti-tTG titre, HLA-DQ2/DQ8 should be checked and be positive. Approximately 25-40% of white Caucasian population has HLA-DQ2/DQ8 haplotype. However, only 0.1-1% of the population will develop coeliac disease. Therefore, HLA-DQ2/DQ8 testing must not be done to 'screen' or 'diagnose' children with coeliac disease. Its use by paediatricians should be limited to children with anti-tTG>10×ULN, where the diagnosis of coeliac disease is being made on serology alone. A review of case referrals made to a tertiary paediatric gastroenterology centre in Southwest England demonstrated that HLA-DQ2/DQ8 testing is being requested inappropriately both in primary and secondary care suggesting a poor understanding of its role in diagnosis of coeliac disease. This article aims to clarify the role of HLA-DQ2/DQ8 testing for clinicians working in non-specialist settings.

Role of proneurotensin as marker of paediatric coeliac disease.

Neurotensin (NT) is a gut hormone functioning proinflammatory through nuclear factor kappa B (NF-κB) and interleukin (IL)-8 secretion or anti-inflammatory through epidermal growth factor receptors. NT mRNA is down-regulated in duodenal biopsies of children with untreated coeliac disease. The aim of this study was to investigate if plasma pro-NT levels correlated with the degree of intestinal mucosal damage and tissue transglutaminase autoantibody (tTGA) levels in children with coeliac disease. Fasting plasma samples from 96 children with coeliac disease and 89 non-coeliac disease controls were analysed for NT precursor fragment pro-NT 1-117 by a chemiluminometric immunoassay. Pro-NT levels were compared with NT mRNA from duodenal biopsies, assessed previously with quantitative polymerase chain reaction (PCR). Illumina core exome arrays were used for human leucocyte antigen (HLA) typing and the Marsh criteria applied to score mucosal damage. Tissue TGA was measured by radio binding assay. A general linear model compared pro-NT levels with diagnosis of coeliac disease, Marsh score and HLA DQ haplotype. Spearman's rank test was used to compare pro-NT levels with tTGA, age and duodenal NT mRNA levels, respectively. Plasma pro-NT levels were elevated in children with coeliac disease (median 23 pmol/l higher, P = 0·003) and in those with severe intestinal mucosal damage (median 24 pmol/l higher for ≥ Marsh 3b versus not, P = 0·0004). Pro-NT levels correlated further with tTGA (r2 = 0·22, P = 0·002), but not with duodenal NTS mRNA levels (r2 = -0·12, P = 0·14). Pro-NT was not associated with any of the HLA risk-haplotypes. Elevated peripheral pro-NT levels reflect more severe forms of active coeliac disease, indicating a potential role of NT in intestinal inflammation.

A population-wide applicable HLA-DQ2 and DQ8 genotyping using DNA from dried blood spots and duplex allele-specific qPCR amplification

Genotyping of HLA-DQ2 and DQ8 haplotypes is important for diagnosis or for screening of early risk detection of celiac disease or type 1 diabetes. Usually, venous blood DNA extraction and expensive and time consuming amplification are used, that hinder population-wide studies. We assayed a friendly HLA-DQ2 and DQ8 genotyping procedure using a combination of DNA from dried blood spot (DBS) and duplex allele-specific qPCR amplification using SYBR Green. DNA was extracted using home-made buffers and compared to an extraction commercial kit. Duplex reactions by qPCR were designed using each Tm allele amplicon for reference samples (positive HLA-DQ2 or DQ8) with allele-specific primers. DBS samples from 558 children (7.99 ± 2.47 y) were collected. The DNA final yield obtained by the home-made extractive procedure was higher than from the commercial kit (1.11 ± 0.56 vs 0.23 ± 0.14 μg), while the quality was similar for both DNA samples. There was concordance in the amplification profiles for DNA samples obtained with both methods. All of four alleles from DQ2 and DQ8 haplotypes were accurately identified in duplex reactions. By using DBS samples and DNA extraction home-made procedure, the costs were reduced by 60%. The whole procedure is cost-effective for HLA-DQ2 and DQ8 genotyping.

Association of HLA-DR/DQ alleles and haplotypes with nephrotic syndrome.

Nephrotic syndrome (NS) is a debilitating renal problem in children resulting from an interaction between environmental and genetic factors including human leukocyte antigen genes (HLA). The aim of this work was to study the probable link between HLA alleles/haplotypes and NS in south India. HLA DRB1*/DQB1* alleles were genotyped in 183 NS (76 steroid sensitive-SSNS; 107 steroid resistant-SRNS) and paediatric healthy controls (PHCs; n = 91) using polymerase chain reaction-sequence specific primers (PCR-SSP). HLA-A/-B genotyping was performed for patients (n = 70) positive for DRB1*07-DQB1*02 haplotype to identify four locus extended haplotype. The following alleles and haplotypes were strongly associated with NS (P < 0.05 as significant): DRB1*07 (SSNS, P < 7.98 × 10(-6) ; SRNS, P < 0.008), DQB1*02 (SSNS, P < 3.99 × 10(-6) ; SRNS, P < 0.002), DRB1*07-DQB1*02 (SSNS, P < 1.32 × 10(-4) ; SRNS, P < 0.010), DRB1*07-DQB1*0301,0304 (DQ7) (SSNS, P < 0.001) and DRB1*03-DQB1*02 (SRNS, P < 0.048). Protective associations were observed for alleles DRB1*10 (SRNS, P < 0.013), DQB1*05 (SSNS, P < 4.34 × 10(-6) ; SRNS, P < 0.01), DQB1*06 (SSNS, P < 0.003), and haplotypes DRB1*10-DQB1*06 (SSNS, P < 0.046; SRNS, P < 0.032) and DRB1*15-DQB1*05 (SSNS, P < 0.018). HLA-A/-B typing of 70 NS cases with two locus haplotype DRB1*07-DQB1*02 (70/183; 38.25%) revealed the presence of an extended haplotype 'A*03-B*07-DRB1*07-DQB1*02' (n = 35; 50%). Our study revealed strong susceptible association of DRB1*07 with SRNS and DQB1*02 with SSNS. A gender predominant protective association was observed for DRB1*10 with SRNS females; DQB1*05 with SSNS and SRNS males. Further, the study documented the presence of an extended haplotype and pleiotropic action of DRB1*/DQB1* alleles in immune-mediated aetiology of NS in south India.

Shared and unique common genetic determinants between pediatric and adult celiac disease.

BackgroundBased on age of presentation, celiac disease (CD) is categorised as pediatric CD and adult CD. It however remains unclear if these are genetically and/or phenotypically distinct disorders or just different spectrum of the same disease. We therefore explored the common genetic components underlying pediatric and adult CD in a well characterized north Indian cohort.MethodsA retrospective analysis of children (n = 531) and adult (n = 871) patients with CD between January 2001 and December 2010 was done. The database included basic demographic characteristics, clinical presentations, associated diseases and complications, if any. The genotype dataset was acquired for children (n = 217) and adult CD patients (n = 340) and controls (n = 736) using Immunochip. Association analysis was performed using logistic regression model to identify susceptibility genetic variants.ResultsThe predominant form of CD was classical CD in both pediatric and adult CD groups. There was remarkable similarity between pediatric and adult CD except for quantitative differences between the two groups such as female preponderance, non-classical presentation, co-occurrence of other autoimmune diseases being more common amongst adult CD. Notably, same HLA-DQ2 and –DQ8 haplotypes were established as the major risk factors in both types of CD. In addition, a few suggestively associated (p < 5 × 10−4) non-HLA markers were identified of which only ANK3 (rs4948256-A; rs10994257-T) was found to be shared and explain risk for ~45 % of CD patients with HLA allele.DiscussionOverall phenotypic similarity between pediatric and adult CD groups can be explained by contribution of same HLA risk alleles. Different non-HLA genes/loci with minor risk seem to play crucial role in disease onset and extra intestinal manifestation of CD. None of the non-HLA risk variants reached genome-wide significance, however most of them were shown to have functional implication to disease pathogenesis. Functional relevance of our findings needs to be investigated to address clinical heterogeneity of CD.ConclusionsThis present study is the first comparative study based on common genetic markers to suggest that CD in pediatric age group and in adults are the spectrum of the same disease with novel and shared genetic risk determinants. Follow-up fine mapping studies with larger study cohorts are warranted for further genetic investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0211-8) contains supplementary material, which is available to authorized users.

Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women.

Over the last few years, medical scholars have reported the significant association between recurrent pregnancy loss (RPL) and celiac disease (CD). Various pathogenic mechanisms underlying the pregnancy failure in CD have been suggested: among them the ability of anti-transglutaminase antibodies to impair the trophoblast invasiveness and endometrial endothelial cells differentiation and disrupt early placentation. CD shows a complex non-Mendelian pattern of inheritance, involving major histocompatibility complex (MHC) genes. The strongest effects are mapped to the classical human leukocyte antigen (HLA)-DQA1 and HLA-DQB1 genes. Specifically, the common haplotypes DQ2.5, DQ2.2, and DQ8 have been shown to increase CD risk by six-fold on average. MHC region contains genes with immunological functions and is responsible for the strongest association signals observed in most immune-mediated diseases. The aim of our study was to investigate the prevalence of the HLA-DQ2/DQ8 haplotypes in RPL, outside of CD. The study population included women with history of RPL (≥3 spontaneous pregnancy losses) and women with at least two previous uncomplicated term pregnancies (control group, CTR). All women gave their informed consent to use their data for research purposes. 97 RPL women and 55 CTR were considered in the study. Mean age of the RPL sample was 37.7 (standard deviation, SD, 3.0; min 27; max 39). Mean age of the control group was 35.6 (SD 3.0; min 26years; m, max 38). A significantly increased prevalence of HLA-DQ2/DQ8 haplotype positivity was found in RPL population compared to control women (52.6% vs 23.6%; p<0.01). Our observations show for the first time a higher proportion of individuals HLA DQ2/DQ8 positive in women with RPL as compared to controls (and to general population estimates). Further studies are needed to better understand (i) the possible pathogenic mechanism to this observation; (ii) the clinical and therapeutic implications of our observation in order to provide a new approach to RPL couples.

ESPGHAN 2012 Guidelines for Coeliac Disease Diagnosis: Validation Through a Retrospective Spanish Multicentric Study.

A large retrospective multicentre study was conducted in Spain to evaluate the efficiency of the new European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) criteria for the diagnosis of coeliac disease (CD). The study protocol was approved by the ethics committee of Hospital Universitari i Politècnic La Fe (Valencia, Spain). The present study included 2177 children (ages 0.6-15.9 years) with small bowel biopsy (SBB) performed for diagnostic purposes (from 2000 to 2009) and with a minimum 2-year follow-up after biopsy. CD was diagnosed in 2126 patients (97.5%) and excluded in 51 (2.5%). Tissue transglutaminase antibodies (TG2A), anti-endomysial antibodies (EMA), and human leukocyte antigen (HLA) were reported in 751 patients, 640 symptomatic and 111 asymptomatic. TG2A levels >10 times the upper limit of normal, plus positive EMA and HLA DQ2 and/or DQ8 haplotypes, were found in 336 symptomatic patients, all of them with final diagnosis of CD. In 65 of 69 asymptomatic patients, 65 had confirmed CD and 4 did not have CD. According to the 2012 ESPGHAN guidelines, SBB may have been omitted in 52% of the symptomatic patients with CD with serologic and HLA available data. Gluten challenge was performed in 158 children, 75 of them <2 years at first biopsy. Only 1 patient in whom according to the new proposed diagnostic criteria gluten challenge would not have been mandatory did not relapse. Our results support the new ESPGHAN 2012 guidelines for diagnosis of CD can be safely used without the risk of overdiagnosis. A prospective multicentre study is needed to confirm our results.

The likelihood ratio and frequency of DQ2/DQ8 haplotypes in Iranian patients with celiac disease.

The aim of this study was to evaluate the likelihood ratio and frequency of DQ2 and DQ8 in Iranian patients with celiac disease (CD). The HLA DQ2 and HLA DQ8 are the important mediators in the development of celiac disease. A few studies evaluated the frequency of HLA DQ2 and HLA DQ8 haplotypes among the Iranian population with low sample size. In this cross-sectional study, to predict HLA-DQ2 and DQ8 haplotypes, 141(73 male, 78 female) confirmed CD patients compared to 151 healthy controls were enrolled into this study during 2013-2014. HLA DQ2/ DQ8 haplotypes was determined in cases and controls using PCR-SSP technique. DQ2 and DQ8 were positive in 80% (n=111) and 49% (n= 69) of CD patients and 36% (n=61) and 13% (n=21) of control group respectively. Moreover, 32% (n=45) of CD patients and 5.3% (n=8) of the control group were carrier of both haplotypes. In the case group about one-third of patients (32.2%) were positive for carrying both DQ2 and DQ8 heterodimers while only 5.3% (n=8) of the control group were carrier. In addition, the positive likelihood ratio of DQ2 and DQ8 were 1.74 (CI: 1.4- 2.1), and 2.6 (CI: 1.8- 2.7), respectively. The result of this study showed that the frequency of DQ8 among our population is higher than those reported by European countries, but it is close to those founded in South America and Middle East. This result suggests that the higher prevalence of HLA DQ8 pattern in Iranian CD patients is similar to non-European patients.

Prevalencia de los haplotipos DQ2 y DQ8 en pacientes referidos al CIHATA por estudio de enfermedad celiaca en los años 2013-2015

Celiac disease is a gluten protein intolerance that can occur in genetically predisposed people. Due to diagnosis difficulties, genetic determination of associated haplotypes of the disease had become relevant, mostly for its high negative predictive value. A retrospective study was conducted in patients studied for celiac disease, referred to CIHATA from January 2013 to June 2015. A total of 201 patients were analyzed, 70% were women, 44% presented at least one of the haplotypes associated with celiac disease, and 68% presented the DQ8 haplotype. Although these results cannot be generalized to the Costa Rican population, draw to attention the prevalence of the DQ8 haplotype over the DQ2 haplotype. Further analysis must be carried out to determine the prevalence of these haplotypes in the Costa Rican population and within people with the disease.

Prevalence of celiac disease among first-degree relatives of Indian celiac disease patients

BackgroundCeliac disease, once thought to be uncommon in Asia, is now recognized in Asian nations as well. We investigated the prevalence of celiac disease in first-degree relatives of celiac disease patients followed in our centre. MethodsFirst-degree relatives were screened prospectively for celiac disease using questionnaire-based interview and anti-tissue transglutaminase antibody. Serology positive first-degree relatives underwent duodenal biopsies. Diagnosis of celiac disease was made based on positive serology and villous abnormality Marsh grade 2 or higher. Human leucocyte antigen DQ2/-DQ8 was also assessed in 127 first-degree relatives. Results434 first-degree relatives of 176 celiac disease patients were prospectively recruited; 282 were symptomatic (64.9%), 58 were positive for serology (13.3%). Seroprevalence was higher in female than in males (19% vs 8.5%; p=0.001) and highest in siblings (16.9%) than parents (13.6%) and children (5.9%) of celiac patients (p=0.055); 87.4% first-degree relatives were human leucocyte antigen-DQ2/-DQ8 positive. Overall prevalence of celiac disease was 10.9% amongst first-degree relatives. ConclusionsThe prevalence of celiac disease in first-degree relatives of celiac disease patients was 10.9% in our cohort, and 87% had human leucocyte antigen-DQ2 or -DQ8 haplotype. All first-degree relatives of celiac disease patients should be screen for celiac disease even if asymptomatic or with atypical manifestations.

Haplotype analysis of DQ2.5 and DQ8 by simple nucleotide polymorphism technique (TAG-SNP) in type 1 diabetes and/or celiac disease patients

Background Celiac disease (CD) is a chronic and permanent enteropathy triggered by ingestion of gluten proteins, present in wheat, rye and barley, in genetically predisposed individuals, as type 1 diabetes mellitus (T1D) patients, who have a higher prevalence of the disease compared to the general population. Both diseases have similar autoimmune origin, being associated to the histocompatibility complex class II antigen (HLA), mainly DQ2.5 and/or DQ8 haplotypes, allowing estimating negative predictive value accurately. Nevertheless, these genetic tests are expensive, making its implementation a challenge in routine clinical practice.

Evaluation of high-risk type 1 diabetes HLA-DR and DQ haplotypes using three single nucleotide polymorphisms in a population from Southern Brazil

Background Type 1 diabetes mellitus (T1D) accounts for ~10% of all diabetes cases, and it is caused by autoimmune destruction of pancreatic beta-cells, which leads to insulin deficiency and fates individuals to require insulin treatment to survive. The triggering of autoimmunity against betacells is caused by interaction between environmental and genetic risk factors. Among the several loci associated with T1D, the human leukocyte antigen (HLA) class II DR/DQ locus is the main genetic risk factor for T1D, accounting for 30-50% of genetic risk for this disease. Other genes have been associated with minor effects on T1D risk when compared with HLA, with different studies indicating that the effect of non-HLA polymorphisms on predisposition for T1D may be different according to HLA DR/DQ types. In this scenario, a recent study identified a minimum set of three polymorphisms (rs3104413, rs2854275, rs9273363) which can predict high-risk HLA-DR/DQ types relevant to T1D.

The Association between Human Leukocyte Antigen Class II DR3-DQ2 Haplotype and Type 1 Diabetes in Children of the East Azerbaijan State of Iran.

Background:Type 1 diabetes mellitus (T1D) is an autoimmune disease. Several associations between human leukocyte antigen (HLA) complex and T1D were found in various populations. Associations with various HLA types depend on the investigated populations. However, such associations have not yet been investigated in the East Azerbaijan state of Iran with Turkish ethnicity.Objectives:The aims of the current study was to describe T1D genetic susceptibility conferred by HLA class II alleles (DRB1*0301, DQA1*0501 and DQB1*0201) and to determine haplotype frequencies among T1D patients.Patients and Methods:This study was a case-control study. The number of samples was determined using the Cochran formula. Eighty unrelated T1D patients, including 42 (52.5%) females and 38 (47.5%) males, were randomly recruited from the East Azerbaijan state of Iran. Typing of HLA was performed by polymerase chain reaction-sequence-specific priming (PCR-SSP) on DNA extracted from peripheral blood mononuclear cells of 80 unrelated patients and 80 unrelated healthy control donors, who were selected randomly. For haplotype analysis, the logistic regression model was performed that allows joint estimation of Single-nucleotide polymorphisms (SNPs) via haplotypes.Results:The frequency of drb1*0301 (82.5% vs. 11.3%), dqa1*0501 (82.5% vs. 36.3%) and dqb1*0201 (81.3% vs. 35%) were significantly higher among patients compared with that of healthy subjects.Conclusions:Our investigation demonstrated that there is a highly significant association between the studied alleles and T1D. It can be construed that haplotype HLA-DR3-DQ2 has a very modest effect with respect to the risk of T1D.

HLA DQ2 Haplotype, Early Onset of Graves Disease, and Positive Family History of Autoimmune Disorders are Risk Factors for Developing Celiac Disease in Patients with Graves Disease

The diagnosis of celiac disease (CD) in patients with different autoimmune diseases including Graves disease (GD) remains a challenge. The aims of our study were to: (1) assess the prevalence of CD in Polish patients with GD and (2) evaluate the prevalence of CD in the subgroups of patients with GD divided on the basis of clinical and human leukocyte antigen (HLA) typing criteria. The prospective study was conducted at an academic referral center. The study groups consisted of consecutive, euthyroid patients with GD (n = 232) and healthy volunteers without autoimmune thyroid diseases (n = 122). The diagnosis of CD was based on elevated immunoglobulin A autoantibodies to the enzyme tissue transglutaminase (IgA-TTG) and small intestine biopsy findings. CD was diagnosed in 8 patients with GD (3.4%) and 1 healthy volunteer (0.8%). The development of CD in patients with GD was strongly associated with HLA-DQ2 haplotype (as predicted from linkage disequilibria, 14.6% vs. 1.5%, P = .009; odds ratio [OR] = 11.3; 95% confidence interval [CI] 1.3-252.7): 6 patients with CD carried HLA-DRB1(*)03, 1 carried an HLA-DRB1(*)04 allele, and 1 had an HLA-DRB1(*)07/(*)11 genotype. Multivariate analysis showed independent associations between CD and early GD onset (P = .014, OR = 9.6), autoimmunity in family (P = .029, OR = 6.3) and gastroenterologic symptoms (P = .031, OR = 8.1). The results of our study suggest that serologic screening for CD may be considered in GD patients (1) with the HLA alleles typical for CD, (2) with an early onset of GD, or (3) a family history of autoimmunity. Moreover, the diagnosis of CD should be explored in euthyroid GD patients with nonspecific gastrointestinal symptoms.