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Celiac Disease: HELP
Articles by Daniel J. Agardh
Based on 47 articles published since 2010
(Why 47 articles?)
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Between 2010 and 2020, D. Agardh wrote the following 47 articles about Celiac Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Gluten in infants and celiac disease risk. 2016

Andrén Aronsson, Carin / Kurppa, Kalle / Agardh, Daniel. ·a Department of Clinical Sciences , Lund University , Malmö , Sweden. · b Centre for Child Health Research , University of Tampere University Hospital , Tampere , Finland. ·Expert Rev Gastroenterol Hepatol · Pubmed #27027529.

ABSTRACT: -- No abstract --

2 Review Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies. 2018

Tye-Din, Jason A / Galipeau, Heather J / Agardh, Daniel. ·Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia. · Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. · Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia. · Centre for Food & Allergy Research, Murdoch Children's Research Institute, Parkville, VIC, Australia. · Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden. · Unit of Endocrinology and Gastroenterology, Department of Pediatrics, Skåne University Hospital, Malmö, Sweden. ·Front Pediatr · Pubmed #30519552.

ABSTRACT: Our understanding of celiac disease and how it develops has evolved significantly over the last half century. Although traditionally viewed as a pediatric illness characterized by malabsorption, it is now better seen as an immune illness with systemic manifestations affecting all ages. Population studies reveal this global disease is common and, in many countries, increasing in prevalence. These studies underscore the importance of specific HLA susceptibility genes and gluten consumption in disease development and suggest that other genetic and environmental factors could also play a role. The emerging data on viral and bacterial microbe-host interactions and their alterations in celiac disease provides a plausible mechanism linking environmental risk and disease development. Although the inflammatory lesion of celiac disease is complex, the strong HLA association highlights a central role for pathogenic T cells responding to select gluten peptides that have now been defined for the most common genetic form of celiac disease. What remains less understood is how loss of tolerance to gluten occurs. New insights into celiac disease are now providing opportunities to intervene in its development, course, diagnosis, and treatment.

3 Review Coeliac disease in children with type 1 diabetes. 2018

Kurppa, Kalle / Laitinen, Anna / Agardh, Daniel. ·Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland. Electronic address: kalle.kurppa@uta.fi. · Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland. · Unit of Diabetes and Celiac Disease, Lund University, Malmö, Sweden. ·Lancet Child Adolesc Health · Pubmed #30169235.

ABSTRACT: Coeliac disease and type 1 diabetes are the most common paediatric autoimmune disorders. Both conditions have increasing incidence and can often coexist in a patient. The diseases share many genetic and immunological features, but diagnostic and treatment approaches vary substantially worldwide. Because of the often subtle presentation of coeliac disease in children with type 1 diabetes, many are diagnosed only upon screening for coeliac disease. In this Review, we summarise approaches to diagnosis and treatment of children with type 1 diabetes and coeliac disease, with a specific emphasis on those with a double diagnosis. In particular, we examine the pros and cons of screening for coeliac disease and assess the challenges of dietary treatment in children with coexisting type 1 diabetes, which can already be a burden. Furthermore, we present the latest research on the shared genetic and pathogenic mechanisms and introduce some future perspectives.

4 Review [Celiac disease is a common illness that is easy to miss]. 2014

Browaldh, Lars / Sandström, Olof / Agardh, Daniel / Stenhammar, Lars / Ivarsson, Anneli. · ·Lakartidningen · Pubmed #24720024.

ABSTRACT: -- No abstract --

5 Clinical Trial Different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. 2017

Alshiekh, S / Zhao, L P / Lernmark, Å / Geraghty, D E / Naluai, Å T / Agardh, D. ·Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden. · Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Waltham. · Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Waltham. · Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. ·HLA · Pubmed #28585303.

ABSTRACT: Celiac disease is associated with the HLA-DR3-DQA1*05:01-DQB1*02:01 and DR4-DQA1*03:01-DQB1*03:02 haplotypes. In addition, there are currently over 40 non-HLA loci associated with celiac disease. This study extends previous analyses on different HLA haplotypes in celiac disease using next generation targeted sequencing. Included were 143 patients with celiac disease and 135 non-celiac disease controls investigated at median 9.8 years (1.4-18.3 years). PCR-based amplification of HLA and sequencing with Illumina MiSeq technology were used for extended sequencing of the HLA class II haplotypes HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1, respectively. Odds ratios were computed marginally for every allele and haplotype as the ratio of allelic frequency in patients and controls as ratio of exposure rates (RR), when comparing a null reference with equal exposure rates in cases and controls. Among the extended HLA haplotypes, the strongest risk haplotype for celiac disease was shown for DRB3*01:01:02 in linkage with DQA1*05:01-DQB1*02:01 (RR = 6.34; P-value < .0001). In a subpopulation analysis, DRB3*01:01:02-DQA1*05:01-DQB1*02:01 remained the most significant in patients with Scandinavian ethnicity (RR = 4.63; P < .0001) whereas DRB1*07:01:01-DRB4*01:03:01-DQA1*02:01-DQB1*02:02:01 presented the highest risk of celiac disease among non-Scandinavians (RR = 7.94; P = .011). The data also revealed 2 distinct celiac disease risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either the DRB3*01:01:02 or DRB3*02:02:01 alleles, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. The associated risk of celiac disease for DR3-DRB3*01:01:02-DQA1*05:01-DQB1*02:01 is predominant among patients of Scandinavian ethnicity.

6 Clinical Trial Serum cytokine pattern in young children with screening detected coeliac disease. 2015

Björck, S / Lindehammer, S R / Fex, M / Agardh, D. ·Department of Pediatrics, Skåne University Hospital, Malmö, Sweden; Unit of Diabetes and Celiac Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden. ·Clin Exp Immunol · Pubmed #25212572.

ABSTRACT: Coeliac disease is an autoimmune disease characterized by inflammation localized to the small bowel, but less is known about systemic signs of inflammation. The aim was to measure cytokines of the T helper 1 (Th1) and T helper 2 (Th2) cell patterns in children with screening-detected coeliac disease before and after treatment with a gluten-free diet. Serum samples selected before and after the start of a gluten-free diet from 26 3-year-old children diagnosed with biopsy-proven coeliac disease and from 52 matched controls were assayed in an multiplex enzyme-linked immunosorbent assay (ELISA) for the 10 cytokines: interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13 and tumour necrosis factor (TNF)-α. Among Th1 cytokines, IFN-γ and IL-12p70 were elevated significantly in children with coeliac disease compared to controls (P < 0.001 and P = 0.001, respectively). Similar findings were demonstrated for the Th2 cytokines IL-5 (P < 0.001), IL-10 (P = 0.001) and IL-13 (P = 0.002). No difference in cytokine levels between the two groups was found for TNF-α, IL-1β, IL-2, IL-4 and IL-8. After gluten-free diet, levels of IL-5, IL-12 and IL-10 decreased significantly (P < 0.001, P = 0.002 and P = 0.007) and IFN-γ levels were reduced (P = 0.059). Young children with coeliac disease detected by screening demonstrate elevated levels of serum cytokines at time of diagnosis. A prolonged systemic inflammation may, in turn, contribute to long-term complications known to be associated with untreated coeliac disease.

7 Article Antibodies against neo-epitope of microbial and human transglutaminase complexes as biomarkers of childhood celiac disease. 2020

Agardh, D / Matthias, T / Wusterhausen, P / Neidhöfer, S / Heller, A / Lerner, A. ·Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden. · Department of Pediatrics, Skåne University Hospital, Malmö, Sweden. · AESKU.KIPP Institute, Wendelsheim, Germany. ·Clin Exp Immunol · Pubmed #31663117.

ABSTRACT: Tissue transglutaminase (tTG) and microbial transglutaminase (mTG) cross-link gliadins to form complexes that expose immunogenic neo-epitopes to produce tTG and mTG-neo-epitope antibodies. The aim of this study was to test the diagnostic performance of antibodies against non-complexed and complexed forms of transglutaminases, to correlate their activities to the intestinal damage and to explore age group dependency in celiac disease (CD). A total of 296 children with untreated CD and 215 non-celiac disease controls were checked by in-house enzyme-linked immunosorbent assays detecting immunoglobulin (Ig)A, IgG or combined detection of IgA and IgG (check) against tTG, AESKULISA

8 Article Further Support for Psychological Symptoms in Pediatric Celiac Disease. 2019

Smith, Laura B / Kurppa, Kalle / Agardh, Daniel. ·University of South Florida Diabetes Center, Health Informatics Institute, and Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, Florida; lsmith5@health.usf.edu. · Department of Paediatrics, Center for Child Health Research, Tampere University Hospital, Tampere, Finland; and. · Unit of Diabetes and Celiac Disease, Malmö University, Malmö, Sweden. ·Pediatrics · Pubmed #31492764.

ABSTRACT: -- No abstract --

9 Article Effects of 2019

Håkansson, Åsa / Andrén Aronsson, Carin / Brundin, Charlotte / Oscarsson, Elin / Molin, Göran / Agardh, Daniel. ·Department of Food Technology Engineering and Nutrition, Lund University, Box 124, 22100 Lund, Sweden. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, 21428 Malmö, Sweden. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, 21428 Malmö, Sweden. daniel.agardh@med.lu.se. ·Nutrients · Pubmed #31426299.

ABSTRACT: Two

10 Article Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk. 2019

Andrén Aronsson, Carin / Lee, Hye-Seung / Hård Af Segerstad, Elin M / Uusitalo, Ulla / Yang, Jimin / Koletzko, Sibylle / Liu, Edwin / Kurppa, Kalle / Bingley, Polly J / Toppari, Jorma / Ziegler, Anette G / She, Jin-Xiong / Hagopian, William A / Rewers, Marian / Akolkar, Beena / Krischer, Jeffrey P / Virtanen, Suvi M / Norris, Jill M / Agardh, Daniel / Anonymous2931083. ·Department of Clinical Sciences, Lund University, Malmö, Sweden. · Health Informatics Institute, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa. · Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany. · University of Warmia and Mazuri, Olsztyn, Poland. · Digestive Health Institute, University of Colorado Denver, Children's Hospital Colorado, Denver. · Tampere Centre for Child Health Research, University of Tampere, Tampere University Hospital, Tampere, Finland. · School of Clinical Sciences, University of Bristol, Bristol, England. · Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland. · Department of Pediatrics, Turku University Hospital, Turku, Finland. · Institute of Diabetes Research, Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes eV, Neuherberg, Germany. · Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, Georgia. · Pacific Northwest Diabetes Research Institute, Seattle, Washington. · Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora. · National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. · National Institute for Health and Welfare, Department of Public Health Solutions, Helsinki, Finland. · Faculty of Social Sciences/Health Sciences, University of Tampere, Tampere, Finland. · Research Center for Child Health, Tampere University, University Hospital, Science Center of Pirkanmaa Hospital District, Tampere, Finland. · Colorado School of Public Health, Department of Epidemiology, University of Colorado, Aurora. ·JAMA · Pubmed #31408136.

ABSTRACT: Importance: High gluten intake during childhood may confer risk of celiac disease. Objectives: To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. Design, Setting, and Participants: The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. Exposures: Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. Main Outcomes and Measures: The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. Results: Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). Conclusions and Relevance: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.

11 Article Early Probiotic Supplementation and the Risk of Celiac Disease in Children at Genetic Risk. 2019

Uusitalo, Ulla / Andren Aronsson, Carin / Liu, Xiang / Kurppa, Kalle / Yang, Jimin / Liu, Edwin / Skidmore, Jennifer / Winkler, Christiane / Rewers, Marian J / Hagopian, William A / She, Jin-Xiong / Toppari, Jorma / Ziegler, Anette-G / Akolkar, Beena / Norris, Jill M / Virtanen, Suvi M / Krischer, Jeffrey P / Agardh, Daniel / Anonymous1141059. ·Health Informatics Institute, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA. ulla.uusitalo@epi.usf.edu. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, 214 28 Malmö, Sweden. · Health Informatics Institute, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA. · Tampere Center for Child Health Research, University of Tampere, 33014 Tampere, Finland. · The University Consortium of Seinäjoki, 60320 Seinäjoki, Finland. · Digestive Health Institute, Children's Hospital Colorado, University of Colorado Denver, Aurora, CO 80045, USA. · Pacific Northwest Research Institute, Seattle, WA 98122, USA. · Institute of Diabetes Research, Helmholtz Zentrum München, 85764 Munich-Neuherberg, Germany. · Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, 80804 Munich, Germany. · Forschergruppe Diabetes e.V., Helmholtz Zentrum München, 85764 Munich-Neuherberg, Germany. · Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA. · Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. · Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, 20014 Turku, Finland. · Department of Pediatrics, Turku University Hospital, 20521 Turku, Finland. · NIDDK, National Institute of Health, Bethesda, MD 20892, USA. · Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO 80045, USA. · Unit of Nutrition, National Institute for Health and Welfare, 00271 Helsinki, Finland. · Tampere University Hospital, and the Science Center of Pirkanmaa Hospital District, 33520 Tampere, Finland. ·Nutrients · Pubmed #31382440.

ABSTRACT: Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (

12 Article Dietitian visits were a safe and cost-effective form of follow-up care for children with celiac disease. 2019

Johansson, Karolina / Malmberg Hård Af Segerstad, Elin / Mårtensson, Helena / Agardh, Daniel. ·Pediatric Gastroenterology Unit, Department of Pediatrics, Skåne University Hospital, SUS, Malmö, Sweden. · Department of Clinical Sciences, Diabetes and Celiac Disease Unit, Lund University, Malmö, Sweden. ·Acta Paediatr · Pubmed #29782665.

ABSTRACT: AIM: This study compared follow-up protocols for paediatric celiac disease (CD) led by either paediatricians or dietitians at Swedish university hospitals. METHODS: We followed 363 CD patients under 18 years at the university hospitals in Malmö (n = 140) and Lund (n = 79) between 2011 and 2013 and after they merged to become Skåne (n = 144) between 2014 and 2016. Both Lund and Malmö provided regular paediatrician follow-up visits, whereas Skåne provided mainly dietitian-led visits. RESULTS: Children at Lund were followed for a mean of 1.0 ± 0.5 visits per year, compared to 0.7 ± 0.6 at Malmö (p < 0.0001) and 0.9 ± 0.6 at Skåne (p = 0.11). The ratio of annual paediatrician to dietitian annual visits was 1.4:1.0 at Lund, which was higher than Malmö (0.9:1.0; p = 0.0017) and Skåne (0.6:1.0; p < 0.0001). There was no difference in the prevalence of non-compliant patients between the clinics (p = 0.26, Malmö 13.6%, Lund 10.1%, Skåne 7.6%). Tissue transglutaminase autoantibody levels reversed equally over time at all three clinics after the subjects started a gluten-free diet (r = -0.55, p < 0.0001). The total mean annual cost per patient was lowest at Malmö and highest at Lund (p < 0.0001). CONCLUSION: Dietary compliance was similar regardless of whether care was provided by a dietitian or paediatrician. Dietitian-led follow-up visits may provide lower long-term costs.

13 Article Daily Intake of Milk Powder and Risk of Celiac Disease in Early Childhood: A Nested Case-Control Study. 2018

Hård Af Segerstad, Elin M / Lee, Hye-Seung / Andrén Aronsson, Carin / Yang, Jimin / Uusitalo, Ulla / Sjöholm, Ingegerd / Rayner, Marilyn / Kurppa, Kalle / Virtanen, Suvi M / Norris, Jill M / Agardh, Daniel / Anonymous2700945. ·The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, 202 05 Malmö, Sweden. elin.malmberg_hard_af_segerstad@med.lu.se. · Health Informatics Institute, Morsani College of Medicine, University of South Florida, 33620 FL Tampa, USA. hye-seung.lee@epi.usf.edu. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, 202 05 Malmö, Sweden. carin.andren_aronsson@med.lu.se. · Health Informatics Institute, Morsani College of Medicine, University of South Florida, 33620 FL Tampa, USA. jimin.yang@epi.usf.edu. · Health Informatics Institute, Morsani College of Medicine, University of South Florida, 33620 FL Tampa, USA. ulla.uusitalo@epi.usf.edu. · Department of Food Technology, Engineering and Nutrition, Chemical Center, Lund University, 221 00 Lund, Sweden. ingegerd.sjoholm@food.lth.se. · Department of Food Technology, Engineering and Nutrition, Chemical Center, Lund University, 221 00 Lund, Sweden. marilyn.rayner@food.lth.se. · Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33521 Tampere, Finland. kalle.kurppa@uta.fi. · Unit of Nutrition, National Institute for Health and Welfare, 00271 Helsinki, Finland; Faculty of Social Sciences, University of Tampere, Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital and the Science Center of Pirkanmaa Hospital District Tampere, 33521 Tampere, Finland. suvi.virtanen@thi.fi. · Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, 80045 CO Aurora, USA. jill.norris@ucdenver.edu. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, 202 05 Malmö, Sweden. daniel.agardh@med.lu.se. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, 202 05 Malmö, Sweden. ·Nutrients · Pubmed #29710789.

ABSTRACT: Milk powder and gluten are common components in Swedish infants' diets. Whereas large intakes of gluten early in life increases the risk of celiac disease in genetically at-risk Swedish children, no study has yet evaluated if intake of milk powder by 2 years of age is associated with celiac disease. A 1-to-3 nested case-control study, comprised of 207 celiac disease children and 621 controls matched for sex, birth year, and HLA genotype, was performed on a birth cohort of HLA-DR3-DQ2 and/or DR4-DQ8-positive children. Subjects were screened annually for celiac disease using tissue transglutaminase autoantibodies (tTGA). Three-day food records estimated the mean intake of milk powder at ages 6 months, 9 months, 12 months, 18 months, and 24 months. Conditional logistic regression calculated odds ratios (OR) at last intake prior to seroconversion of tTGA positivity, and for each time-point respectively and adjusted for having a first-degree relative with celiac disease and gluten intake. Intake of milk powder prior to seroconversion of tTGA positivity was not associated with celiac disease (OR = 1.00; 95% CI = 0.99, 1.03;

14 Article Altered peripheral amino acid profile indicate a systemic impact of active celiac disease and a possible role of amino acids in disease pathogenesis. 2018

Torinsson Naluai, Åsa / Saadat Vafa, Ladan / Gudjonsdottir, Audur H / Arnell, Henrik / Browaldh, Lars / Nilsson, Staffan / Agardh, Daniel. ·Institute of Biomedicine, Department of Microbiology & Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. · Department of Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Division of Pediatrics, CLINTEC, Karolinska Institute, Stockholm, Sweden. · Department of Clinical Science and Education, Karolinska Institute, Sodersjukhuset, Stockholm, Sweden. · Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden. · Diabetes & Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden. ·PLoS One · Pubmed #29538446.

ABSTRACT: BACKGROUND: We have previously performed a Genome Wide Association and linkage study that indicated a new disease triggering mechanism involving amino acid metabolism and nutrient sensing signaling pathways. OBJECTIVE: The aim of this study was to investigate if plasma amino acid levels differed among children with celiac disease compared with disease controls. MATERIALS AND METHODS: Fasting plasma samples from 141 children with celiac disease and 129 non-celiac disease controls, were analyzed for amino acid levels by liquid chromatography-tandem mass spectrometry (LC/MS). A general linear model using age and experimental effects as covariates was used to compare amino acid levels between children with a diagnosis of celiac disease and controls. RESULTS: Seven out of twenty-three analyzed amino acids were elevated in children with celiac disease compared with controls (tryptophan, taurine, glutamic acid, proline, ornithine, alanine and methionine). The significance of the individual amino acids do not survive multiple correction, however, multivariate analyses of the amino acid profile showed significantly altered amino acid levels in children with celiac disease overall and after correction for age, sex and experimental effects (p = 8.4 × 10-8). CONCLUSION: These findings support the idea that amino acids could influence systemic inflammation and play a possible role in disease pathogenesis.

15 Article Cesarean Section on the Risk of Celiac Disease in the Offspring: The Teddy Study. 2018

Koletzko, Sibylle / Lee, Hye-Seung / Beyerlein, Andreas / Aronsson, Carin A / Hummel, Michael / Liu, Edwin / Simell, Ville / Kurppa, Kalle / Lernmark, Åke / Hagopian, William / Rewers, Marian / She, Jin-Xiong / Simell, Olli / Toppari, Jorma / Ziegler, Anette-G / Krischer, Jeffrey / Agardh, Daniel / Anonymous8211111. ·*Dr. v. Hauner Children's Hospital, University Munich Medical Center, Munich, Germany †Health Informatics Institute, Department of Paediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, USA ‡Institute of Diabetes Research, Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V., Neuherberg, Germany §Department of Clinical Sciences, Lund University, Skane University Hosptial, Malmo, Sweden ||Digestive Health Institute, University of Colorado, Children's Hospital Colorado, Aurora, CO, USA ¶Medicity Laboratory, University of Turku, Turku, Finland #Tampere Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland **Pacific Northwest Diabetes Research Institute, Seattle WA, USA ††Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora CO, USA ‡‡Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta GA, USA §§Department of Paediatrics, Turku University Hospital, Turku, Finland ||||Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland ¶¶Departments of Physiology, University of Turku, Turku, Finland. ·J Pediatr Gastroenterol Nutr · Pubmed #28753178.

ABSTRACT: OBJECTIVE: Cesarean section (C-section) is associated with various immune-mediated diseases in the offspring. We investigated the relationship between mode of delivery and celiac disease (CD) and CD autoimmunity (CDA) in a multinational birth cohort. METHODS: From 2004 to 2010, infants from the general population who tested positive for HLA DR3-DQ2 or DR4-DQ8 were enrolled in The Environmental Determinants for Diabetes in the Young (TEDDY) study. Children were annually screened for transglutaminase autoantibodies, if positive, they are retested after 3 to 6 months and those persistently positive defined as CDA. Associations of C-section with maternal (age, education level, parity, pre-pregnancy weight, diabetes, smoking, weight gain during pregnancy) and child characteristics (gestational age, birth weight) were examined by Fisher exact test or Wilcoxon rank-sum test. Hazard ratios (HRs) for CDA or CD were calculated by Cox proportional hazard regression models. RESULTS: Of 6087 analyzed singletons, 1600 (26%) were born by C-section (Germany 38%, United States 37%, Finland 18%, Sweden 16%), and the remaining were born vaginally without instrumental support; 979 (16%) had developed CDA and 343 (6%) developed CD. C-section was associated with lower risk for CDA (hazard ratio [HR] = 0.85; 95% confidence interval [CI] 0.73, 0.99 P = 0.032) and CD (HR = 0.75; 95% CI 0.58, 0.98; P = 0.034). After adjusting for country, sex, HLA-genotype, CD in family, maternal education, and breast-feeding duration, significance was lost for CDA (HR = 0.91; 95% CI 0.78, 1.06; P = 0.20) and CD (HR = 0.85; 95% CI 0.65, 1.11; P = 0.24). Presurgical ruptured membranes had no influence on CDA or CD development. CONCLUSION: C-section is not associated with increased risk for CDA or CD in the offspring.

16 Article Association Between Early-Life Antibiotic Use and the Risk of Islet or Celiac Disease Autoimmunity. 2017

Kemppainen, Kaisa M / Vehik, Kendra / Lynch, Kristian F / Larsson, Helena Elding / Canepa, Ronald J / Simell, Ville / Koletzko, Sibylle / Liu, Edwin / Simell, Olli G / Toppari, Jorma / Ziegler, Anette G / Rewers, Marian J / Lernmark, Åke / Hagopian, William A / She, Jin-Xiong / Akolkar, Beena / Schatz, Desmond A / Atkinson, Mark A / Blaser, Martin J / Krischer, Jeffrey P / Hyöty, Heikki / Agardh, Daniel / Triplett, Eric W / Anonymous1080924. ·Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville. · Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa. · Department of Clinical Sciences, Lund University Clinical Research Center, Skåne University Hospital, Malmö, Sweden. · MediCity Laboratory, University of Turku, Turku, Finland. · Division of Paediatric Gastroenterology and Hepatology, Dr von Hauner Children's Hospital, Ludwig Maximilian University, München, Germany. · Digestive Health Institute, Children's Hospital Colorado, Anschutz Medical Campus, University of Colorado Denver, Aurora. · Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. · Department of Pediatrics, University of Turku, Turku University Hospital, Turku, Finland. · Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland. · Institute of Diabetes Research, Helmholtz Zentrum München, München, Germany. · Klinikum Rechts der Isar, Technische Universität München, München, Germany. · Forschergruppe Diabetes e.V., Neuherberg, Germany. · Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora. · Pacific Northwest Diabetes Research Institute, Seattle, Washington. · Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta. · National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. · Department of Pediatrics, College of Medicine, University of Florida, Gainesville. · Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville. · Department of Medicine and Microbiology, New York School of Medicine, New York. · Department of Virology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. · Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland. ·JAMA Pediatr · Pubmed #29052687.

ABSTRACT: Importance: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. Objective: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. Design, Setting, and Participants: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. Exposures: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. Main Outcomes and Measures: Islet autoimmunity and CD autoimmunity were defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95% CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. Results: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). Conclusions and Relevance: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.

17 Article Co-occurrence of Type 1 Diabetes and Celiac Disease Autoimmunity. 2017

Hagopian, William / Lee, Hye-Seung / Liu, Edwin / Rewers, Marian / She, Jin-Xiong / Ziegler, Anette-G / Lernmark, Åke / Toppari, Jorma / Rich, Stephen S / Krischer, Jeffrey P / Erlich, Henry / Akolkar, Beena / Agardh, Daniel / Anonymous10101111. ·Diabetes Programs Division, Pacific Northwest Research Institute, Seattle, Washington; wah@uw.edu. · Department of Pediatrics, Health Informatics Institute, University of South Florida, Tampa, Florida. · Department of Pediatrics, Children's Hospital Colorado, University of Colorado, Aurora, Colorado. · Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, Georgia. · Institute of Diabetes Research, Helmholtz Zentrum München, Oberschleißheim, Germany. · Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden. · Department of Pediatrics, Turku University Central Hospital, Turku, Finland. · Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. · Children's Hospital of Oakland Research Institute, Oakland, California; and. · Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. ·Pediatrics · Pubmed #29018046.

ABSTRACT: BACKGROUND AND OBJECTIVES: Few birth cohorts have prospectively followed development of type 1 diabetes (T1D) and celiac disease (CD) autoimmunities to determine timing, extent of co-occurrence, and associated genetic and demographic factors. METHODS: In this prospective birth cohort study, 8676 children at high genetic risk of both diseases were enrolled and 5891 analyzed in median follow-up of 66 months. Along with demographic factors and HLA-DR-DQ, genotypes for HLA-DPB1 and 5 non-HLA loci conferring risk of both T1D and CD were analyzed. RESULTS: Development of persistent islet autoantibodies (IAs) and tissue transglutaminase autoantibodies (tTGAs), as well as each clinical disease, was evaluated quarterly from 3 to 48 months of age and semiannually thereafter. IAs alone appeared in 367, tTGAs alone in 808, and both in 90 children. Co-occurrence significantly exceeded the expected rate. IAs usually, but not always, appeared earlier than tTGAs. IAs preceding tTGAs was associated with increasing risk of tTGAs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.15-1.91). After adjusting for country, sex, family history, and all other genetic loci, significantly greater co-occurrence was observed in children with a T1D family history (HR: 2.80), HLA-DR3/4 (HR: 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR: 1.53). However, observed co-occurrence was not fully accounted for by all analyzed factors. CONCLUSIONS: In early childhood, T1D autoimmunity usually precedes CD autoimmunity. Preceding IAs significantly increases the risk of subsequent tTGAs. Co-occurrence is greater than explained by demographic factors and extensive genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the increased risk.

18 Article Reduced Bone Mineral Density in Children With Screening-detected Celiac Disease. 2017

Björck, Sara / Brundin, Charlotte / Karlsson, Magnus / Agardh, Daniel. ·*Unit of Diabetes and Celiac Disease, Department of Clinical Sciences, Lund University, Malmö †Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences and Orthopedics, Lund University, Malmö, Sweden. ·J Pediatr Gastroenterol Nutr · Pubmed #28319607.

ABSTRACT: OBJECTIVES: The aim of the study was to assess whether bone mass and metabolism are impaired in genetically at-risk children with screening-detected celiac disease. METHODS: Included were 71 children with screening-detected celiac disease diagnosed at 10.0 ± 0.7 (mean ± standard deviation) years and 142 matched controls and 30 children with screening-detected celiac disease diagnosed at 3.3 ± 0.4 years of age presently on a gluten-free diet for 6.9 ± 1.1 years and 60 matched controls. All participants were assessed for bone mineral density (BMD) of total body and spine by dual x-ray absorptiometry, serum 25(OH) vitamin D3, parathyroid hormone (PTH), interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-15, interferon gamma, and tumor necrosis factor alpha. RESULTS: At diagnosis, screening-detected celiac disease children as compared to controls had a mean -0.03 g/cm reduced BMD of both total body and spine (P = 0.009 and P = 0.005, respectively), a mean -11.4 nmol/L lower level of 25(OH) vitamin D3 (P < 0.001), and a mean +1.0 pmol/L higher PTH level (P < 0.001). Systemic levels of the cytokines IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor alpha were all increased in screening-detected celiac disease as compared to controls (P < 0.001). No difference in BMD, 25(OH) vitamin D3, PTH, and cytokine levels were detected in children on a gluten-free diet compared with controls. CONCLUSIONS: Children with screening-detected celiac disease have reduced BMD, lower levels of vitamin D3, higher levels of PTH, and signs of systemic inflammation compared with controls. These differences were not found in celiac disease children on a gluten-free diet, indicating that children with screening-detected celiac disease benefit from an early diagnosis and treatment.

19 Article Maternal use of dietary supplements during pregnancy is not associated with coeliac disease in the offspring: The Environmental Determinants of Diabetes in the Young (TEDDY) study. 2017

Yang, Jimin / Tamura, Roy N / Aronsson, Carin A / Uusitalo, Ulla M / Lernmark, Åke / Rewers, Marian / Hagopian, William A / She, Jin-Xiong / Toppari, Jorma / Ziegler, Anette G / Akolkar, Beena / Krischer, Jeffrey P / Norris, Jill M / Virtanen, Suvi M / Agardh, Daniel / Anonymous4221111. ·1Health Informatics Institute,Morsani College of Medicine,University of South Florida,Tampa,FL 33612,USA. · 2The Diabetes and Celiac Disease Unit,Department of Clinical Sciences,Lund University,20502 Malmö,Sweden. · 3Barbara Davis Center for Childhood Diabetes,University of Colorado School of Medicine,Aurora,CO 80045,USA. · 4Pacific Northwest Diabetes Research Institute,Seattle,WA 98122,USA. · 5Center for Biotechnology and Genomic Medicine,Augusta University,Augusta,GA 30912,USA. · 6Department of Physiology,Institute of Biomedicine,University of Turku,20014 Turku,Finland. · 8Institute of Diabetes Research,Helmholtz Zentrum München and Klinikum rechts der Isar,Technische Universität München, and Forschergruppe Diabetes e.V.,80804 Neuherberg,Germany. · 9National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MA 20892,USA. · 10Department of Epidemiology,Colorado School of Public Health,University of Colorado Anschutz Medical Campus,Aurora,CO 80045,USA. · 11Unit of Nutrition,National Institute for Health and Welfare,00300 Helsinki,Finland. ·Br J Nutr · Pubmed #28249640.

ABSTRACT: Perinatal exposure to nutrients and dietary components may affect the risk for coeliac disease (CD). We investigated the association between maternal use of vitamin D, n-3 fatty acids (FA) and Fe supplements during pregnancy and risk for CD autoimmunity (CDA) and CD in the offspring. Children at increased genetic risk were prospectively followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. CDA was defined as having persistently positive tissue transglutaminase autoantibodies (tTGA). Diagnosis of CD was either biopsy-confirmed or considered likely if having persistently elevated levels of tTGA>100 AU. Of 6627 enrolled children, 1136 developed CDA at a median 3·1 years of age (range 0·9-10) and 409 developed CD at a median 3·9 years of age (range 1·2-11). Use of supplements containing vitamin D, n-3 FA and Fe was recalled by 66, 17 and 94 % of mothers, respectively, at 3-4 months postpartum. The mean cumulative intake over the entire pregnancy was 2014 μg vitamin D (sd 2045 μg), 111 g n-3 FA (sd 303 g) and 8806 mg Fe (sd 7017 mg). After adjusting for country, child's human leucocyte antigen genotype, sex, family history of CD, any breast-feeding duration and household crowding, Cox's proportional hazard ratios did not suggest a statistically significant association between the intake of vitamin D, n-3 FA or Fe, and risk for CDA or CD. Dietary supplementation during pregnancy may help boost nutrient intake, but it is not likely to modify the risk for the disease in the offspring.

20 Article Psychological Manifestations of Celiac Disease Autoimmunity in Young Children. 2017

Smith, Laura B / Lynch, Kristian F / Kurppa, Kalle / Koletzko, Sibylle / Krischer, Jeffrey / Liu, Edwin / Johnson, Suzanne Bennett / Agardh, Daniel / Anonymous3991111. ·Diabetes Center & Health Informatics Institute, Department of Pediatrics, and. · Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida. · Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland. · Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany. · Digestive Health Institute, University of Colorado, Children's Hospital Colorado, Denver, Colorado. · Department of Medical Humanities and Social Sciences, Florida State University College of Medicine, Tallahassee, Florida; and. · Unit of Diabetes and Celiac Disease, Malmö University, Malmö, Sweden daniel.agardh@med.lu.se. ·Pediatrics · Pubmed #28219962.

ABSTRACT: BACKGROUND AND OBJECTIVES: Psychological symptoms can be associated with celiac disease; however, this association has not been studied prospectively in a pediatric cohort. We examined mother report of psychological functioning in children persistently positive for tissue transglutaminase autoantibodies (tTGA), defined as celiac disease autoimmunity (CDA), compared with children without CDA in a screening population of genetically at-risk children. We also investigated differences in psychological symptoms based on mothers' awareness of their child's CDA status. METHODS: The Environmental Determinants of Diabetes in the Young study followed 8676 children to identify triggers of type 1 diabetes and celiac disease. Children were tested for tTGA beginning at 2 years of age. The Achenbach Child Behavior Checklist assessed child psychological functioning at 3.5 and 4.5 years of age. RESULTS: At 3.5 years, 66 mothers unaware their child had CDA reported more child anxiety and depression, aggressive behavior, and sleep problems than 3651 mothers of children without CDA (all CONCLUSIONS: In 3.5-year-old children, CDA is associated with increased reports of child depression and anxiety, aggressive behavior, and sleep problems when mothers are unaware of their child's CDA status. Mothers' knowledge of their child's CDA status is associated with fewer reports of psychological symptoms, suggesting that awareness of the child's tTGA test results affects reporting of symptoms.

21 Article Coeliac patients detected during type 1 diabetes surveillance had similar issues to those diagnosed on a clinical basis. 2017

Laitinen, Anna U / Agardh, Daniel / Kivelä, Laura / Huhtala, Heini / Lähdeaho, Marja-Leena / Kaukinen, Katri / Kurppa, Kalle. ·School of Medicine, University of Tampere, Tampere, Finland. · Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland. · The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden. · School of Health Sciences, University of Tampere, Tampere, Finland. · Department of Internal Medicine, Tampere University Hospital, Tampere, Finland. ·Acta Paediatr · Pubmed #27935157.

ABSTRACT: AIM: Screening children with type 1 diabetes for coeliac disease is controversial, because they often appear asymptomatic. Our aim was to establish whether active screening should be recommended. METHODS: This study focused on 22 children whose coeliac disease was detected by serological screening during diabetes surveillance and 498 children diagnosed because of a clinical suspicion. We compared the clinical and histological data at diagnosis and the children's adherence and responses to a gluten-free diet. RESULTS: The serological screening group suffered less from decreased growth (p = 0.016) and clinical symptoms (p < 0.001) at diagnosis than the clinical group. The groups did not differ in terms of age at diagnosis (p = 0.903), gender (p = 0.353), anaemia (p = 0.886), endomysial antibody titres (p = 0.789) and the severity of small-bowel mucosal atrophy (p = 0.104). They also showed equal adherence (p = 0.086) and clinical responses (p = 0.542) to a gluten-free diet after a median follow-up of 13 months. CONCLUSION: Coeliac patients detected during diabetes surveillance had signs of malabsorption and advanced mucosal damage that was similar to those diagnosed on a clinical basis. They often suffered from unrecognised gluten-dependent symptoms and showed excellent adherence and responses to a gluten-free diet. Our findings support active screening for coeliac disease in patients with type 1 diabetes.

22 Article Factors That Increase Risk of Celiac Disease Autoimmunity After a Gastrointestinal Infection in Early Life. 2017

Kemppainen, Kaisa M / Lynch, Kristian F / Liu, Edwin / Lönnrot, Maria / Simell, Ville / Briese, Thomas / Koletzko, Sibylle / Hagopian, William / Rewers, Marian / She, Jin-Xiong / Simell, Olli / Toppari, Jorma / Ziegler, Anette-G / Akolkar, Beena / Krischer, Jeffrey P / Lernmark, Åke / Hyöty, Heikki / Triplett, Eric W / Agardh, Daniel / Anonymous2050887. ·Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida. · Health Informatics Institute, University of South Florida, Tampa, Florida. · Digestive Health Institute, Children's Hospital Colorado, University of Colorado, Denver; Barbara Davis Center, University of Colorado Denver, Aurora, Colorado. · Department of Virology, School of Medicine, University of Tampere, Tampere, Finland; Department of Dermatology, Tampere University Hospital, Tampere, Finland. · MediCity Laboratory, University of Turku, Turku, Finland. · Center for Infection and Immunity, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York. · Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany. · Pacific Northwest Diabetes Research Institute, Seattle, Washington. · Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. · Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. · Department of Pediatrics, University of Turku, Turku, Finland; Departments of Physiology and Pediatrics, University of Turku, Turku, Finland. · Institute of Diabetes Research, Helmholtz Zentrum München, Klinikum Rechts der Isar, Technische Universität München, Forschergruppe Diabetes eV, Neuherberg, Germany. · National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. · Department of Clinical Sciences, Lund University, Malmo, Sweden. · Department of Virology, School of Medicine, University of Tampere, Tampere, Finland; Department of Dermatology, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland. · Department of Clinical Sciences, Lund University, Malmo, Sweden. Electronic address: daniel.agardh@med.lu.se. ·Clin Gastroenterol Hepatol · Pubmed #27840181.

ABSTRACT: BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of gluten immunogenicity in patients with celiac disease. We studied temporal associations between infections and the development of celiac disease autoimmunity, and examined effects of HLA alleles, rotavirus vaccination status, and infant feeding. METHODS: We monitored 6327 children in the United States and Europe carrying HLA risk genotypes for celiac disease from 1 to 4 years of age for presence of tissue transglutaminase autoantibodies (the definition of celiac disease autoimmunity), until March 31, 2015. Parental reports of gastrointestinal and respiratory infections were collected every third month from birth. We analyzed time-varying relationships among reported infections, rotavirus vaccination status, time to first introduction of gluten, breastfeeding, and risk of celiac disease autoimmunity using proportional hazard models. RESULTS: We identified 13,881 gastrointestinal infectious episodes (GIE) and 79,816 respiratory infectious episodes. During the follow-up period, 732 of 6327 (11.6%) children developed celiac disease autoimmunity. A GIE increased the risk of celiac disease autoimmunity within the following 3 months by 33% (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.11-1.59). This risk increased 2-fold among children born in winter and introduced to gluten before age 6 months (HR, 2.08; 95% CI, 1.46-2.98), and increased 10-fold among children without HLA-DQ2 alleles and breastfed for fewer than 4 months (HR, 9.76; 95% CI, 3.87-24.8). Risk of celiac disease autoimmunity was reduced in children vaccinated against rotavirus and introduced to gluten before age 6 months (HR, 0.57; 95% CI, 0.36-0.88). CONCLUSIONS: Gastrointestinal infections increase the risk of celiac disease autoimmunity in children with genetic susceptibility to this autoimmune disorder. The risk is modified by HLA genotype, infant gluten consumption, breastfeeding, and rotavirus vaccination, indicating complex interactions among infections, genetic factors, and diet in the etiology of celiac disease in early childhood.

23 Article Role of proneurotensin as marker of paediatric coeliac disease. 2016

Montén, C / Torinsson Naluai, Å / Agardh, D. ·Department of Clinical Sciences, Diabetes and Celiac Disease Unit, Lund University, Malmö, Sweden. · Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden. ·Clin Exp Immunol · Pubmed #27612962.

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

24 Article Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases. 2016

Mostowy, Joanna / Montén, Caroline / Gudjonsdottir, Audur H / Arnell, Henrik / Browaldh, Lars / Nilsson, Staffan / Agardh, Daniel / Torinsson Naluai, Åsa. ·Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. · Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden. · Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. · Department of Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden. · Department of Clinical Science and Education, Karolinska Institutet, Sodersjukhuset, Stockholm, Sweden. · Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden. ·PLoS One · Pubmed #27483138.

ABSTRACT: BACKGROUND AND OBJECTIVES: Genome-wide association studies (GWAS) have identified several genetic regions involved in immune-regulatory mechanisms to be associated with celiac disease. Previous GWAS also revealed an over-representation of genes involved in type 2 diabetes and anorexia nervosa associated with celiac disease, suggesting involvement of common metabolic pathways for development of these chronic diseases. The aim of this study was to extend these previous analyses to study the gene expression in the gut from children with active celiac disease. MATERIAL AND METHODS: Thirty six target genes involved in type 2 diabetes and four genes associated with anorexia nervosa were investigated for gene expression in small intestinal biopsies from 144 children with celiac disease at median (range) age of 7.4 years (1.6-17.8) and from 154 disease controls at a median (range) age 11.4.years (1.4-18.3). RESULTS: A total of eleven of genes were differently expressed in celiac patients compared with disease controls of which CD36, CD38, FOXP1, SELL, PPARA, PPARG, AGT previously associated with type 2 diabetes and AKAP6, NTNG1 with anorexia nervosa remained significant after correction for multiple testing. CONCLUSION: Shared genetic factors involved in celiac disease, type 2 diabetes and anorexia nervosa suggest common underlying molecular pathways for these diseases.

25 Article Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort. 2016

Sharma, Ashok / Liu, Xiang / Hadley, David / Hagopian, William / Liu, Edwin / Chen, Wei-Min / Onengut-Gumuscu, Suna / Simell, Ville / Rewers, Marian / Ziegler, Anette-G / Lernmark, Åke / Simell, Olli / Toppari, Jorma / Krischer, Jeffrey P / Akolkar, Beena / Rich, Stephen S / Agardh, Daniel / She, Jin-Xiong / Anonymous5430862. ·Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA, United States of America. · Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL, United States of America. · Division of Population Health Sciences and Education, St George's University of London, London, United Kingdom. · Pacific Northwest Diabetes Research Institute, Seattle, WA, United States of America. · Digestive Health Institute, Children's Hospital Colorado, University of Colorado Denver, Aurora, CO, United States of America. · Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States of America. · Department of Pediatrics, University of Turku, Turku, Finland. · Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States of America. · Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V., Munich-Neuherberg, Germany. · Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden. · National Institutes of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD, United States of America. · Diabetes and Celiac Disease Unit, Lund University, Malmo, Sweden. ·PLoS One · Pubmed #27015091.

ABSTRACT: OBJECTIVES: There are significant geographical differences in the prevalence and incidence of celiac disease that cannot be explained by HLA alone. More than 40 loci outside of the HLA region have been associated with celiac disease. We investigated the roles of these non-HLA genes in the development of tissue transglutaminase autoantibodies (tTGA) and celiac disease in a large international prospective cohort study. METHODS: A total of 424,788 newborns from the US and European general populations and first-degree relatives with type 1 diabetes were screened for specific HLA genotypes. Of these, 21,589 carried 1 of the 9 HLA genotypes associated with increased risk for type 1 diabetes and celiac disease; we followed 8676 of the children in a 15 y prospective follow-up study. Genotype analyses were performed on 6010 children using the Illumina ImmunoChip. Levels of tTGA were measured in serum samples using radio-ligand binding assays; diagnoses of celiac disease were made based on persistent detection of tTGA and biopsy analysis. Data were analyzed using Cox proportional hazards analyses. RESULTS: We found 54 single-nucleotide polymorphisms (SNPs) in 5 genes associated with celiac disease (TAGAP, IL18R1, RGS21, PLEK, and CCR9) in time to celiac disease analyses (10-4>P>5.8x10-6). The hazard ratios (HR) for the SNPs with the smallest P values in each region were 1.59, 1.45, 2.23, 2.64, and 1.40, respectively. Outside of regions previously associated with celiac disease, we identified 10 SNPs in 8 regions that could also be associated with the disease (P<10-4). A SNP near PKIA (rs117128341, P = 6.5x10-8, HR = 2.8) and a SNP near PFKFB3 (rs117139146, P<2.8x10-7, HR = 4.9) reached the genome-wide association threshold in subjects from Sweden. Analyses of time to detection of tTGA identified 29 SNPs in 2 regions previously associated with celiac disease (CTLA4, P = 1.3x10-6, HR = 0.76 and LPP, P = 2.8x10-5, HR = .80) and 6 SNPs in 5 regions not previously associated with celiac disease (P<10-4); non-HLA genes are therefore involved in development of tTGA. CONCLUSIONS: In conclusion, using a genetic analysis of a large international cohort of children, we associated celiac disease development with 5 non-HLA regions previously associated with the disease and 8 regions not previously associated with celiac disease. We identified 5 regions associated with development of tTGA. Two loci associated with celiac disease progression reached a genome-wide association threshold in subjects from Sweden.

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