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      Is Open Access

      Novel genetic risk variants for pediatric celiac disease

      research-article
      1 , 2 , 1 , 2 , 3 , 4 , 5 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 6 , 6 , 7 , 6 , 8 , 5 , 9 , 3 , 4 , 7 , 2 , 7 , 2 , 1 , 5 , 1 ,
      Human Genomics
      BioMed Central
      Celiac disease, Genomic variants, Family genomics, Next-generation sequencing, Disease predisposition

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          Abstract

          Background

          Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic.

          Methods

          Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition.

          Results

          Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c.4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek ( n = 109) and Serbian ( n = 73) descent and their healthy counterparts ( n = 111 and n = 32, respectively) indicated that HoxD12 c.418G>A is more prevalent in celiac disease patients in the Serbian population ( P < 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent ( P = 0.03). SLC9A4 c.1919G>A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance.

          Conclusions

          The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s40246-016-0091-1) contains supplementary material, which is available to authorized users.

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          Most cited references19

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          Newly identified genetic risk variants for celiac disease related to the immune response.

          Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.
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            A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.

            We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.
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              SH3 domains: complexity in moderation.

              B Mayer (2001)
              The SH3 domain is perhaps the best-characterized member of the growing family of protein-interaction modules. By binding with moderate affinity and selectivity to proline-rich ligands, these domains play critical roles in a wide variety of biological processes ranging from regulation of enzymes by intramolecular interactions, increasing the local concentration or altering the subcellular localization of components of signaling pathways, and mediating the assembly of large multiprotein complexes. SH3 domains and their binding sites have cropped up in many hundreds of proteins in species from yeast to man, which suggests that they provide the cell with an especially handy and adaptable means of bringing proteins together. The wealth of genetic, biochemical and structural information available provides an intimate and detailed portrait of the domain, serving as a framework for understanding other modular protein-interaction domains. Processes regulated by SH3 domains also raise important questions about the nature of specificity and the overall logic governing networks of protein interactions.
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                Author and article information

                Contributors
                agg_balasopoulou@hotmail.com
                bi.stankovic@gmail.com
                pha2331@upnet.gr
                gordnik@imgge.bg.ac.rs
                bpeters@completegenomics.com
                anne.john@uaeu.ac.ae
                evelinako@windowslive.com
                eiro13@yahoo.gr
                elinalegaki@gmail.com
                pha2246@upnet.gr
                aristi_92_@hotmail.com
                pha2429@upnet.gr
                sofiagovari@gmail.com
                zoizag@upatras.gr
                kpoulas@upatras.gr
                m.kanariou@gmail.com
                nikico13@hotmail.com
                marokrini@gmail.com
                spanoukelly@yahoo.gr
                n.radlovic@beotel.net
                bassam.ali@uaeu.ac.ae
                acidmucin@yahoo.co.uk
                rade@completegenomics.com
                chrousge@med.uoa.gr
                sonya@sezampro.rs
                roma2el@med.uoa.gr
                branka.petrucev@gmail.com
                gpatrinos@upatras.gr
                +30-2610-962368 , thkatsila@upatras.gr
                Journal
                Hum Genomics
                Hum. Genomics
                Human Genomics
                BioMed Central (London )
                1473-9542
                1479-7364
                24 October 2016
                24 October 2016
                2016
                : 10
                : 34
                Affiliations
                [1 ]Department of Pharmacy, School of Health Sciences, University of Patras, University Campus, Rion, 265 04 Patras, Greece
                [2 ]Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
                [3 ]Complete Genomics Inc., Mountain View, CA USA
                [4 ]BGI Shenzhen, Shenzhen, 51803 China
                [5 ]Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
                [6 ]Department of Immunology and Histocompatibility, “Aghia Sophia” Children’s Hospital, Athens, Greece
                [7 ]First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, Athens, Greece
                [8 ]Department of Gastroenterology and Nutrition, University Children’s Hospital, Medical Faculty, University of Belgrade, Belgrade, Serbia
                [9 ]Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
                Article
                91
                10.1186/s40246-016-0091-1
                5105295
                27836013
                921cc849-8c4e-4107-b716-d4c0dedefb5b
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 August 2016
                : 16 October 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004431, Directorate-General for Research and Innovation;
                Award ID: 305444
                Award Recipient :
                Categories
                Primary Research
                Custom metadata
                © The Author(s) 2016

                Genetics
                celiac disease,genomic variants,family genomics,next-generation sequencing,disease predisposition

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