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Rouvroye MD, Roos A, Bergkamp F, Haagen IA, van der Pol P, Neefjes-Borst EA, Bouma G, Bontkes HJ. The frequency of HLA-DQ7 in patients at risk of coeliac disease: A haplotype to be reckoned with for screening? Hum Immunol 2024; 85:111158. [PMID: 39423728 DOI: 10.1016/j.humimm.2024.111158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/05/2024] [Accepted: 10/10/2024] [Indexed: 10/21/2024]
Abstract
HLA-DQ2 and -DQ8 carriers are genetically predisposed to develop coeliac disease (CD). Testing negative for HLA-DQ2/DQ8 has a high negative predictive value. Full HLA-DQ genotyping as well as tests only typing for HLA-DQ2/DQ8 are therefore used for screening at-risk populations. However, HLA-DQ7 positive and HLA-DQ2/DQ8 negative CD patients have been described in various populations. In this study we examine the relevance for HLA-DQ7 typing in a large at-risk CD population. The HLA-DQ status of all paediatric and adult patients at-risk of CD that were typed in a tertiary medical centre laboratory between 2012 and 2016 (n = 3983) was obtained. HLA-DQ7 (HLA-DQB1*03:01) positive and HLA-DQ2/DQ8 negative patients were selected. We gathered information on serology, histology and dietary status, and CD diagnosis. In total, 489/3983 patients were HLA-DQ7-positive and HLA-DQ2/DQ8 negative, and after exclusion (missing data on diet or serology/histology), 325 were included. Only one adult patient was diagnosed with CD, based on a duodenal biopsy and a clinical response to a gluten-free diet. Homozygosity was observed in 14.8 %. Based on the current cohort additional typing of HLA-DQ7 does not seem relevant for screening at-risk populations for CD in the Netherlands. It should be considered in patients with a high suspicion of CD.
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Affiliation(s)
- M D Rouvroye
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location VU Medical Center, AGEM Research Institute, Amsterdam, The Netherlands; Department of Gastroenterology and Hepatology, Spaarne Gasthuis, Boerhavelaan 22, 2035 RC Haarlem, The Netherlands.
| | - A Roos
- Department of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - F Bergkamp
- Department of Clinical Chemistry, Atalmedial, Louwesweg 6, 1066 EC Amsterdam, The Netherlands
| | - I A Haagen
- Department of Clinical Chemistry, OLVG Lab, Amsterdam, The Netherlands
| | - P van der Pol
- Reinier Haga MDC, Delft, Medical Laboratories, Department of Immunology, The Netherlands
| | - E A Neefjes-Borst
- Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Amsterdam, The Netherlands
| | - G Bouma
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location VU Medical Center, AGEM Research Institute, Amsterdam, The Netherlands
| | - H J Bontkes
- Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Immunology Laboratory, Department of Clinical Chemistry, Amsterdam Infection and Immunity Institute, Amsterdam, The Netherlands
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Pritchard D, Anand A, De'Ath A, Lee H, Rees MT. UK NEQAS and BSHI guideline: Laboratory testing and clinical interpretation of HLA genotyping results supporting the diagnosis of coeliac disease. Int J Immunogenet 2024; 51 Suppl 1:3-20. [PMID: 38153308 DOI: 10.1111/iji.12649] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 12/08/2023] [Indexed: 12/29/2023]
Abstract
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.
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Affiliation(s)
| | - Arthi Anand
- H&I Laboratory, North West London Pathology, Imperial College Healthcare NHS Trust, London, UK
| | - Amy De'Ath
- UK NEQAS for H&I, Velindre University NHS Trust, Cardiff, UK
| | - Helena Lee
- Transplantation Laboratory, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK
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Sullivan HC, Gandhi MJ, Gaitonde S, Narasimhan R, Gendzekhadze K, Pandey S, Roby RK, Maha GC, Kaur H, Schiller JJ, McDowell J, Smith M, Liu C, Morris GP. Seventy-five years of service: an overview of the College of American Pathologists' proficiency testing program in histocompatibility and identity testing. Front Genet 2023; 14:1331169. [PMID: 38169613 PMCID: PMC10758433 DOI: 10.3389/fgene.2023.1331169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 11/20/2023] [Indexed: 01/05/2024] Open
Abstract
The Histocompatibility and Identity Testing Committee offers an overview of the College of American Pathologists' (CAP) Proficiency Testing (PT) program, commemorating its significant 75th anniversary in 2024. The CAP PT program has undergone significant growth and evolution over the years, ultimately achieving Centers for Medicare and Medicaid Services approval. In 1979, CAP's partnership with the American Association for Clinical Histocompatibility Testing marked a pivotal moment, leading to the creation of the first proficiency testing survey in 1980. This laid the foundation for various PT programs managed by the CAP Histocompatibility and Identity Testing Committee, including HLA antibody testing, HLA molecular typing, engraftment monitoring, parentage/relationship testing, HLA disease associations and drug risk, and HLA-B27 typing. Each program's distinctive considerations, grading methodologies, and future prospects are detailed here, highlighting the continual evolution of histocompatibility and identity testing PT to support emerging technologies and evolving laboratory practices in the field.
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Affiliation(s)
- H. Cliff Sullivan
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
| | - Manish J. Gandhi
- Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN, United States
| | - Sujata Gaitonde
- Department of Pathology, University of Illinois Chicago, Chicago, IL, United States
| | - Ramya Narasimhan
- Boston University Medical Center, Department of Pathology and Laboratory Medicine, Boston, MA, United States
| | | | - Soumya Pandey
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Rhonda K. Roby
- Alameda County Sheriff’s Office Crime Laboratory, Oakland, CA, United States
| | | | - Harmeet Kaur
- Cuyahoga County Regional Forensic Science Lab, Cleveland, OH, United States
| | | | - Julie McDowell
- College of American Pathologist (CAP), Chicago, IL, United States
| | - Maria Smith
- College of American Pathologist (CAP), Chicago, IL, United States
| | - Chang Liu
- Washington University in St. Louis, Department of Pathology and Immunology, Saint Louis, MO, United States
| | - Gerald P. Morris
- Department of Pathology, Univeristy of California San Diego, San Diego, CA, United States
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"Geographical distribution of risk genotypes in pediatric patients with celiac disease in Spain". Hum Immunol 2023; 84:290-295. [PMID: 36858916 DOI: 10.1016/j.humimm.2023.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/22/2022] [Accepted: 01/31/2023] [Indexed: 03/02/2023]
Abstract
Celiac disease is strongly associated with HLA DQ, specifically with haplotypes. DRB1*03-DQA1*05:01/DQB1*02:01 (DQ2.5),DRB1*07-DQA1*02:01/DQB1*02:02 (DQ2.2), DRB1*11-DQA1*05:05/DQB1*03:01 (DQ7.5), and DRB1*04-DQA1*03:01/DQB1*03:02 (DQ8). The distribution of these risk haplotypes in patients with celiac disease is different in the geographical areas investigated. A high frequency of DRB1*07- DQA1*02:01/DQB1*02:02 (DQ2.2) and DRB1*11-DQA1*05:05/DQB1*03:01 (DQ7.5), has been described in Southern Europe. We analyzed 2102 confirmed CD cases with information on both DQB1* alelles and their distribution by geographical area in Spain. According to the presence of this haplotype in one or two chromosomes, the genotype is classified in: DQ2 homozygous, DQ2 heterozygous (cis or trans), DQ8 homozygous, DQ8/DQ2.5, DQ 2.2 homozygous and genotype known as "half DQ2". Two different patterns of risks related to CD were identified. In the Basque Country and Navarre, the Mediterranean Area (Aragon, Catalonia, Valencia, Balearic Islands, and Murcia), the South of Spain (Andalucía and Extremadura), and the Canary Islands, higher frequency of DQ2.5 trans, and more than 80% of DQ2.5/DQ2.2 homozygosis were described. The Cantabrian Coast (Cantabria, Asturias, and Galicia) and Central Areas (Castilla-León and Castilla-La Mancha) showed a higher percentage of DQ2.5/DQ2.5 homozygosis and a lower DQ2.5 in trans frequency, as in Northern Europe. Madrid has an intermediate model between the two described above. 17 cases (0.8%) did not carry any CD risk haplotypes.
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Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease. Int J Mol Sci 2023; 24:ijms24021188. [PMID: 36674702 PMCID: PMC9863503 DOI: 10.3390/ijms24021188] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/23/2022] [Accepted: 10/04/2022] [Indexed: 01/11/2023] Open
Abstract
Although people with human leukocyte antigens (HLA) DQ2 and/or DQ8 are more likely to develop celiac disease (CD), the condition cannot be fully explained by this genetic predisposition alone. Multiple, as yet unidentified, factors contribute to the genesis of CD, including genetics, the environment, and the immune system. In order to provide insight into a prospective possibility and an expanded screening technique, we aim to undertake a comprehensive and meta-analytical study of the assessment and distribution of HLA class II (HLA-DQ2/DQ8) in adult CD patients. A systematic review was conducted using an electronic search of databases (PubMed, Google Scholar, Embase, and Direct Science) from January 2004 to February 2022. DQ2/DQ2 homozygotes have the highest risk of developing CD. DQ2/DQ8 typing is an effective test to exclude CD from the differential diagnosis of a patient with CD symptoms. Although other non-HLA genes have been associated with CD, they are rarely considered at diagnosis because they account for only a small proportion of the heritability of CD. This finding, together with the information gathered previously, may be useful in considering widely available and economically feasible screening options for celiac disease in young people.
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Zubkiewicz-Kucharska A, Jamer T, Chrzanowska J, Akutko K, Pytrus T, Stawarski A, Noczyńska A. Prevalence of haplotype DQ2/DQ8 and celiac disease in children with type 1 diabetes. Diabetol Metab Syndr 2022; 14:128. [PMID: 36096955 PMCID: PMC9465882 DOI: 10.1186/s13098-022-00897-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022] Open
Abstract
UNLABELLED Type 1 diabetes (T1D) and celiac disease (CD) coexist very often. Identification of the human leukocyte antigen (HLA) DQ2/DQ8 can confirm the genetic predisposition to CD. Negative result of this test allows to exclude CD with a high probability. It was suggested that in individuals with higher risk of CD, including T1D patients, the implementation of genetic testing should reduce the number of patients requiring systematic immunological screening. The aim of this study was to analyze the prevalence of different haplotypes predisposing to CD in children and adolescents with previously diagnosed T1D. MATERIAL AND METHODS A retrospective analysis was performed on 166 T1D children (91 girls) in whom HLA DQ2/DQ8 alleles were tested. In 9.6% CD was also diagnosed. RESULTS In 12.7% both HLA DQ2/DQ8 were negative. In 87.3% patients HLA DQ2 and/or DQ8 was positive, including 27.7% patients with both haplotypes DQ2.5 and DQ8 positive. In all CD patients the disease predisposing alleles were positive, while none of the HLA DQ2/DQ8 negative children were diagnosed with CD. CONCLUSIONS The prevalence of HLA DQ2.5 and the HLA DQ2.5 / HLA DQ8 configuration is higher in patients with T1D, and CD compared to children with T1D alone. The combination of HLA DQ2 and HLA DQ8 most significantly increases the risk of developing CD. The group of HLA DQ2/DQ8 negative patients with improbable CD diagnosis, is relatively small. Most of T1D patients HLA DQ2/DQ8 positive need further regular antibody assessment. In patients with T1D, who are at high risk of developing CD, genetic testing may be considered to select those who require further systematic serological evaluation. Due to its retrospective nature, the study was not registered in the database of clinical trials and the Clinical trial registration number is not available.
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Affiliation(s)
- Agnieszka Zubkiewicz-Kucharska
- Department of Pediatric Endocrinology and Diabetology for Children and Adolescents, Wroclaw Medical University, Wroclaw, Poland
| | - Tatiana Jamer
- Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland.
| | - Joanna Chrzanowska
- Department of Pediatric Endocrinology and Diabetology for Children and Adolescents, Wroclaw Medical University, Wroclaw, Poland
| | - Katarzyna Akutko
- Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland
| | - Tomasz Pytrus
- Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland
| | - Andrzej Stawarski
- Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland
| | - Anna Noczyńska
- Department of Pediatric Endocrinology and Diabetology for Children and Adolescents, Wroclaw Medical University, Wroclaw, Poland
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Sahin Y, Mermer S. Frequency of celiac disease and distribution of HLA-DQ2/DQ8 haplotypes among siblings of children with celiac disease. World J Clin Pediatr 2022; 11:351-359. [PMID: 36052110 PMCID: PMC9331400 DOI: 10.5409/wjcp.v11.i4.351] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/18/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Celiac disease (CD) is a multifactorial disease, but genetic factors play a major role in its etiology. It has been known that human leucocyte antigen (HLA)-DQ2/DQ8 haplotypes are one of the most important predisposing genetic factors. The risk of developing CD in first-degree relatives and especially siblings of celiac patients is quite high because of having the same HLA haplotypes. AIM To evaluate the frequency of CD and the distribution of the HLA-DQ2/DQ8 haplotypes in siblings of celiac patients. METHODS Patients with biopsy-proven CD and their siblings were included in the study; those who did not have HLA genotyping were excluded from the study. All siblings were on a gluten-containing diet. The HLA genotyping, tissue transglutaminase antibody IgA antibody test, and total IgA test were performed in all participants. RESULTS A total of 57 celiac patients and their 112 siblings were included in the study. The mean age of celiac patients and siblings were 10.30 ± 3.87 years and 9.90 ± 6.11 years, respectively. HLA-DQ2/DQ8 alleles were detected in 98.2% of patients with CD and 90.2% of siblings of celiac patients. HLA-DQ genotypes were present in all siblings diagnosed with CD. Tissue transglutaminase antibody IgA test was found to be positive in 16 siblings. CD was diagnosed in 12 siblings (10.7%) by intestinal biopsy. CONCLUSION The prevalence of CD was found to be 10.7% in siblings of celiac patients in our study. One-third of the siblings diagnosed with CD were asymptomatic. We detected HLA-DQ alleles in 98.2% of celiac patients and 100% in siblings diagnosed with CD. In addition, 1 of the 2 siblings was diagnosed with CD 1 year later and the other 4 years later. Therefore, we suggest that siblings of celiac patients should be followed up with clinical findings as well as HLA analysis and serological examination. Since the risk of developing CD is much higher in asymptomatic siblings, we recommend that siblings should be screened for CD even if they are asymptomatic.
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Affiliation(s)
- Yasin Sahin
- Department of Pediatric Gastroenterology, Mersin Training and Research Hospital, Mersin 33240, Mersin, Turkey
| | - Serdar Mermer
- Department of Medical Genetics, Mersin Training and Research Hospital, Mersin 33240, Mersin, Turkey
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Horton RK, Hagen CE, Snyder MR. Pediatric Celiac Disease: A Review of Diagnostic Testing and Guideline Recommendations. J Appl Lab Med 2022; 7:294-304. [PMID: 34996069 DOI: 10.1093/jalm/jfab143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/21/2021] [Indexed: 11/13/2022]
Abstract
BACKGROUND The history of how our knowledge of celiac disease (CD) evolved points to its importance in children. Although it is now appreciated that CD can present at any age, it was originally thought to occur only in children and, if untreated, led to serious consequences. CONTENT This review includes a brief discussion of small bowel physiology and the pathogenesis of CD. Next, the varied clinical presentations of CD in children are reviewed, including both gastrointestinal and nongastrointestinal manifestations and how these contribute to the difficulty in diagnosis. In addition, information on specific conditions that are associated with CD is presented, particularly as it applies to diagnostic testing of apparently asymptomatic children. The review will also focus on diagnostic testing available for CD and their general performance characteristics. The review will end with a comparison between published guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition for diagnosis of pediatric CD. In particular, this review will focus on differences in the incorporation of serologic and genetic testing, and the role of biopsies in the pediatric population. SUMMARY It is important for laboratorians to understand the evolution of diagnostic guidelines for pediatric CD and how serologic and genetic testing are being applied to and interpreted in this particular patient group.
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Affiliation(s)
- Rachel K Horton
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Catherine E Hagen
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Melissa R Snyder
- Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
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Ramakrishna BS, Venugopal G, Singh A, Pugazhendhi S, Dutta S, Ahuja V, Makharia GK. Human Leukocyte Antigen DQ (HLA-DQ) genotypes and haplotypes and their association with phenotype in patients with celiac disease in India. JGH Open 2021; 5:1190-1196. [PMID: 34622007 PMCID: PMC8485407 DOI: 10.1002/jgh3.12651] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/28/2021] [Accepted: 08/21/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND AND AIM Human Leukocyte Antigen DQ (HLA-DQ) genotypes play a permissive role in the genesis of celiac disease (CeD). In this case-control study, we used next-generation sequencing to determine HLA-DQA1 and ~DQB1 genotypes and haplotypes associated with CeD in Indian patients. METHODS HLA-DQA1 and ~DQB1 loci were amplified, using long-range polymerase chain reaction (PCR), from DNA of 259 patients with symptomatic CeD (160 typical and 99 atypical), 45 asymptomatic CeD, 96 potential CeD, and 300 healthy adults. Amplicons were fragmented and sequenced on the Illumina platform, and alleles and haplotypes were assigned by matching against the HLA-international ImMunoGeneTics (IMGT) database. RESULTS HLA-DQA1*05:01 (odds ratio [OR] 8.39, 95% confidence interval [CI] 5.64-12.47) and HLA-DQB1*02:01 (OR 8.59, 95% CI 5.75-12.83) were the genotypes that showed a risk association with symptomatic CeD. Among the haplotypes, HLA-DQA1*05:01 ~ HLA-DQB1*02:01 (OR 8.56, 95% CI 5.67-13.19) showed a strong risk association with symptomatic CeD. When comparing symptomatic CeD with subclinical forms (asymptomatic and potential) CeD, HLA-DQA1*05:01 ~ HLA-DQB1*02:01 (OR 2.34, 95% CI 1.61-3.43) was significantly associated with risk of symptomatic disease. The strength of association between the HLA-DQA1*05:01 ~ HLA-DQB1*02:01 haplotype and the CeD phenotype showed a gradient in the order typical > atypical > asymptomatic > potential CeD. Genotypes consistent with expression of HLA DQ2 and/or 8 were noted in 128 (80%) typical, 73 atypical (74%), 27 (60%) asymptomatic, and 52 (54%) potential CeD participants. CONCLUSION HLA-DQA1*05:01 ~ HLA-DQB1*02:01 (haplotype DQ2.5) showed a very strong risk association with symptomatic CeD in Indian patients. The strength of association showed a gradient of increase from potential to typical CeD, coinciding with a phenotypic change in the celiac iceberg.
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Affiliation(s)
| | | | - Alka Singh
- Department of Gastroenterology and Human NutritionAll India Institute for Medical SciencesNew DelhiIndia
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10
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Paavola S, Lindfors K, Kivelä L, Cerqueira J, Huhtala H, Saavalainen P, Tauschi R, Kaukinen K, Kurppa K. Presence of high-risk HLA genotype is the most important individual risk factor for coeliac disease among at-risk relatives. Aliment Pharmacol Ther 2021; 54:805-813. [PMID: 34278595 DOI: 10.1111/apt.16534] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/07/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure. AIMS To investigate the individual risk of coeliac disease among patients' relatives. METHODS Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression. RESULTS There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18 years at diagnosis (odds ratio 1.60, 95% CI 1.04-2.45) in index, and age 41-60 years (1.73, 1.10-2.73), being a sibling (1.65, 1.06-2.59) and having the high-risk genotype (3.22, 2.01-5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80-4.78) in multivariable analysis. CONCLUSIONS Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. ClinicalTrials.gov identifier NCT03136731.
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Affiliation(s)
- Saana Paavola
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Katri Lindfors
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Laura Kivelä
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Juliana Cerqueira
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, University of Tampere, Tampere, Finland
| | - Päivi Saavalainen
- Translational Immunology Research Program, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Riku Tauschi
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Katri Kaukinen
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Kalle Kurppa
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.,The University Consortium of Seinäjoki, Seinäjoki, Finland
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11
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Smithson G, Siegelman J, Oki T, Maxwell JR, Leffler DA. The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development. Front Immunol 2021; 12:665756. [PMID: 33897715 PMCID: PMC8060282 DOI: 10.3389/fimmu.2021.665756] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/19/2021] [Indexed: 12/17/2022] Open
Abstract
Celiac disease is a common immune-mediated disease characterized by abnormal T-cell responses to gluten. For many patients, symptoms and intestinal damage can be controlled by a gluten-free diet, but, for some, this approach is not enough, and celiac disease progresses, with serious medical consequences. Multiple therapies are now under development, increasing the need for biomarkers that allow identification of specific patient populations and monitoring of therapeutic activity and durability. The advantage of identifying biomarkers in celiac disease is that the underlying pathways driving disease are well characterized and the histological, cellular, and serological changes with gluten response have been defined in gluten challenge studies. However, there is room for improvement. Biomarkers that measure histological changes require duodenal biopsies and are invasive. Less invasive peripheral blood cell and cytokine biomarkers are transient and dependent upon gluten challenge. Here, we discuss established biomarkers and new approaches for biomarkers that may overcome current limitations.
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Affiliation(s)
- Glennda Smithson
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Jenifer Siegelman
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Toshihiko Oki
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Joseph R Maxwell
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Daniel A Leffler
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States.,Celiac Disease Research Program, Harvard Medical School, Boston, MA, United States
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12
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Espino L, Núñez C. The HLA complex and coeliac disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 358:47-83. [PMID: 33707057 DOI: 10.1016/bs.ircmb.2020.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- Laura Espino
- Laboratorio de investigación en Genética de enfermedades complejas, Hospital Clínicos San Carlos, IdISSC, Madrid, Spain
| | - Concepción Núñez
- Laboratorio de investigación en Genética de enfermedades complejas, Hospital Clínicos San Carlos, IdISSC, Madrid, Spain.
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