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Jossen J, Lebwohl B, Söderling J, Duberg AS, Aleman S, Sharma R, Hagström H, Green PHR, Ludvigsson JF. No Increased Risk of Hepatitis B Virus Infection in Patients with Celiac Disease: A Population-Based Study. Dig Dis Sci 2025; 70:1521-1529. [PMID: 39984784 PMCID: PMC11972206 DOI: 10.1007/s10620-025-08878-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 01/16/2025] [Indexed: 02/23/2025]
Abstract
OBJECTIVES Celiac disease (CeD) has been associated with a low response to hepatitis B (HBV) vaccination, but guidelines for testing and revaccination among individuals with CeD are sparse. We examined the risk of future HBV among individuals with CeD in a population-based Swedish cohort. Furthermore, we examined the rate of prior HBV infection in CeD patients. METHODS All individuals in Sweden diagnosed with biopsy-verified CeD between 1990 and 2017 were identified through the ESPRESSO cohort. Each individual with CeD was matched by age, sex, calendar year, and birth country (Nordic vs. other) with up to 5 reference individuals. RESULTS We identified 44,721 CeD and 222,238 reference individuals. The incidence rates of diagnosed HBV were 2.3 and 2.9 per 100,000 person-years, respectively. This represented no association with CeD (HR 0.77 (0.45-1.30)). This null association was similar for those with a Nordic (HR 0.80 (0.40-1.60)) and non-Nordic ((HR 0.31 (0.09-1.08)) country of birth. Rates of prior HBV infection were low (CeD 0.08%, controls 0.06%). This corresponded to a small but insignificant increase among individuals with CeD (odds ratio, OR 1.41 (0.97-2.05). CONCLUSION In a population-based Swedish cohort, there was no increased risk of developing HBV in individuals with CeD. This finding does not support current practices of testing and revaccination for HBV. Additional studies should be completed in areas with higher endemic rates of HBV. Slightly higher rates of prior HBV infection in CeD may be secondary to increased testing in those seeking medical care for another disease process.
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Affiliation(s)
- Jacqueline Jossen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA
- Celiac Disease Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
| | - Benjamin Lebwohl
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
- Celiac Disease Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
| | - Jonas Söderling
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institute, Stockholm, Sweden
| | - Ann-Sofi Duberg
- Department of Infectious Diseases, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Soo Aleman
- Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Rajani Sharma
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
- Center for Liver Disease and Transplantation, Columbia University Irving Medical Center, New York, NY, USA
| | - Hannes Hagström
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden
| | - Peter H R Green
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
- Celiac Disease Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
| | - Jonas F Ludvigsson
- Celiac Disease Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
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Farrier CE, Wanat M, Harnden A, Paterson A, Roberts N, Saatci D, Hirst J. Predictive factors for the diagnosis of coeliac disease in children and young people in primary care: A systematic review and meta-analysis. PLoS One 2024; 19:e0306844. [PMID: 39705224 DOI: 10.1371/journal.pone.0306844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 11/23/2024] [Indexed: 12/22/2024] Open
Abstract
BACKGROUND Coeliac Disease (CD) often has its onset in childhood and affects 1% of the population. This review aimed to identify important predictive factors for coeliac disease in children and young people which could help GPs decide when to offer testing. METHODS We searched MEDLINE, Embase and Cochrane Library to April 2024. Included studies were observational or randomized trials reporting the risk of CD when exposed to predictive factor(s) in people ≤25 years of age. Genetic factors were excluded. Risk of Bias was assessed using the Newcastle-Ottawa Scale. Random effects meta-analysis was performed for factors reported in ≥5 studies to calculate pooled odds ratios (OR) or standardized mean differences (SMD). RESULTS Of 11,623 unique abstracts, 183 were included reporting on 140+ potentially associated factors. Meta-analyses of 28 factors found 14 significant associations with CD diagnosis: having type 1 diabetes (OR 8.70), having a first degree relative with coeliac disease (OR 5.19), being of white ethnicity (OR 2.56), having thyroid disease (OR 2.16), being female (OR 1.53), more frequent gastroenteritis in early childhood (OR 1.48), having frequent respiratory infections in early childhood (OR 1.47), more gluten ingestion in early life (OR 1.25), having more infections in early life (OR 1.22), antibiotic use in early childhood (OR 1.21), being born in the summer (OR 1.09), breastfeeding (OR 0.79) older age at diagnosis of type 1 diabetes (OR 0.64), and heavier weight (SMD -0.21). The final three were associated with lower risk of CD diagnosis. DISCUSSION This is the first systematic review and meta-analysis of predictive factors for CD in children. Amongst the 14 factors we identified that were significant, three were potentially modifiable: breast feeding, antibiotic use and amount of gluten ingestion in early childhood. This work could inform the development of clinical support tools to facilitate the early diagnosis of CD.
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Affiliation(s)
- Christian E Farrier
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
- Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Marta Wanat
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Anthony Harnden
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Amy Paterson
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Nia Roberts
- Bodleian Healthcare Libraries, Knowledge Centre, University of Oxford, Oxford, United Kingdom
| | - Defne Saatci
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Jennifer Hirst
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
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Hård Af Segerstad EM, Borge TC, Guo A, Mårild K, Stene LC, Brantsæter AL, Størdal K. Associations of Pregnancy Dietary Quality and Diversity with Childhood Celiac Disease. J Nutr 2024; 154:3770-3779. [PMID: 39428068 DOI: 10.1016/j.tjnut.2024.10.033] [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: 07/01/2024] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024] Open
Abstract
BACKGROUND High gluten and low dietary fiber in pregnancy intake is associated with an increased risk of celiac disease (CeD) in the child. Early life higher dietary quality is suggested to reduce the subsequent risk of CeD. OBJECTIVES The aim was to investigate associations of pregnancy dietary quality and diversity with child risk of CeD. METHODS In The Norwegian Mother, Father and Child Cohort Study, 85,122 mother-child pairs had available data from a validated pregnancy food frequency questionnaire. Pregnancy dietary quality and diversity were estimated by a Pregnancy Healthy Eating Index [mean 99.3, standard deviation (SD) 9.9, range 48.8-128.3], and a Diet Diversity Score (mean 7.0, SD 1.0, range 1.6-9.8), respectively. Child CeD was captured by ≥2 diagnostic codes in the Norwegian Patient Registry. Logistic regression was used to estimate associations between pregnancy dietary quality, diversity and child CeD, adjusted for socioeconomic factors, and parents CeD [adjusted odds ratio (aOR), 95% confidence intervals (CI)]. CeD-susceptible human leukocyte antigen haplotypes (DQ2/DQ8) were present in 30,718 (45.5%). RESULTS Up to mean age 16.0 (SD 1.8, 12.4-19.8) y, 1363 (1.6%) children were diagnosed with CeD. Lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD in the child (<5th percentile aOR = 0.67, 95% CI: 0.48, 0.93, >95th percentile aOR = 0.71, 95% CI: 0.52, 0.98, respectively, nonlinear squared term P = 0.011). Analyses on genetically susceptible children, adjustments for pregnancy iron supplementation, gluten, and dietary fiber intake, and child early life dietary quality, gluten intake and iron supplementation, supported the finding. Pregnancy dietary diversity was not associated with child CeD (aOR = 1.00, 95% CI: 0.94, 1.07/score). CONCLUSIONS In this population-based study, lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD diagnosis in the child. In contrast, no such association was observed with maternal dietary diversity.
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Affiliation(s)
- Elin M Hård Af Segerstad
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway; Unit for Celiac and Diabetes Research, Clinical Sciences, Lund University, Malmoe, Sweden.
| | - Tiril Cecilie Borge
- Cluster for Reviews and Health Technology Assessments, Norwegian Institute of Public Health, Oslo, Norway
| | - Annie Guo
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Karl Mårild
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Lars C Stene
- Cluster for Reviews and Health Technology Assessments, Norwegian Institute of Public Health, Oslo, Norway
| | - Anne Lise Brantsæter
- Department of Food Safety, Center for Sustainable Diets, Norwegian Institute of Public Health, Oslo, Norway
| | - Ketil Størdal
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway; Faculty of Clinical Medicine, University of Oslo, Oslo, Norway
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Eurén A, Lynch K, Lindfors K, Parikh H, Koletzko S, Liu E, Akolkar B, Hagopian W, Krischer J, Rewers M, Toppari J, Ziegler A, Agardh D, Kurppa K. Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures. Sci Rep 2024; 14:25463. [PMID: 39462122 PMCID: PMC11567144 DOI: 10.1038/s41598-024-75496-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study. Altogether 6523 genetically predisposed children were enrolled to long-term follow-up with prospective sampling and data collection at six research centers in the USA, Germany, Sweden and Finland. Celiac disease autoimmunity was defined as positive tissue transglutaminase antibodies in two consecutive serum samples. There was a significant season of birth effect on the risk of celiac autoimmunity. The effect was dependent on polymorphisms in CD247 gene encoding for CD3ζ chain of TCR-CD3 complex. In particular, children with major alleles for SNP rs864537A > G, in CD247 (AA genotype) had an excess risk of celiac autoimmunity when born March-August as compared to other months. The interaction of CD247 with season of birth on autoimmunity risk was accompanied by interactions with febrile infections between the ages of 3-6 months. Considering the important role of TCR-CD3 complex in the adaptive immune response and our findings here, CD247 variants and their possible effect of subgroups in autoimmunity development could be of interest in the design of future gene-environment studies of celiac disease. ClinicalTrials.gov Identifier: NCT00279318.
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Affiliation(s)
- Anna Eurén
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Kristian Lynch
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Hemang Parikh
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Sibylle Koletzko
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Edwin Liu
- Digestive Health Institute, Children's Hospital, Anschutz Medical Campus, University of Colorado, Denver, CO, USA
| | - Beena Akolkar
- National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA
| | - William Hagopian
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jeffrey Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Marian Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, USA
| | - Jorma Toppari
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland
- Department of Pediatrics, Turku University Hospital, 20520, Turku, Finland
| | - Anette Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany
- Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
- Forschergruppe Diabetes e.V., Neuherberg -Munich, Germany
| | | | - Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Faculty of Medicine and Health Technology, Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University and Tampere University Hospital, Arvo Ylpön Katu 34, 33520, Tampere, Finland.
- Seinäjoen yliopistokeskus, Seinäjoki, Finland.
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Størdal K, Tapia G, Lund-Blix NA, Stene LC. Genotypes predisposing for celiac disease and autoimmune diabetes and risk of infections in early childhood. J Pediatr Gastroenterol Nutr 2024; 78:295-303. [PMID: 38374560 DOI: 10.1002/jpn3.12078] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/28/2023] [Accepted: 11/28/2023] [Indexed: 02/21/2024]
Abstract
OBJECTIVES Infections in early childhood have been associated with risk of celiac disease (CD) and type 1 diabetes (T1D). We investigated whether this is driven by susceptibility genes for autoimmune disease by comparing infection frequency by genetic susceptibility variants for CD or T1D. METHODS We genotyped 373 controls and 384 children who developed CD or T1D in the population-based Norwegian Mother, Father and Child Cohort study (MoBa) study for human leukocyte antigen (HLA)-DQ, FUT2, SH2B3, and PTPN22, and calculated a weighted non-HLA genetic risk score (GRS) for CD and T1D based on over 40 SNPs. Parents reported infections in questionnaires when children were 6 and 18 months old. We used negative binomial regression to estimate incidence rate ratio (IRR) for infections by genotype. RESULTS HLA genotypes for CD and T1D or non-HLA GRS for T1D were not associated with infections. The non-HLA GRS for CD was associated with a nonsignificantly lower frequency of infections (aIRR: 0.95, 95% CI: 0.87-1.03 per weighted allele score), and significantly so when restricting to healthy controls (aIRR: 0.89, 0.81-0.99). Participants homozygous for rs601338(A;A) at FUT2, often referred to as nonsecretors, had a nonsignificantly lower risk of infections (aIRR: 0.91, 95% CI: 0.83-1.01). SH2B3 and PTPN22 genotypes were not associated with infections. The association between infections and risk of CD (OR: 1.15 per five infections) was strengthened after adjustment for HLA genotype and non-HLA GRS (OR: 1.24). CONCLUSIONS HLA variants and non-HLA GRS conferring susceptibility for CD were not associated with increased risk of infections in early childhood and is unlikely to drive the observed association between infections and risk of CD or T1D in many studies.
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Affiliation(s)
- Ketil Størdal
- Department of Pediatric Research, Faculty of Medicine, University of Oslo, Oslo, Norway
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - German Tapia
- Norwegian Institute of Public Health, Oslo, Norway
| | | | - Lars C Stene
- Norwegian Institute of Public Health, Oslo, Norway
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Stahl M, Koletzko S, Andrén Aronsson C, Lindfors K, Liu E, Agardh D. Coeliac disease: what can we learn from prospective studies about disease risk? THE LANCET. CHILD & ADOLESCENT HEALTH 2024; 8:63-74. [PMID: 37972632 PMCID: PMC10965251 DOI: 10.1016/s2352-4642(23)00232-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 11/19/2023]
Abstract
Paediatric prospective studies of coeliac disease with longitudinal collection of biological samples and clinical data offer a unique perspective on disease risk. This Review highlights the information now available from international paediatric prospective studies on genetic and environmental risk factors for coeliac disease. In addition, recent omics studies have made it possible to study complex interactions between genetic and environmental factors and thereby further our insight into the causes of the disease. In the future, paediatric prospective studies will be able to provide more detailed risk prediction models combining genes, the environment, and biological corroboration from multiomics. Such studies could also contribute to biomarker development and an improved understanding of disease pathogenesis.
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Affiliation(s)
- Marisa Stahl
- Pediatric Gastroenterology, Hepatology, and Nutrition, Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Sibylle Koletzko
- Department of Pediatrics, Dr von Hauner Kinderspital, LMU University Hospital, LMU Munich, Munich, Germany; Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Carin Andrén Aronsson
- Unit of Celiac Disease and Diabetes, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Edwin Liu
- Pediatric Gastroenterology, Hepatology, and Nutrition, Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Daniel Agardh
- Unit of Celiac Disease and Diabetes, Department of Clinical Sciences, Lund University, Malmö, Sweden
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Crawley C, Sander SD, Nohr EA, Nybo Andersen AM, Husby S. Early environmental risk factors and coeliac disease in adolescents: a population-based cohort study in Denmark. BMJ Open 2023; 13:e061006. [PMID: 38011980 PMCID: PMC10685961 DOI: 10.1136/bmjopen-2022-061006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 10/19/2023] [Indexed: 11/29/2023] Open
Abstract
OBJECTIVES Our aim was to investigate the association between early environmental factors and the development of coeliac disease (CeD) in adolescents, recruited from a cohort nested in the Danish National Birth Cohort (DNBC). DESIGN The study was designed as a prospective cohort study, nested in DNBC PARTICIPANTS: The Glutenfunen cohort comprises 1266 participants, nested in DNBC. All participants were screened for CeD, and in total, 28 cases of biopsy proven CeD were identified. Data about breastfeeding, timing of introduction to solid food in infancy, use of antibiotics, infections and symptoms were parentally reported prospectively at 6 months and 18 months, respectively. We estimated ORs and 95% CIs of CeD in adolescents using logistic regression analysis. RESULTS Viral croup reported at 18 months of age was associated with CeD in adolescents with an OR of 3.2 (95% CI: 1.2 to 8.7). Furthermore, otitis media also reported at 18 months of age was linked with CeD with an OR of 3.2 (95% CI: 1.5 to 7.3). We were not able to find any statistical associations between CeD and breastfeeding, frequency of infections, parentally reported use of antibiotic and timing of solid foods. CONCLUSION In this study, we present an overview of the relationship between early environmental factors and occurrence of CeD in adolescents. Our findings, despite limitations due to a limited number of cases of CeD, suggest a role of viral infections in the pathogenesis of CeD.
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Affiliation(s)
- Cæcilie Crawley
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Hans Christian Anderson Children's Hospital, Odense University Hospital, Odense, Denmark
| | | | - Ellen Aagaard Nohr
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Research Unit of Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark
| | | | - Steffen Husby
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Hans Christian Anderson Children's Hospital, Odense University Hospital, Odense, Denmark
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Cohen R, Mahlab-Guri K, Atali M, Elbirt D. Viruses and celiac disease: what do we know ? Clin Exp Med 2023; 23:2931-2939. [PMID: 37103650 PMCID: PMC10134706 DOI: 10.1007/s10238-023-01070-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/05/2023] [Indexed: 04/28/2023]
Abstract
The aim of this review is to provide a comprehensive overview about the link between viruses and celiac disease. A systematic search on PubMed, Embase, and Scopus was conducted on March 07, 2023. The reviewers independently selected the articles and chose which articles to include. The review is a textual systemic review, and all relevant articles were included based on title and abstract. If there was a disagreement between the reviewers, they came to a consensus during deliberation sessions. A total of 178 articles were selected for the review and read in full; only part of them was retained. We found studies between celiac disease and 12 different viruses. Some of the studies were done only on small groups. Most studies were on pediatric population. Evidence for an association was found with several viruses (trigger or protective). It seems that only a part of the viruses could induce the disease. Several points are important to keep in mind: firstly, simple mimicry or that the virus induces a high level of TGA is not sufficient to promote the disease. Secondly, inflammatory background is necessary to induce CD with virus. Thirdly, IFN type 1 seems to have an important role. Some of the viruses are potential or known triggers like enteroviruses, rotaviruses, reoviruses, and influenza. Further studies are needed to better understand the role of viruses in celiac disease to better treat and prevent the disease.
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Affiliation(s)
- Ramon Cohen
- Internal Department B, Kaplan Medical Center, Rehovot, Israel.
- Department of Clinical Immunology Allergy and AIDS, Kaplan Medical Center, Rehovot, Israel.
| | - Keren Mahlab-Guri
- Department of Clinical Immunology Allergy and AIDS, Kaplan Medical Center, Rehovot, Israel
| | - Malka Atali
- Internal Department B, Kaplan Medical Center, Rehovot, Israel
| | - Daniel Elbirt
- Department of Clinical Immunology Allergy and AIDS, Kaplan Medical Center, Rehovot, Israel
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Wu Y, Pei S, Wu J, Tu X, Ren L, Ji Y, Yao Y, Liu Y. The Abnormal Accumulation of Lipopolysaccharide Secreted by Enriched Gram-Negative Bacteria Increases the Risk of Rotavirus Colonization in Young Adults. Microorganisms 2023; 11:2280. [PMID: 37764124 PMCID: PMC10535061 DOI: 10.3390/microorganisms11092280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/03/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Human rotavirus (HRV) is an enteric virus that causes infantile diarrhea. However, the risk factors contributing to HRV colonization in young adults have not been thoroughly investigated. Here, we compared the differences in dietary habits and composition of gut microbiota between asymptomatic HRV-infected young adults and their healthy counterparts and investigated potential risk factors contributing to HRV colonization. Our results indicated that asymptomatic HRV-infected adults had an excessive intake of milk and dairy and high levels of veterinary antibiotics (VAs) and preferred veterinary antibiotic (PVAs) residues in urine samples. Their gut microbiota is characterized by abundant Gram-negative (G-) bacteria and high concentrations of lipopolysaccharide (LPS). Several opportunistic pathogens provide discriminatory power to asymptomatic, HRV-infected adults. Finally, we observed an association between HRV colonization and disrupted gut microbiota caused by the exposure to VAs and PVAs. Our study reveals the traits of disrupted gut microbiota in asymptomatic HRV-infected adults and provides a potential avenue for gut microbiota-based prevention strategies for HRV colonization.
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Affiliation(s)
- Yifan Wu
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
| | - Shuang Pei
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
| | - Jie Wu
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
| | - Xinru Tu
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
| | - Lingling Ren
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
| | - Yanli Ji
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
| | - Yuyou Yao
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
| | - Yehao Liu
- Department of Hygiene Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei 230000, China
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Chang D, O’Shea D, Therrien A, Silvester JA. Review article: Becoming and being coeliac-special considerations for childhood, adolescence and beyond. Aliment Pharmacol Ther 2022; 56 Suppl 1:S73-S85. [PMID: 35815825 PMCID: PMC9441244 DOI: 10.1111/apt.16851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/10/2022] [Accepted: 02/13/2022] [Indexed: 12/09/2022]
Abstract
Classically considered a disease of early childhood characterised by malabsorption and failure to thrive, coeliac disease is now recognised to arise in genetically susceptible individuals at any age. Although permissive HLA genotypes are the strongest predictor of coeliac disease, they are not sufficient. Several prospective cohort studies enrolling genetically at-risk infants have investigated the role of potential triggers of coeliac disease autoimmunity, such as timing of gluten introduction, viral infections and dietary patterns. Much less is known about triggers of coeliac disease in adulthood. Better understanding of factors leading to coeliac disease may be helpful in the management of those with potential coeliac disease (elevated serum celiac antibodies without villous atrophy in the small intestine), many of whom initiate a gluten-free diet without demonstration of villous atrophy. There are a range of clinical presentations of celiac disease in childhood and patterns of coeliac serology, including fluctuation and spontaneous reversion on a gluten-containing diet, vary. There is a current debate over best strategies to manage adults and children with potential coeliac disease to avoid over-treatment and under-treatment. Childhood and adolescence carry unique issues pertaining to the diagnosis and management of coeliac disease, and include nutrition and growth, rescreening, repeat biopsy, dietary adherence concerns and transition to adult care. In conclusion, while coeliac disease has similar pathogenesis and general clinical manifestations in paediatric and adult populations, diagnostic and management approaches need to adapt to the developmental stages.
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Affiliation(s)
- Denis Chang
- 1. Boston Children’s Hospital, Boston, MA,2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA
| | - Delia O’Shea
- 1. Boston Children’s Hospital, Boston, MA,2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA
| | - Amelie Therrien
- 2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA,3. Beth Israel Deaconess Medical Center, Boston, MA
| | - Jocelyn A Silvester
- 1. Boston Children’s Hospital, Boston, MA,2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA,3. Beth Israel Deaconess Medical Center, Boston, MA
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11
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Amundsen SF, Stamnaes J, du Pré MF, Sollid LM. Transglutaminase 2 affinity and enzyme-substrate intermediate stability as determining factors for T-cell responses to gluten peptides in celiac disease. Eur J Immunol 2022; 52:1474-1481. [PMID: 35715890 PMCID: PMC9545004 DOI: 10.1002/eji.202249862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/06/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022]
Abstract
The adaptive immune response of celiac disease (CeD) involves presentation of gluten peptides to CD4+ T cells by transglutaminase 2 (TG2) specific B cells. This B‐cell/T‐cell crosstalk is facilitated by involvement of TG2:gluten peptide complexes that act principally in the form of enzyme‐substrate intermediates. Here, we have addressed how gluten peptide affinity and complex stability in the presence of secondary substrates affect the uptake of TG2:gluten peptide complexes by TG2‐specific B cells and the activation of gluten‐specific T cells. We studied affinity of various gluten peptides for TG2 by biochemical assay, and monitored uptake of gluten peptides by TG2‐specific B cells by flow cytometry. Crosstalk between TG2‐specific B cells and gluten‐specific T cells was assayed with transfectants expressing antigen receptors derived from CeD patients. We found that gluten peptides with high TG2 affinity showed better uptake by TG2‐specific B cells. Uptake by B cells, and subsequent activation of T cells, was negatively affected by polyamines acting as secondary TG2 substrates. These results show that affinity between gluten peptide and TG2 governs the selection of T‐cell epitopes via enhanced uptake of TG2:gluten complexes by TG2‐specific B cells, and that exogenous polyamines can influence the CeD immune responses by disrupting TG2:gluten complexes.
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Affiliation(s)
- Sunniva F Amundsen
- KG Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jorunn Stamnaes
- KG Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marie Fleur du Pré
- KG Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department Immunology, Oslo University Hospital, Oslo, Norway
| | - Ludvig M Sollid
- KG Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department Immunology, Oslo University Hospital, Oslo, Norway
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12
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Singh A, Kaur H, Midha V, Sood A. Microorganisms in the Pathogenesis and Management of Celiac Disease (CeD). ROLE OF MICROORGANISMS IN PATHOGENESIS AND MANAGEMENT OF AUTOIMMUNE DISEASES 2022:287-307. [DOI: 10.1007/978-981-19-4800-8_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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13
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Airaksinen L, Cerqueira JXM, Huhtala H, Saavalainen P, Yohannes DA, Mäki M, Kurppa K, Kilpeläinen E, Shcherban A, Palotie A, Kaukinen K, Lindfors K. Dissecting the contribution of single nucleotide polymorphisms in CCR9 and CCL25 genomic regions to the celiac disease phenotype. J Transl Autoimmun 2021; 4:100128. [PMID: 34901814 PMCID: PMC8640869 DOI: 10.1016/j.jtauto.2021.100128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/02/2021] [Accepted: 10/13/2021] [Indexed: 11/30/2022] Open
Abstract
PURPOSE AND OBJECTIVES Given their role in homing immune cells to the intestine, CC motif chemokine receptor 9 (CCR9) and its specific ligand CC motif chemokine ligand 25 (CCL25) are interesting candidate genes for celiac disease. These genes are located in regions previously shown to be associated with or linked to celiac disease, but no investigations on their association with various celiac disease phenotypes have so far been conducted. Here we studied such associations of both genotyped and imputed single nucleotide polymorphisms (SNPs) with either regulatory function or exonic location of the CCR9 and CCL25 loci. RESULTS Exploiting a carefully phenotyped cohort of 625 celiac disease patients and 1817 non-celiac controls, we identified that multiple SNPs with predicted regulatory function (RegulomeDB score ≤3a and/or eQTL effect) located between 100 kB upstream and downstream of CCR9 and CCL25 are associated with celiac disease and/or selected phenotypes. Of the genotyped SNPs in the CCR9 loci, rs213360 with an eQTL effect on CCR9 expression in blood was associated with celiac disease and all investigated phenotypes except high HLA risk. Rs1545985 with an eQTL on CCR9 expression and rs7652331 and rs12493471, both with RegulomeDB score ≤3a, were all associated with gastrointestinal symptoms and malabsorption and the latter additionally with anemia. The genotyped CCL25 SNPs rs952444 and rs882951, with RegulomeDB scores 1d and 1f respectively and eQTL effect on CCL25 expression in small intestine, were associated with gastrointestinal symptoms and malabsorption. The CCL25 SNP rs2303165 identified in sequencing followed by imputation was associated with partial villous atrophy. However, the association did not pass the permutation based multiple testing correction (PEMP2 > 0.05). CONCLUSIONS We conclude that SNPs in the region of CCR9 and CCL25 with predicted functional effect or exonic localization likely contribute only modestly to various celiac disease phenotypes.
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Key Words
- CCL25, CC motif chemokine ligand 25
- CCR9, CC motif chemokine receptor 9
- CI, confidence interval
- Celiac disease
- Chemokine receptor
- Clinical picture
- FUMA, Functional Mapping and Annotation of GWAS
- GWAS, genome-wide association study
- Genetic association
- Genetic variation
- HLA, human leukocyte antigen
- HWE, Hardy-Weinberg equilibrium
- MAF, minor allele frequency
- OR, odds ratio
- PBMC, peripheral blood mononuclear cell
- QC, quality control
- SNP, single nucleotide polymorphism
- TG2, transglutaminase 2
- eQTL, expression quantitative trait loci
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Affiliation(s)
- Laura Airaksinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Juliana XM. Cerqueira
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Päivi Saavalainen
- Translational Immunology Research Program, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Dawit A. Yohannes
- Translational Immunology Research Program, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Markku Mäki
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University, and Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University, and Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- University Consortium of Seinäjoki, Seinäjoki, Finland
| | - Elina Kilpeläinen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Anastasia Shcherban
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Analytic and Translational Genetics Unit, Department of Medicine, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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14
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Wang M, Yu M, Kong WJ, Cui M, Gao F. Association between intestinal neoplasms and celiac disease: A review. World J Gastrointest Oncol 2021; 13:1017-1028. [PMID: 34616509 PMCID: PMC8465454 DOI: 10.4251/wjgo.v13.i9.1017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/02/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
Celiac disease (CD) is a chronic immune-mediated intestinal disease with genetic susceptibility. It is characterized by inflammatory damage to the small intestine after ingestion of cereals and products containing gluten protein. In recent years, the global prevalence rate of CD has been approximately 1%, and is gradually increasing. CD patients adhere to a gluten-free diet (GFD) throughout their entire life. However, it is difficult to adhere strictly to a GFD. Untreated CD may be accompanied by gastrointestinal symptoms, such as diarrhea, abdominal pain, and extraintestinal symptoms caused by secondary malnutrition. Many studies have suggested that CD is associated with intestinal tumors such as enteropathy-associated T-cell lymphoma (EATL), small bowel cancer (SBC), and colorectal cancer. In this study, we reviewed related studies published in the literature to provide a reference for the prevention and treatment of intestinal tumors in patients with CD. Compared with the general population, CD patients had a high total risk of SBC and EATL, but not colorectal cancer. The protective effect of GFD on CD-related malignancies is controversial. Further studies are needed to confirm whether GFD treatment can reduce the risk of intestinal neoplasms in CD.
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Affiliation(s)
- Man Wang
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
| | - Ming Yu
- Department of General Practice, Xiangyang Central Hospital, The Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021 Hubei Province, China
| | - Wen-Jie Kong
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
| | - Mei Cui
- Department of Pathology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
| | - Feng Gao
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
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15
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Rueda-Robles A, Rubio-Tomás T, Plaza-Diaz J, Álvarez-Mercado AI. Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review. Pathogens 2021; 10:875. [PMID: 34358024 PMCID: PMC8308520 DOI: 10.3390/pathogens10070875] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the stomach and can induce gastric disease and intra-gastric lesions, including chronic gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This bacterium is responsible for long-term complications of gastric disease. The conjunction of host genetics, immune response, bacterial virulence expression, diet, micronutrient availability, and microbiome structure influence the disease outcomes related to chronic H. pylori infection. In this regard, the consumption of unhealthy and unbalanced diets can induce microbial dysbiosis, which infection with H. pylori may contribute to. However, to date, clinical trials have reported controversial results and current knowledge in this field is inconclusive. Here, we review preclinical studies concerning the changes produced in the microbiota that may be related to H. pylori infection, as well as the involvement of diet. We summarize and discuss the last approaches based on the modulation of the microbiota to improve the negative impact of H. pylori infection and their potential translation from bench to bedside.
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Affiliation(s)
- Ascensión Rueda-Robles
- Center of Biomedical Research, Institute of Nutrition and Food Technology “José Mataix”, University of Granada, Avda. del Conocimiento s/n., Armilla, 18016 Granada, Spain;
| | - Teresa Rubio-Tomás
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
- School of Medicine, University of Crete, 70013 Heraklion, Crete, Greece
| | - Julio Plaza-Diaz
- Children’s Hospital Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada;
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Ana I. Álvarez-Mercado
- Center of Biomedical Research, Institute of Nutrition and Food Technology “José Mataix”, University of Granada, Avda. del Conocimiento s/n., Armilla, 18016 Granada, Spain;
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
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16
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Oikarinen M, Puustinen L, Lehtonen J, Hakola L, Simell S, Toppari J, Ilonen J, Veijola R, Virtanen SM, Knip M, Hyöty H. Enterovirus Infections Are Associated With the Development of Celiac Disease in a Birth Cohort Study. Front Immunol 2021; 11:604529. [PMID: 33603739 PMCID: PMC7884453 DOI: 10.3389/fimmu.2020.604529] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/23/2020] [Indexed: 11/13/2022] Open
Abstract
Enterovirus and adenovirus infections have been linked to the development of celiac disease. We evaluated this association in children who developed biopsy-proven celiac disease (N = 41) during prospective observation starting from birth, and in control children (N = 53) matched for the calendar time of birth, sex, and HLA-DQ genotype. Enterovirus and adenovirus infections were diagnosed by seroconversions in virus antibodies in longitudinally collected sera using EIA. Enterovirus infections were more frequent in case children before the appearance of celiac disease-associated tissue transglutaminase autoantibodies compared to the corresponding period in control children (OR 6.3, 95% CI 1.8-22.3; p = 0.005). No difference was observed in the frequency of adenovirus infections. The findings suggest that enterovirus infections may contribute to the process leading to celiac disease.
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Affiliation(s)
- Maarit Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Leena Puustinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Jussi Lehtonen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Leena Hakola
- Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.,Research, Development and Innovation Center, Tampere University Hospital, Tampere, Finland
| | - Satu Simell
- Department of Paediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland
| | - Jorma Toppari
- Department of Paediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland.,Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Riitta Veijola
- PEDEGO Research Unit, Medical Research Centre, Department of Paediatrics, University of Oulu, Oulu, Finland.,Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Suvi M Virtanen
- Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.,Research, Development and Innovation Center, Tampere University Hospital, Tampere, Finland.,Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland.,Center for Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
| | - Mikael Knip
- Center for Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland.,Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
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