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

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