Douroudis, K.

Kingo, K.

Kõks, S.

Mössner, R.

Raud, K.

Reimann, E.

Rätsep, R.

Silm, H.

Traks, T.

Vasar, E.

English

Research Repository

Acta Derm Venereol 9285Letters to the Editor© 2012 The Authors. doi: 10.2340/00015555-1183Journal Compilation © 2012 Acta Dermato-Venereologica. ISSN 0001-5555Psoriasis is an immune-mediated inflammatory disorder of the skin with a complex pathogenesis and a strong genetic component (1). Several regions in the genome, including the psoriasis susceptibility locus 1 (PSOR1), have been identified as conferring susceptibility to pso-riasis (2–4). However, the complete genetic background of psoriasis remains to be established. Autophagy is a fundamental biological process that is involved in cell growth and plays a role in innate and adaptive immunity. In particular, autophagy-selective responses contribute to inflammatory bowel disease (IBD) (5, 6), neuro-degeneration (7), and cancer (8). The ATG16L1 protein, which is encoded by the ATG16L1 gene (2q37), is a key component of a large protein complex essential for au-tophagy (9), and polymorphisms within this gene have been reported to be associated with Crohn’s disease (5). Taking into consideration that genes in the autophagy pathway play an important role in inflammation and immunity, and as a part of our ongoing research on the impact of genetic variants to the risk of psoriasis vulga-ris, the aim of the present study was to assess whether polymorphisms in ATG16L1 gene might also contribute to the risk of psoriasis.MATeRIALS AnD MeThODSA cohort of 241 unaffected controls (mean age 35.01 ± 13.60 years, 131 females) with no personal or family history of pso-riasis and 299 patients with plaque-type (non-pustular) psoriasis vulgaris (mean age 41.11 ± 13.87 years, age of onset 20.90 ± 8.16 years, 132 females) of estonian origin were enrolled into a case control study. Clinical examination was performed at the outpa-tient clinic in the Department of Dermatology and Venereology, University of Tartu. The ethics committee of the University of Tartu approved the study and informed consent was obtained from all participants. Six single nucleotide polymorphisms (SnPs) (rs10210302, rs12994971, rs2241880, rs2241879, rs7587633 and rs13005285) spanning a region of 36 Kb within the ATG16L1 gene were selected in our analysis, based on the criteria that SnPs had a minor allele frequency (MAF) > 5% in the Utah population of European descent (CEU) and had been validated. The polymorphic sites in the study except the rs2241880 SnP were genotyped using the SnPlex Genotyping System (Applied Biosystems, Foster City, CA, USA) according to manufactures’ instructions (10). The rs2241880 SNP was genotyped using the Taqman SnP 5´ allelic discrimination as-say (Applied Biosystems) as reported previously (11). Logistic regression was used to obtain odds ratio (OR) values and Walds’ confidence intervals (CI) for alleles and genotypes using the R program (www.r-project.org). Linkage disequilibrium (LD) and haplotype analysis was performed using Shesis software (http://analysis.bio-x.cn/myAnalysis.php). A p-value of < 0.05 was considered statistically significant for all analyses.ReSULTSno significant deviation from the hardy–Weinberg equilibrium in psoriasis or in the control group was observed (data not shown). The frequencies of alleles and genotypes are presented in Table I. The data ana-lysis showed that the frequencies of the rs10210302 CC (35.5% vs. 27.8%), rs12994971 CC (35.8% vs. 27.8%), rs2241880 AA (36.5% vs. 27.8%), rs2241879 GG (35.5% vs. 27.4%) and rs13005285 TT (19.4% vs. 13.3%) were higher in psoriasis group compared with controls, respectively. Moreover, the frequency distribu-tion (45.0% vs. 38.2%) of the rs13005285 T allele was significantly different (OR = 1.32, 95% CI = 1.03–1.69, p = 0.024). LD analysis of the ATG16L1 SnPs showed a highly significant association for each locus pair D´> 0.95 (data not shown). haplotype analysis of the ATG16L1 loci (rs10210302–rs12994971–rs2241880–rs2241879–rs7587633–rs13005285) revealed 5 haplo-types (frequency > 0.004) in both the affected and unaf-fected subjects (Table II). In particular, the frequency distribution of the CCAGTT haplotype was higher (37.3 vs. 32.7%) in the psoriasis group compared with the controls; but it did not reach the level of statistical significance (Table II). On the other hand, the frequency distribution of the CCAGTG was significantly lower (OR = 0.20, 95% CI = 0.04–0.90, p = 0.021). DISCUSSIOnWe should take into account that, since the frequency distribution of the CCAGTG haplotype is low in our studied population, this might reflect that a larger cohort is required in order to be able to control our findings. Taking into consideration that the autophagy genes play an important role in the immune regulation including thymic selection, lymphocyte development and survi-val, antigen presentation and tissue homeostasis (12), the autophagy pathway consequently has an impact in several immunological stimuli. Thus, we could spe-culate that, since the ATG16L1 molecule is a member of this pathway, it probably also plays an important role in immune response, which needs further investigation. noticeably, it has been reported that defects in the ATG16L1 protein might result in reduced production of antimicrobial peptides by small-intestinal Paneth cells and increased production of secreted pro-inflammatory cytokines, including the IL-1β and IL18, by macro-Polymorphisms in the ATG16L1 Gene are Associated with Psoriasis VulgarisKonstantinos Douroudis1,2, Külli Kingo2,3, Tanel Traks1,2, Ene Reimann1,2, Kristi Raud1,2, Ranno Rätsep1,2, Rotraut Mössner4, Helgi Silm2,3, Eero Vasar1,2 and Sulev Kõks1,21Department of Physiology, 2Centre of Translational Medicine, 3Department of Dermatology and Venereology, University of Tartu, Tartu, Estonia, and 4Department of Dermatology, Georg-August University, Göttingen, Germany. E-mail: drkmb@email.comAccepted March 28, 2011.86 Letters to the Editorphages, which might lead to intestinal inflammation (13, 14). Most recent, it has also been documented that dendritic cells from individuals with Crohn’s disease carrying a mutation in ATG16L1 gene are defective in autophagy, bacterial handling and antigen presentation (15). Hence, the latter evidence supports the notion of an important role of the ATG16L1 molecule in immune signalling and cell activation, and a putative role of ATG16L1 in susceptibility of psoriasis might also be considered. In particular, a possible defect in the ATG16L1 molecule might affect the autophagy machinery on signalling pathways that regulate cyto-kine production and result in accumulation of damaged proteins and organelles that are toxic, leading to cell death, tissue damage and chronic inflammation. The precise mechanisms by which the disease-associated autophagy genes affect autophagy pathways are not yet known. however, elucidation of the function of the autophagy genes in the future may lead to potentially novel therapies for treating the diseases in which they are involved. In conclusion, to our knowledge the present study is the first report addressing a possible impact of the ATG16L1 gene on the risk of psoriasis. Meanwhile, additional molecular and functional studies in different ethnic groups will be required to ascertain the contribu-tion of the ATG16L1 gene in psoriasis susceptibility.ACKnOWLeDGeMenTSThis study was supported by a grant from the european Union through the european Regional Development Fund and the Archimedes Foundation; and by the estonian Ministry of education grant no:SF0180043s07 and by the estonian Science Foundation Grant no: 7549.ReFeRenCeSCampalani e, Barker JnWn. The clinical genetics of pso-1. riasis. Curr Genomics 2005; 6: 51–60. Genetic Analysis of Psoriasis Consortium & the Wellcome 2. Trust Case Control Consortium 2, Strange A, Capon F, Spencer CC, Knight J et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between hLA-C and eRAP1. nat Genet 2010; 42: 985–990. Stuart Pe, nair RP, ellinghaus e, Ding J, Tejasvi T, Gudjons-3. son Je, et al. Genome-wide association analysis identifies three psoriasis susceptibility loci. nat Genet 2010; 42: 1000–1004.Trembath RC, Clough RL, Rosbotham JL, Jones AB, Camp 4. RDR, Frodsham A, et al. Identification of a major suscepti-bility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. hum Mol Genet 1997; 6: 813–820.hampe J, Franke A, Rosenstiel P, Till A, Teuber M, huse K, 5. et al. A genome-wide association scan of nonsynonymous SnPs identifies a susceptibility variant for Crohn disease in ATG16L1. nat Genet 2007; 39: 207–211.Törkvist L, halfvarson J, Ong RT, Lördal M, Sjöqvist U, 6. Bresso F, et al. Analysis of 39 Crohn’s disease risk loci in Swedish inflammatory bowel disease patients. Inflamm Bowel Dis 2009; 16: 907–909.Wang QJ, Ding Y, Kohtz S, Mizushima n, Cristea IM, Rout 7. MP, et al. Induction of autophagy in axonal dystrophy and degeneration. J neurosci 2006; 26: 8057–8068.Mathew R, Karp CM, Beaudoin B, Vuong n, Chen G, Chen 8. hY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009; 137: 1062–1075.Mizushima n, Kuma A, Kobayashi Y, Yamamoto A, Mat-9. subae M, Takao T, et al. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 2003; 116: 1679–1688.Table I. Genotype and allele frequency (%) distribution of ATG16L1 SNPs in psoriasis patients and controlsATG16L1SNPsControls, n (%)(n = 241)Psoriasis, n (%)(n = 299) OR (95% CI) prs10210302CC 67 (27.8) 106 (35.5) 1aCT 132 (54.8) 142 (47.4) 0.67 (0.46–1.00) 0.050TT 42 (17.4) 51 (17.1) 0.76 (0.46–1.27) 0.30C 266 (55.2) 354 (59.2) 1aT 216 (44.8) 244 (40.8) 0.84 (0.66–1.08) 0.18rs12994971CC 67 (27.8) 107 (35.8) 1aCT 132 (54.8) 142 (47.5) 0.67 (0.45–0.99) 0.045TT 42 (17.4) 50 (16.7) 0.74 (0.44–1.24) 0.26C 266 (55.2) 356 (59.5) 1aT 216 (44.8) 242 (40.5) 0.83 (0.65–1.06) 0.15rs2241880AA 67 (27.8) 109 (36.5) 1aAG 132 (54.8) 140 (46.8) 0.65 (0.44–0.95) 0.029GG 42 (17.4) 50 (16.7) 0.73 (0.43–1.21) 0.23A 266 (55.2) 358 (59.9) 1aG 216 (44.8) 240 (40.1) 0.82 (0.64–1.05) 0.12rs2241879AA 42 (17.4) 50 (16.7) 0.74 (0.44–1.23) 0.25AG 133 (55.2) 143 (47.8) 0.66 (0.45–0.98) 0.042GG 66 (27.4) 106 (35.5) 1aA 217 (45.0) 243 (40.6) 0.83 (0.65–1.06) 0.14G 265 (55.0) 355 (59.4) 1ars7587633CC 96 (39.8) 112 (37.5) 1aCT 123 (51.1) 149 (49.8) 1.03 (0.72–1.49) 0.83TT 22 (9.1) 38 (12.7) 1.48 (0.81–2.67) 0.19C 315 (65.4) 373 (62.4) 1aT 167 (34.6) 225 (37.6) 1.13 (0.88–1.46) 0.31rs13005285GG 89 (36.9) 88 (29.4) 1aGT 120 (49.8) 153 (51.2) 1.28 (0.88–1.88) 0.18TT 32 (13.3) 58 (19.4) 1.83 (1.08–3.09) 0.023G 298 (61.8) 329 (55.0) 1aT 184 (38.2) 269 (45.0) 1.32 (1.03–1.69) 0.024aReferent estimate.Table II. Haplotype frequency distribution of ATG16L1 polymorphisms in psoriasis patients and controlsATG16L1 haplotypesaControls (%)(n = 482)Psoriasis (%)(n = 598) OR (95% CI) pCCAGCG 15.2 13.9 0.89 (0.63–1.25) 0.52CCAGCT 5.3 7.7 1.50 (0.91–2.47) 0.10CCAGTG 1.8 0.4 0.20 (0.04–0.90) 0.021CCAGTT 32.7 37.3 1.22 (0.95–1.57) 0.11TTGACG 44.8 40.0 0.82 (0.64–1.04) 0.11ars10210302–rs12994971–rs2241880–rs2241879–rs7587633–rs13005285.Acta Derm Venereol 9287Letters to the EditorTobler AR, Short S, Andersen MR, Paner TM, Briggs JC, 10. Stephen M, et al. The SnPlex genotyping system: a flexible and scalable platform for SnP genotyping. J Biomol Tech 2005; 16: 398–406. Douroudis K, Kingo K, Silm h, Reimann e, Traks T, Vasar 11. e, et al. The CD226 Gly307Ser gene polymorphism is as-sociated with severity of psoriasis. J Dermatol Sci 2010; 58: 160–161.Virgin hW, Levine B. Autophagy genes in immunity. nat 12. Immunol 2009; 10: 461–469.Cadwell K, Liu JY, Brown SL, Miyoshi h, Loh J, Lennerz 13. JK, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. nature 2008; 456: 259–263. Saitoh T, Fujita n, Jang Mh, Uematsu S, Yang BG, Satoh 14. T, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. nature 2008; 456: 264–268. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et 15. al. nOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. nat Med 2010; 6: 90–97.Acta Derm Venereol 92

Polymorphisms in the ATG16L1 Gene are associated with psoriasis vulgaris

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Polymorphisms in the ATG16L1 Gene are associated with psoriasis vulgaris

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