Although many studies have investigated the influence of HLA on the risk of Alzheimer's Disease (AD), there have been inconsistent results. Part of this problem has been attributed to limitations of a clinical assessment in the absence of histopathological confirmation or other quantitative assessments. This study employed a subset of the AD Sequencing Project, representing 2663 cases with histopathological confirmation of AD and confirmation of 881 cognitively normal cases. Two HLA allelic subtypes, DQB1*02:01 and DQB1*02:02, were associated with lower Braak staging, a measure of tauopathy in the brain. These HLA subtypes were also associated with a later age of onset. There was a lower occurrence of HLA-DQB1*02:01 and HLA-DQB1*02:02 in AD cases compared to cognitively normal cases. For all of the above results, replicative sets were confirmatory. The above results were also maintained for both HLA-DQB1*02:01 and HLA-DQB1*02:02 when removing the effect of APOE4 or APOE2. Interestingly, the HLA-DQB1*02 allele binds tau better than all other HLA-DQB1 alleles tested, per an in silico assessment, raising the question of whether deletion of tau binding, auto-reactive T-cells in the thymus could reduce the likelihood of the onset of AD?

Celiac disease (CD) is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals. It is characterized by intestinal histological damage and the production of specific autoantibodies. The latest European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2020 guidelines have excluded human leukocyte antigen (HLA) genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value, limited availability, and high cost in some countries. However, HLA genetic testing remains valuable in certain clinical contexts. This study provided practical indications for when to request and how to interpret HLA genotyping, emphasizing its continued relevance for CD diagnosis in specific cases. We also proposed a strategy for monitoring the risk of developing type 1 diabetes (T1D) in patients with CD, based on the risk stratification carried by different HLA genotypes. A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in 2012, when HLA genotyping became mandatory for the diagnosis of CD. We identified key clinical scenarios where HLA testing remains useful. Several high risk HLA-DQ genotypes strongly associated with CD were highlighted, including HLA-DQ2.5/HLA-DQ2.2 and HLA-DQ2.5/HLA-DQ2.5. Notably, while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD, it appears to confer protection against T1D. To support clinical practice, we presented a table clarifying commonly used HLA terminology, and another summarized the main clinical situations in which HLA genotyping should still be considered. These findings underscore the dual role of HLA testing: Not only can it help rule out CD in selected cases, but it also identifies patients with CD at risk for T1D, guiding personalized monitoring strategies.

Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals. The haplotypes HLA-DQ2 and DQ8, transglutaminase (TGA) antibodies, and biopsy findings are the main tests performed in the evaluation and CD diagnosis. The objective was to establish possible correlations between transglutaminase levels, genetic markers tests, and qualitative intestinal biopsy findings (modified Marsh classification) at the diagnosis.

A retrospective cohort study. The selection criteria were confirmed CD cases with genetic tests performed. Statistical analysis was done mainly through One-way ANOVA, Kendall's correlation coefficient (T), and linear regression.

The study included 112 patients, with a mean age of 6 ± 4 years. All cases were tested to HLA-DQ2, and it was positive in 93%. HLA-DQ8 was tested in 73% of cases and it was positive in 61%. The percentage of negative genetic markers (DQ2/DQ8) was 4.5% for patients tested to both haplotypes. A comparison of DQ2/DQ8 (positive and negative) with clinical findings and tests performed did not identify any differences for most of the parameters analyzed. Cases of type I diabetes presented significant negative expression for DQ2(-); p = 0.05 and positive expression for DQ8(+); p = 0.023. The TGA antibody levels ranged from 18 to 36,745 U/ml. An inverse correlation was found between age and TGA-L level (p = 0.043). In 23% of the cases, the TGA levels were greater than 1,000 U/ml and presented a moderate positive correlation with the atrophy biopsy profile (T = 0.245). Patients with an atrophic biopsy profile (Marsh III) had a moderate positive correlation with growth failure (T = 0.218) but a negative correlation with constipation (T = -0.277).

In terms of diagnosis tests for CD, transglutaminase levels and age presented an inverse correlation, with the level decreasing as age increased. A moderately positive correlation was found between mean transglutaminase with intestinal atrophy and growth retardation. The genetic test DQ2 was positive for 93% and negative genetic markers (DQ2/DQ8) represented 4.5% of cases studied.

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

Celiac disease (CeD) is a chronic immune-mediated enteropathy, which occurs in genetically predisposed individuals by the ingestion of gluten proteins present in wheat, barley and rye. The global pooled prevalence of CeD is 0.7% and it has been reported from nations all around the globe and can affect individuals of any age. It has a wide clinical spectrum ranging from being asymptomatic to being symptomatic with severe manifestations. Though initial descriptions of CeD focused on the classical presentation with gastrointestinal manifestations, in recent years it has been found that more patients have non-classical manifestations such as anemia, osteoporosis, increased transaminases, failure to thrive or short stature. The definitive diagnosis of CeD is based on a combination of clinical history, serologic testing with/without examination of duodenal biopsies. The preferred initial serologic test regardless of age for the detection of CeD is the tissue transglutaminase (IgA anti-tTG). Children with a high tTG-IgA (≥10 ULN) AND a positive anti-endomysial IgA antibody (EMA) can be diagnosed to have CeD without the need for duodenal biopsies. The rest should undergo biopsies with at least 4 biopsies from the distal duodenum and at least 1 from the bulb. A correctly orientated biopsy showing increased intraepithelial cells and a villous to crypt ratio of <2 is suggestive of CeD. The management of CeD is a lifelong complete dietary avoidance of gluten. IgA-TGA acts as a surrogate marker for healing of the small-bowel mucosa and should be performed every 6 mo until normalization and then every 12-24 mo thereafter.

Coeliac disease is a common immune-mediated inflammatory disorder caused by dietary gluten in genetically susceptible individuals. While the diagnosis of coeliac disease is based on serological and histological criteria, HLA-DQ genotyping can be useful, especially in excluding the diagnosis in patients who do not carry the relevant DQ heterodimers: DQA1*05 DQB1*02, DQB1*03:02 or DQA1*02 DQB1*02 (commonly referred to as DQ2.5, DQ8 and DQ2.2, respectively). External quality assessment results for HLA genotyping in coeliac disease have revealed concerning errors in HLA genotyping, reporting and clinical interpretation. In response, these guidelines have been developed as an evidence-based approach to guide laboratories undertaking HLA genotyping for coeliac disease and provide recommendations for reports to standardise and improve the communication of results.

Celiac disease (CD) is a complex disorder influenced by genetic and environmental factors. When people with a genetic predisposition to CD consume gluten, an inflammatory response is triggered in the small intestine, and this reaction can be alleviated by the elimination of gluten from the diet. The clinical manifestations of CD vary greatly from person to person and begin at a young age or in adulthood. Influence of genetic factors on CD development is evident in carriers of the DQ2 and/or DQ8 allele. HLA genotypes are associated with gut colonization by bacteria, particularly in individuals suffering from CD. In addition, beneficial gut microbes are crucial for the production of DPP-4, which plays a key role in immune function, as well as metabolic and intestinal health. Therefore, probiotics have been recommended as a complementary food supplement in CD.

Celiac disease (CD) is an autoimmune small bowel disease. Genetic susceptibility for CD is mainly determined by the human leukocyte antigen (HLA)-DQ haplotypes. The risk of CD conferred by HLA genotypes varies geographically and across populations, however, this has not yet been documented in Chinese patients with CD.

To investigate the distribution of HLA-DQ and the related risks of CD development in Northwest China.

A total of 75 CD patients and 300 healthy individuals were genotyped for HLA-DQ using the Illumina NextSeq, and the relative risks of the different genotypes were evaluated.

In total, 68.00% of CD patients and 21.00% of controls carried HLA-DQ2.5 heterodimers (p < 0.001). We identified four CD risk gradients. Individuals carrying a double dose of DQB1*02 had the highest risk of developing CD (1:16); however, with heterozygosis (DQB1*02:02/DQB1*02:01) having the highest risk (1:9). HLA-DQ2.5 individuals with a single copy of HLA-DQB1*02, in either the cis or trans configuration, were at a medium risk (1:38). Non-DQ2.5 carriers of DQ8 or DQ2.2 were at low risk, while only carriers of DQ7.5 or DQX.5 were at very low risk. Patients with the HLA-DQ2.5 genotype had more severe mucosal damage compared with the HLA-DQ2.5 genotype negative CD patients (70.59% vs. 41.67%, p = 0.016).

Genetic susceptibility to CD is highly prevalent in the Northwest Chinese population and the highest risk of developing CD was associated with the DQ2.5/DQ2.2 genotype. The DQ2.5 allele is involved in the severity of mucosal injury.

Celiac disease (CD) is a complex condition, whose main genetic determinant involves HLA molecules, specifically the HLA-DQ2 and/or HLA-DQ8 heterodimers. Nevertheless, the frequency of the alleles encoding those molecules has not been reported in Venezuelan celiac patients. Therefore, the aim of our study was to evaluate the frequency of the HLA-DQB1 alleles in individuals with symptoms suggestive of CD and define the diagnostic markers of the condition in a Venezuelan population.

A cross-sectional study included 516 individuals with symptoms suggestive of CD. Molecular typing of the HLA-DQB1 locus was performed using a polymerase chain reaction-sequence-specific oligonucleotide procedure (PCR-SSO).

A total of 58.3% of the individuals with clinical manifestations consistent with CD presented with at least one risk allele (DQB1*0201 and/or DQB1*0302), and the diagnosis was confirmed in 40 of them. The patients with CD had a higher frequency of the DQB1*0201 risk allele (26.25%), followed by the DQB1*0302 (17.5%) allele. There was an association between the presence of risk alleles and the presence of lesions characteristic of CD (P = 0.001), and a correlation was found between the genetic predisposition to develop CD and the presence of anti-tissue transglutaminase antibodies (P = 0.0127).

The results support the role of the DQB1*02 and DQB1*0302 alleles in CD susceptibility and the histologic alterations of the intestinal mucosa, in a Venezuelan population.

. In a biopsy-proven adult celiac disease (CeD) cohort from the Netherlands, male patients were diagnosed with CeD at significantly older ages than female patients.

To identify which factors contribute to diagnosis later in life and whether diagnostic delay influences improvement of symptoms after starting a gluten-free diet (GFD).

. We performed a questionnaire study in 211 CeD patients (67:144, male:female) with median age at diagnosis of 41.8 years (interquartile range: 25-58) and at least Marsh 2 histology.

. Classical symptoms (diarrhea, fatigue, abdominal pain and/or weight loss) were more frequent in women than men, but sex was not significantly associated with age at diagnosis. In a multivariate analysis, a non-classical presentation (without any classical symptoms) and a negative family history of CeD were significant predictors of older age at diagnosis (coefficients of 8 and 12 years, respectively). A delay of >3 years between first symptom and diagnosis was associated with slower improvement of symptoms after start of GFD, but not with sex, presentation of classical symptoms or age at diagnosis.

. Non-classical CeD presentation is more prevalent in men and is associated with a diagnosis of CeD later in life. Recognizing CeD sooner after onset of symptoms is important because a long diagnostic delay is associated with a slower improvement of symptoms after starting a GFD.

It is not known if genetic background, characteristics at diagnosis, physical and psychological well-being, and adherence to a gluten-free diet are comparable between patients with familial or sporadic celiac disease. These issues were investigated in a follow-up study.

Altogether 1064 patients were analyzed for celiac disease-associated serology, predisposing HLA-DQ, and non-HLA genotypes. Medical data were collected from patient records and supplementary interviews. Current symptoms and quality of life were further evaluated with the Gastrointestinal Symptom Rating Scale (GSRS), the Psychological General Well-Being questionnaire (PGWB), and Short Form 36 (SF-36) questionnaires.

Familial and sporadic groups differed (P < 0.001) in the reason for diagnosis and clinical presentation at diagnosis, familial patients being more often screen-detected (26% vs. 2%, P < 0.001) and having less often gastrointestinal (49% vs. 69%) and severe symptoms (47% vs. 65%). The groups were comparable in terms of histological damage, frequency of malabsorption, comorbidities, childhood diagnoses, and short-term treatment response. At the time of the study, familial cases reported fewer symptoms (21% vs. 30%, P = 0.004) and lower prevalence of all (78% vs. 86%, P = 0.007), neurological (10% vs. 15%, P = 0.013), and dermatological (9% vs. 17%, P = 0.001) comorbidities. Dietary adherence and GSRS scores were comparable, but familial cases had better quality of life according to PGWB and SF-36. High-risk genotype HLA-DQ2.5/DQ2.5 was more frequent among familial cases, and four non-HLA SNPs were associated with familial celiac disease.

Despite the greater proportion of high-risk genotypes, familial cases had milder symptoms at presentation than did sporadic cases. Worse experience of symptoms and poorer quality of life in sporadic disease indicate a need for intensified support.

The Human Leukocyte Antigen (HLA) has a crucial role in the development and pathogenesis of coeliac disease (CD). The genes HLA-DQA1 and HLA-DQB1, both lying in this region and encoding the HLA-DQ heterodimer, are the main genetic predisposing factors to CD. Approximately 90% of CD patients carry the heterodimer HLA-DQ2.5, leaving only a small proportion of patients with lower risk heterodimers (HLA-DQ8, HLA-DQ2.2 or HLA-DQ7.5). These HLA-DQ molecules act as receptors present in the surface of antigen presenting cells and show high affinity for deamidated gluten peptides, which bind and present to CD4⁺ T cells. This triggers the immunological reaction that evolves into CD. Since specific HLA genetics is present in almost the totality of CD patients, HLA typing has a very high negative predictive value, and it can be used to support diagnosis in specific scenarios. HLA risk has been associated to different CD-related features, such as age at onset, clinical outcomes, antibody levels and grade of histological lesion; but further research is needed. HLA-DQ genotypes have been also suggested to modulate the composition of the gut microbiota.

Coeliac disease (CD) is an autoimmune condition, characterised by an immunological response to ingestion of gluten in genetically susceptible individuals, affecting about 1% of the population in many regions of the world. Increased knowledge regarding the pathogenesis, improved diagnostic techniques and increased awareness over the years have transformed our understanding of CD such that it is no longer a rare enteropathy, but rather a common multisystem disorder which affects individuals of all ages and results in wide-ranging clinical manifestations. Only a minority of children now present with the classical clinical picture of profound diarrhoea and malnutrition. An increasing number of children with CD present with either mild, non-specific gastrointestinal symptoms or extra-intestinal manifestations or even be asymptomatic, as in many screening-detected children. Knowledge about these diverse manifestations and a high index of suspicion is essential so that appropriate investigations can be undertaken, diagnosis established and treatment initiated. Although traditionally small bowel biopsy is considered essential for the diagnosis, recent guidelines from various professional bodies have paved the way to a biopsy-free diagnosis in a subset of symptomatic children. Life long, strict gluten-free diet still remains the only effective treatment at present, although several novel therapeutic agents are in various phases of clinical trials.

Single nucleotide polymorphism-based genetic risk scores (GRS) model genetic risk as a continuum and can discriminate coeliac disease but have not been validated in clinic. Human leukocyte antigen (HLA) DQ gene testing is available in clinic but does not include non-HLA attributed risk and is limited by discrete risk stratification.

To accurately characterise both HLA and non-HLA coeliac disease genetic risk as a single nucleotide polymorphism-based GRS and evaluate diagnostic utility.

We developed a 42 single nucleotide polymorphism coeliac disease GRS from a European case-control study (12 041 cases vs 12 228 controls) using HLA-DQ imputation and published genome-wide association studies. We validated the GRS in UK Biobank (1237 cases) and developed direct genotyping assays. We tested the coeliac disease GRS in a pilot clinical cohort of 128 children presenting with suspected coeliac disease.

The GRS was more discriminative of coeliac disease than HLA-DQ stratification in UK Biobank (receiver operating characteristic area under the curve [ROC-AUC] = 0.88 [95% CIs: 0.87-0.89] vs 0.82 [95% CIs: 0.80-0.83]). We demonstrated similar discrimination in the pilot clinical cohort (114 cases vs 40 controls, ROC-AUC = 0.84 [95% CIs: 0.76-0.91]). As a rule-out test, no children with coeliac disease in the clinical cohort had a GRS below 38th population centile.

A single nucleotide polymorphism-based GRS may offer more effective and cost-efficient testing of coeliac disease genetic risk in comparison to HLA-DQ stratification. As a comparatively inexpensive test it could facilitate non-invasive coeliac disease diagnosis but needs detailed assessment in the context of other diagnostic tests and against current diagnostic algorithms.

Immune response to vaccinations in celiac patients is of growing scientific interest. However, some aspects of the relationship between celiac disease (CD) and vaccines are still unclear. A comprehensive search of published literature using the PubMed database was carried out using the following key terms: "adaptive immunity", "celiac disease", "humoral immune response", "immunization", and "vaccination". To date, there is no evidence showing any causative association between vaccines and CD development. Therefore, vaccinations may be administered according to the modalities and timing of the National Immunization Schedule for each country. The rotavirus vaccine is currently recommended for the general population, and according to some data, it appears to reduce the risk for the development of CD autoimmunity in the early years of life. Regarding the hepatitis B virus, a booster dose of the vaccine is often required due to the low or the lost immune response rate in CD. Furthermore, determination of hepatitis B antibody titers could be useful in newly diagnosed CD subjects regardless of age at diagnosis. Finally, pneumococcal vaccines may be administered in patients with advancing age at diagnosis and concomitant risk factors. Future clinical practice guidelines for vaccination and monitoring programs in celiac patients could be recommended.

Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with DRB3*01:01, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a-alloimmunized women, identified in a prospective study, and random donors were typed for selected DRB3, DRB4, DRB1, DQA1 and DQB1 alleles to determine allele and DR-DQ haplotype frequencies. DRB3*01:01 was carried by 94% HPA-1a-immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (P < .003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of DRB3*01:01-positive individuals. Further, we examined DQB1*02 and DRB4*01:01 alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since ~ 80% of DQB1*02 alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the DQB1*02:02-associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As DRB4*01:01 is predominantly associated with the DR7-DQ2 haplotype in HPA-1a-alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.

Objectives: Celiac disease (CD) is barely known if the quantitative effect of DQB1*02 (DQ2) double dose in antigen presentation to T-cells has translation into the clinic. For this, we have conducted a case-control study in a cohort of two hundred and nineteen patients with CD. Material and methods: For the control group, individuals were enrolled with single dose of DQ2, carrying DQ2.5 heterodimers in heterozygous state (n = 109). The cases with CD were diving into three groups: cases with overall DQ2 double dose (n = 110), DQ2.5 homozygous (n = 33) and DQ2.5/DQ2.2 heterozygous (n = 77). Prevalence and associations of demographic, laboratory, histological and clinical characteristics between the control group and cases were studied. Results: No differences were found for the total of 16 variables analyzed between the control group and overall DQ2 double dose as well as DQ2.5 homozygous cases. In contrast to DQ2.5/DQ2.2, heterozygous cases presented a protection factor for developing allergy to airway allergens regarding the control group (OR = 0.210, p = .019). Conclusions: To date, this negative association has not been described. Further studies will be necessary to elucidate the implication of this protection factor in CD. Since, until now the association between CD and allergic diseases has been poorly studied.