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Online Supplement, Henström Et Al. This Document Contains Support Data for “TRPM8 Polymorphisms As Online supplement, Henström et al. This document contains support data for “TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M” Maria Henström, Fatemeh Hadizadeh, Arthur Beyder, Ferdinando Bonfiglio, Tenghao Zheng, Ghazaleh Assadi, Joseph Rafter, Luis Bujanda, Lars Agreus, Anna Andreasson, Aldona Dlugosz, Greger Lindberg, Peter Thelin Schmidt, Pontus Karling, Bodil Ohlsson, Nicholas J Talley, Magnus Simren, Susanna Walter, Mira Wouters, Gianrico Farrugia, Mauro D’Amato Items included: • Methods • Table S1 • Table S2 • Table S3 • Figure S1 METHODS Study subjects IBS cases and controls. The replication case-control cohort is based on a Swedish multicenter study of Rome III defined IBS patients recruited at secondary or tertiary care centers and clinics throughout the country, together with asymptomatic healthy controls. In this study, we included 386 IBS cases (95 IBS-C, 127 IBS-D and 163 IBS-M; 64% females, mean age 42.2) and 357 controls (43% females, mean age 42.4), who have all been included in previous genetic studies and already described in detail.1-4 Establishment of a diagnosis of IBS and specific subtypes according to Rome III Criteria was obtained in all cases based on electronic medical record, validated bowel symptom questionnaires, and physicians’ examination. Subjects with inflammatory bowel disease or celiac disease were excluded. Informed consent was obtained from all IBS patients and controls from the respective centers, and the study was approved by Karolinska Institutet’s Research Ethics Committee. PopCol. The Population-based Colonoscopy study (PopCol) is a general population-based cohort with randomly selected participants from Stockholm, Sweden, also previously described in detail and included in genetic studies.5-7 A total of 1186 men and women, aged 1 Online supplement, Henström et al. 18-70 years and born in Sweden, filled in questionnaires (containing Rome criteria bowel symptom modules) and visited a physician for a physical exam and routine blood tests. For 130 of these, genotype data (see next section) and weekly recordings of defecation patterns and abdominal symptoms were also available. Upon exclusion of individuals fulfilling Rome Criteria for IBS (from questionnaire), 120 subjects (66% females, mean age 55.1) were included in the statistical analyses of correlation between BSFS scores and TRPM8 genotype. Informed consent was obtained from all participants and the PopCol study protocol was approved by Karolinska Institutet’s Research Ethics Committee. Genotype data Discovery SNP association results for the ion channel genes of interest (Supplementary Table 1) were extracted from available GWAS summary statistics, generated during our previously published GWAS study of IBS in the Swedish general population.3 Nominally significant association findings were detected for the genes CACNA1A, CACNA1E, TRPM8 and TRPV3, and 33 significant (tagging) markers were selected from these loci for replication in the case-control cohort. SNP genotyping and quality control was carried out at the Mutation Analysis Facility (MAF) at Karolinska Institutet, using the iPLEX chemistry on Sequenom MassARRAY platform (SEQUENOM USA). For PopCol participants, QC’ed TRPM8 genotypes were extracted from available Illumina HumanOmniExpressExome-8v1 array data, produced and analyzed as previously published.7 Statistical analyses SNP association testing with IBS was performed in SNP & Variation Suite (SVS) v.8.3.4 (Golden Helix, Inc., Bozeman, MT, www.goldenhelix.com) using logistic regression under an additive genetic model, adjusting for gender. Meta-analysis of TRPM8 GWAS and replication results was performed in SVS using the fixed-effect model and inverse-variance-based approach (based on METAL and Impute2 algorithms). Negative (for risk alleles) and positive (for protecting alleles) correlation between TRPM8 genotype and average BSFS scores was tested using non-parametric Spearman’s rank test in SPSS (v.22.0.0.0). 2 Online supplement, Henström et al. In silico analyses Computational prediction of transcription factor (TF) binding to TRPM8 promoter SNPs was performed with sTRAP tool according to the described method.8 In particular, the two SNP variants rs10166942 and rs2362290 +/- 10-nt sequences were used for both SNPs mapping to to the TRPM8 promoter in order to test changes in the TF’s affinity using matrices from the Transfac database.9 We selected TF with a difference log(P) > 1 for the two sequences (with and without the risk variant). The identification of TRPM8 co-expressed genes was obtained screening publicly available transcriptomic data using the Genevestigator search engine (http://www.genevestigator.com),10 by selecting probe signals with a correlation coefficient r > 0.25 across the Perturbation dataset. Pathway analyses of TFs and TRPM8 co-expressed gene lists were performed using the EnrichR web-based software (http://amp.pharm.mssm.edu/Enrichr)) to screen the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway (http://www.genome.jp/kegg/) database and the Gene Ontology (GO) terms Biological Process, Molecular Function and Mammalian Phenotype (geneontology.org). References 1. Zucchelli M, et al. Gut 2011;60:1671-7. 2. Wouters MM, et al. Gut 1014;63:1103-11. 3. Ek WE, et al. Gut 2015;64:1774-82. 4. Beyder A, et al. Gastroenterology 2014;146:1659-68. 5. Walter SA, et al. Scand J Gastroenterol 2010;45:556-66. 6. Kjellström L, et al. Eur J Gastroenterol Hepatol 2014;26:268-75. 7. Jankipersadsing SA, et al. Gut. 2016 Jul 29 [Epub ahead of print] 8. Thomas-Chollier M, et al. Nat Protoc. 2011;6:1860-9. 9. Wingender E, et al. Nucleic Acids Res. 1996;24:238-41. 10. Hruz T, et al. Adv Bioinformatics 2008;2008:420747. 3 Online supplement, Henström et al. Table S1. Candidate Ion channel genes inspected for follow-up of GWAS results Gene Protein Function ANO1 Ano1 Pacemaking, secretion ASIC1 ASIC1 Visceral afferents mechanosensitivity ASIC2 ASIC2 Visceral afferents mechanosensitivity ASIC3 ASIC3 Visceral afferents mechanosensitivity CACNA1A CaV2.1 Gastrointestinal motility, visceral sensation CACNA1B CaV2.2 ENS development CACNA1E CaV2.3 Visceral sensation CACNA1G CaV3.1 Smooth muscle pacemaking CACNA1H CaV3.2 Pacemaking HCN2 HCN2 Pacemaking (?), ENS development (?) KCNJ3 Kir3.1 Hormone secretion, smooth muscle excitability KCNJ5 Kir3.4 Hormone secretion KCNK3 K2p3.1 Pacemaking KCNK9 K2p9.1 Smooth muscle /myenteric nerve excitability P2RX3 P2X3 Smooth muscle electrical excitability, myenteric neurons P2RX4 P2X4 Smooth muscle electrical excitability P2RX7 P2X7 Glia and enteric neurons SCN10A NaV1.8 Vagal neurons, vagal tension receptors, afferent neurons SCN1A NaV1.1 Mechanical visceral sensitivity SCN2A NaV1.2 Myenteric neurons SCN9A NaV1.7 Afferent neurons TRPM2 TRPM2 Visceral sensation TRPM3 TRPM3 Visceral sensation TRPM8 TRPM8 Temperature (cold), chemical (menthol), and pressure sensor TRPV1 TRPV1 Visceral sensation TRPV3 TRPV3 Secretion/absorption, temperature, visceral mechanical sensitivity TRPV4 TRPV4 Visceral sensation 4 Online supplement, Henström et al. Table S2. Significantly (adjusted P < 0.05) enriched Pathways and Ontologies relative to TFs binding affected by TRPM8 promoter SNPs * Adjusted Term KEGG 2016 P-value P-value - - - Adjusted GO Term BIOLOGICAL PROCESS P-value P-value gland development (GO:0048732) 3.94E-06 1.39E-03 transcription from RNA polymerase II promoter (GO:0006366) 7.56E-05 1.20E-02 hematopoietic or lymphoid organ development (GO:0048534) 1.02E-04 1.20E-02 leukocyte differentiation (GO:0002521) 2.92E-04 1.72E-02 angiogenesis (GO:0001525) 2.44E-04 1.72E-02 thymus development (GO:0048538) 2.45E-04 1.72E-02 liver development (GO:0001889) 1.03E-03 4.53E-02 myeloid leukocyte differentiation (GO:0002573) 9.59E-04 4.53E-02 regeneration (GO:0031099) 1.30E-03 4.77E-02 cellular response to metal ion (GO:0071248) 1.35E-03 4.77E-02 cellular response to inorganic substance (GO:0071241) 1.66E-03 4.87E-02 positive regulation of leukocyte differentiation (GO:1902107) 1.90E-03 4.87E-02 embryonic organ development (GO:0048568) 1.93E-03 4.87E-02 cell maturation (GO:0048469) 1.90E-03 4.87E-02 Adjusted GO Term MOLECULAR FUNCTION P-value P-value sequence-specific DNA binding RNA polymerase II transcription factor activity 2.36E-10 8.73E-09 (GO:0000981) RNA polymerase II transcription regulatory region sequence-specific DNA binding 4.76E-10 8.80E-09 transcription factor activity involved in positive regulation of transcription (GO:0001228) RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor 8.11E-10 1.00E-08 activity (GO:0003705) RNA polymerase II regulatory region sequence-specific DNA binding (GO:0000977) 3.53E-09 2.83E-08 RNA polymerase II regulatory region DNA binding (GO:0001012) 3.83E-09 2.83E-08 transcription regulatory region sequence-specific DNA binding (GO:0000976) 1.02E-08 6.28E-08 RNA polymerase II core promoter proximal region sequence-specific DNA binding 1.39E-08 7.36E-08 transcription factor activity involved in positive regulation of transcription (GO:0001077) RNA polymerase II core promoter proximal region sequence-specific DNA binding 6.05E-08 2.80E-07 transcription factor activity (GO:0000982) HMG box domain binding (GO:0071837) 2.14E-07 8.80E-07 RNA polymerase II core promoter proximal region sequence-specific DNA binding 2.09E-06 7.73E-06 (GO:0000978) core promoter proximal region DNA binding (GO:0001159) 2.68E-06 8.26E-06 core promoter proximal region sequence-specific DNA binding (GO:0000987) 2.56E-06 8.26E-06 RNA polymerase
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