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Association of ATG16L1 and IRGM Genes Polymorphisms with Inflammatory Bowel Disease: a Meta-Analysis Approach

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Genes and Immunity (2009) 10, 356–364 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach RJ Palomino-Morales1, J Oliver1,MGo´mez-Garcı´a2,MALo´pez-Nevot3, L Rodrigo4, A Nieto5, BZ Alizadeh6 and J Martı´n1 1Instituto de Parasitologı´a y Biomedicina ‘Lo´pez-Neyra’, CSIC, Granada, Spain; 2Servicio de Digestivo, Hospital Universitario Virgen de las Nieves, Granada, Spain; 3Servicio de Inmunologı´a, Hospital Universitario Virgen de las Nieves, Granada, Spain; 4Servicio de Digestivo, Hospital Universitario Central de Asturias, Oviedo, Spain; 5Servicio de Inmunologı´a, Hospital Puerta del Mar, Ca´diz, Spain and 6University Medical Center Utrecht, Utrecht, The Netherlands The aim of this study was to determine the role of the ATG16L1 (rs2241880) and IRGM (rs13361189 and rs4958847) genes polymorphism in Crohn’s disease (CD) and ulcerative colitis (UC). Our study included 557 CD and 425 UC patients and 672 ethnically matched Spanish controls and a meta-analysis with the data published to date. The polymorphisms were genotyped using predesigned TaqMan single nucleotide polymorphism genotyping assays. There was a statistically significant difference in the distribution of the ATG16L1 rs2241880 G allele between CD patients and controls in the Spanish population: P ¼ 6.5 Â 10À9, odds ratio (OR) ¼ 1.62. Although no differences were observed between UC patients and controls in the Spanish cohort, a meta-analysis demonstrated that the ATG16L1 G allele increase significantly risk for UC (P ¼ 0.0003, pooled OR ¼ 1.08). In addition, our meta-analysis data showed that IRGM rs13361189 and rs4958847 polymorphisms were associated with CD (rs13361189 C allele P ¼ 1.07 Â 10À19, pooled OR ¼ 1.34; rs4958847 A allele P ¼ 2.78 Â 10À17, pooled OR ¼ 1.31) and UC (rs13361189 P ¼ 0.0069, pooled OR ¼ 1.16; rs4958847 P ¼ 0.014, pooled OR ¼ 1.13). In conclusion, our results confirm the ATG16L1 rs2241880 and IRGM rs13361189 and rs4958847 polymorphisms as important markers for CD susceptibility and indicate that these variants are also associated with UC. Genes and Immunity (2009) 10, 356–364; doi:10.1038/gene.2009.25 Keywords: ATG16L1; IRGM; autophagy; polymorphism; Crohn’s disease; ulcerative colitis Introduction involved in the innate immune response to microbial antigens. This fact and evidence derived from animal Inflammatory bowel disease (IBD), which is usually models and clinical studies11–13 suggest that an inappro- classified into two clinical presentations, Crohn’s disease priate innate response to normal constituents of the (CD) and ulcerative colitis (UC), is a chronic relapsing luminal microflora plays a crucial role in the develop- and remitting disease of the intestinal tract. Although the ment of these diseases. aetiology of these diseases is not fully understood, there Recently, autophagy has been shown to be a key is strong support for a genetic component based on process in the innate immune response. Autophagy also findings of familial aggregation, higher concordance in contributes to endogenous major histocompatibility monozygotic twins and ethnic differences in disease complex class II antigen presentation, reflecting its role prevalence.1,2 in the adaptive response. Interestingly, recent genome- To date, different genetic studies have shown several wide association studies (GWASs) of CD have reported genes playing a relevant role in these diseases, including a strong association with two crucial genes in the NOD2/CARD15,3 DGL5,4 SLC22A4 and SLC22A5,5,6 autophagy process, ATG16L1 and IRGM.14–17 TNFSF15,7,8 NOD1/CARD47 and IL23R.9,10 ATG16L1 encodes a protein that interacts with the NOD2/CARD15 is likely to be the major genetic factor Atg12p–Atg5p conjugate during formation of the pre- contributing to CD. This gene encodes a protein directly autophagosomal structure, which is essential for auto- phagy.18–20 Association of CD with the ATG16L1 T300A (rs2241880) polymorphism was reported simultaneously Correspondence: Dr J Martin, Instituto de Parasitologı´a y Biome- by different GWASs.14–16 A large number of subsequent dicina ‘Lo´pez-Neyra’, CSIC, Parque Tecnolo´gico de Ciencias de la association studies have replicated the strong association Salud, Avenida del Conocimiento s/n, 18100-Armilla (Granada), of this gene with CD.21–34 Spain. E-mail: [email protected] IRGM (immunity-related guanosine triphosphatase, Received 25 September 2008; revised 12 February 2009; accepted 18 the human homologue of mouse Irgm/Lrg47) encodes February 2009 a GTP-binding protein that induces autophagy and plays Association of ATG16L1 and IRGM with IBD RJ Palomino-Morales et al 357 an important role in innate immunity against intra- for the ATG16L1 rs2241880 were observed in genotype cellular pathogens.35,36 Association of two immediately and allele frequencies between UC patients and controls. flanking IRGM gene polymorphisms (rs13361189 and When we combined CD and UC patients, an increased rs4958847) with CD has recently been reported.17,30,37 frequency of the G allele was observed compared with Reduced activity of these genes would be expected to controls (58.9 vs 51.2%, P ¼ 1.3 Â 10À05,OR¼ 1.37, 95% CI lead to persistence of intracellular bacteria, consistent 1.18–1.58), mainly due to the CD subgroup. No correla- with existing models of CD pathogenesis and the recent tion was observed between this genetic variant and ATG16L1 and IRGM association reports. the following variables: disease localization, disease The aim of this study was to determine the potential behaviour, disease severity, need for surgery and age implication of IRGM and ATG16L1 polymorphisms to of onset for both CD and UC patients (Supplementary CD and UC in a Spanish population. In addition, our Table 1). data were pooled with results from other available The distribution of IRGM rs13361189 and rs4958847 studies in a meta-analysis to determine the global role genotypic and allelic frequencies in the Spanish popula- of these gene variants in IBD. tion is shown in Table 2. The minor allele frequency of IRGM rs13361189 shows a clear trend of association with CD (16.7% patients vs 13.8% controls, P ¼ 0.05, OR ¼ 1.25, 95% CI 0.99–1.57), UC (16.8% patients vs 13.8% controls, Results P ¼ 0.06, OR ¼ 1.26, 95% CI 0.99–1.61) and IBD (16.7% Association study patients vs 13.8% controls, P ¼ 0.03, OR ¼ 1.25, 95% CI Deviation from Hardy–Weinberg equilibrium was not 1.02–1.53). For the IRGM rs4958847 variant, we observed observed in the entire cohorts for the ATG16L1 rs2241880 an association with CD compared with controls (22.2% and IRGM rs13361189 and rs4958847 polymorphisms. CD patients vs 18.4% controls, P ¼ 0.02, OR ¼ 1.26, 95% Table 1 shows the ATG16L1 rs2241880 genotype and CI 1.03–1.55). However, no association was detected with allele distribution in healthy controls and in CD, UC UC in our population. and IBD patients. The ATG16L1 rs2241880 G allele was We observed no specific genotype–phenotype strongly associated with susceptibility to CD in the associations for the IRGM gene variants with disease Spanish population (63.0 vs 51.2%, P ¼ 6.5 Â 10À09, odds localisation, disease behaviour, disease severity, need for ratio (OR) ¼ 1.62 95% confidence interval (CI) 1.37–1.91). surgery and age of onset for both CD and UC patients On the other hand, no statistically significant differences (Supplementary Table 1). Table 1 Genotype and allele distribution of the ATG16L1 rs2241880 polymorphism in healthy controls and in CD, UC and IBD patients ATG16L1 Controls CD P value OR (95% CI) UC P value OR (95% CI) IBD P value OR (95% CI) T300A n ¼ 666 (%) n ¼ 544 (%) n ¼ 414 (%) n ¼ 958 (%) AA 167 (25.1) 75 (13.8) 1.1 Â10À6 0.48 (0.35–0.65) 95 (22.9) 0.43 0.89 (0.66–1.20) 170 (17.7) 3.4 Â 10À4 0.64 (0.50–0.83) AG 316 (47.4) 253 (46.5) 0.75 0.96 (0.76–1.22) 194 (46.9) 0.85 0.98 (0.76–1.26) 447 (46.7) 0.75 0.97 (0.79–1.19) GG 183 (27.5) 216 (39.7) 6.8 Â 10À6 1.74 (1.35–2.23) 125 (30.2) 0.34 1.14 (0.86–1.51) 341 (35.6) 5.8 Â 10À4 1.46 (1.17–1.82) A 650 (48.8) 403 (37.0) 6.5 Â 10À9 0.62 (0.52–0.73) 384 (46.4) 0.29 0.91 (0.76–1.09) 787 (41.1) 1.3 Â 10À5 0.73 (0.63–0.84) G 682 (51.2) 685 (63.0) 6.5 Â 10À9 1.62 (1.37–1.91) 444 (53.6) 0.29 1.10 (0.92–1.32) 1129 (58.9) 1.3 Â 10À5 1.37 (1.18–1.58) Abbreviations: CD, Crohn’s disease; CI, confidence intervals; IBD, inflammatory bowel disease; OR, odds ratio; UC, ulcerative colitis. Table 2 Genotype and allele distribution of the IRGM rs13361189 and rs4958847 polymorphisms in healthy controls and in CD, UC and IBD patients IRGM Controls CD P value OR (95% CI) UC P value OR (95% CI) IBD P value OR (95% CI) rs13361189 n ¼ 654 (%) n ¼ 555 (%) n ¼ 425 (%) n ¼ 980 (%) CC 17 (2.6) 17 (3.1) 0.62 1.18 (0.57–2.46) 13 (3.1) 0.65 1.18 (0.54–2.59) 30 (3.1) 0.58 1.18 (0.62–2.26) CT 147 (22.5) 151 (27.2) 0.06 1.29 (0.98–1.69) 117 (27.5) 0.06 1.31 (0.98–1.75) 268 (27.3) 0.03 1.30 (1.02–1.65) TT 490 (74.9) 387 (69.7) 0.04 0.77 (0.59–1.00) 295 (69.4) 0.05 0.76 (0.58–1.01) 682 (69.6) 0.02 0.77 (0.61–0.96) C 181 (13.8) 185 (16.7) 0.05 1.25 (0.99–1.57) 143 (16.8) 0.06 1.26 (0.99–1.61) 328 (16.7) 0.03 1.25 (1.02–1.53) T 1127 (86.2) 925 (83.3) 0.05 0.80 (0.64–1.01) 707 (83.2) 0.06 0.79 (0.62–1.02) 1632 (83.3) 0.03 0.01 (0.65–0.98) IRGM Controls CD P value OR (95% CI) UC P value OR (95% CI) IBD P value OR (95% CI) rs4958847 n ¼ 644 (%) n ¼ 539 (%) n ¼ 421 (%) n ¼ 960 (%) AA 22 (3.4) 27 (5.0) 0.17 1.49 (0.81–2.75) 14 (3.3) 0.94 0.97 (0.47–2.01) 41 (4.5) 0.38 1.22 (0.72–2.21) GA 193 (30.0) 185 (34.2) 0.11 1.22 (0.95–1.57) 136 (32.3) 0.42 1.12 (0.85–1.47) 321 (33.5) 0.14 1.17 (0.98–1.46) GG 429 (66.6) 327 (60.7) 0.03 0.77 (0.60–0.99) 271 (64.4) 0.45 0.91 (0.69–1.18) 598 (62.0) 0.08 0.83 (0.67–1.03) G 237 (18.4) 239 (22.2) 0.02 1.26 (1.03–1.55) 164 (19.5) 0.53 1.07 (0.85–1.35) 409 (21.2) 0.05 1.19 (1.00–1.15) A 1051 (81.6) 839 (77.8) 0.02 0.79 (0.64–0.97) 678 (80.5) 0.53 0.93 (0.74–1.17) 1519 (78.8) 0.05 0.84 (0.70–1.00) Abbreviations: CD, Crohn’s disease; CI, confidence intervals; IBD, inflammatory bowel disease; OR, odds ratio; UC, ulcerative colitis.
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    Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin
  • Identifying RNA-Protein Interaction Sites Throughout Eukaryotic Transcriptomes

    Identifying RNA-Protein Interaction Sites Throughout Eukaryotic Transcriptomes

    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2015 Identifying RNA-Protein Interaction Sites Throughout Eukaryotic Transcriptomes Ian M. Silverman University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, Biology Commons, and the Genetics Commons Recommended Citation Silverman, Ian M., "Identifying RNA-Protein Interaction Sites Throughout Eukaryotic Transcriptomes" (2015). Publicly Accessible Penn Dissertations. 2016. https://repository.upenn.edu/edissertations/2016 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2016 For more information, please contact [email protected]. Identifying RNA-Protein Interaction Sites Throughout Eukaryotic Transcriptomes Abstract Gene expression is regulated at both the transcriptional and post-transcriptional levels. While transcription controls only the rate of RNA production, numerous and diverse mechanisms regulate the processing, stability and translation of RNAs at the post-transcriptional level. At the heart of this regulation are RNA-binding proteins (RBPs) and their RNA targets. Thousands of RBPs are encoded in mammalian genomes, each with hundreds to thousands of RNA targets. Therefore, cataloging these interactions represents a significant challenge. Recent advances in high-throughput sequencing technologies have greatly expanded the toolkit that researchers have to probe RNA-protein interactions, but these technologies are still in their infancy and thus new methods and applications are required to move our understanding forward. We developed a novel, high-throughput approach to globally identify regions of RNAs that interact with proteins throughout a transcriptome of interest. We applied this technique to human HeLa cells and provide evidence that our approach captures both known and novel RNA-protein interaction sites.
  • The ATG5-Binding and Coiled Coil Domains of ATG16L1 Maintain

    The ATG5-Binding and Coiled Coil Domains of ATG16L1 Maintain

    AUTOPHAGY 2019, VOL. 15, NO. 4, 599–612 https://doi.org/10.1080/15548627.2018.1534507 RESEARCH PAPER The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis Shashank Raia*, Maryam Arasteha*, Matthew Jeffersona*, Timothy Pearsona, Yingxue Wanga, Weijiao Zhanga, Bertalan Bicsaka, Devina Divekara, Penny P. Powella, Ronald Naumannb, Naiara Berazac, Simon R. Cardingc, Oliver Floreyd, Ulrike Mayer e, and Thomas Wilemana,c aNorwich Medical School, University of East Anglia, Norwich, Norfolk, UK; bMax-Planck-Institute of Molecular Cell Biology and Genetics, Dresden, Germany; cQuadram Institute Bioscience, Norwich, Norfolk, UK; dSignalling Programme, Babraham Institute, Cambridge, UK; eSchool of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK ABSTRACT ARTICLE HISTORY Macroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, Received 8 February 2018 and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The transloca- Revised 28 September 2018 tion of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during Accepted 5 October 2018 autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An KEYWORDS autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and ATG16L1; brain; endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen LC3-associated endosomes containing particulate material or apoptotic cells. We have investigated the roles played by phagocytosis; sequestosome autophagy and LAP in vivo by exploiting the observation that the WD domain of ATG16L1 is required for 1/p62 inclusions; tissue LAP, but not autophagy.