Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n=13), direct disruption of transcription-factor binding sites (n=3), and tissue-specific epigenetic marks (n=10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms. Other papers with impact factor associated with Deloverable 2: discovery of causal variant using genotype/gene expression analysis eQTL; biological pathways; molecular mechanisms of disease; genotype/biochemical parameters correlations; 9. eQTL analysis links inflammatory bowel disease associated 1q21 locus to ECM1 gene. J Appl Genet. 2016 Aug;57(3):363-72. doi: 10.1007/s13353-015-0334-1. [COBISS.SI-ID 512573240] 10. Comprehensive genetic study of fatty acids helps explain the role of noncoding inflammatory bowel disease associated SNPs and fatty acid metabolism in disease pathogenesis. Prostaglandins, leukotrienes, and essential fatty acids. 2018 Mar 1-10 doi: 10.1016/j.plefa.2018.02.002 [COBISS.SI-ID 6249791] 11. Reference genes for real-time qPCR in leukocytes from asthmatic patients before and after anti-asthma treatment. Gene. 2015 Oct 1;570(1):71-7. doi: 10.1016/j.gene.2015.06.001. [COBISS.SI-ID 512505400] 12. CTLA4 Expression in Childhood Asthma and the Effect of Treatment with Inhaled Corticosteroid and Leukotriene Receptor Antagonist. Annual Research & Review in Biology, ISSN: 2347-565X,Vol.: 10, Issue.: 2 doi: 10.9734/ARRB/2016/24564. [COBISS.SI-ID 5693759] 14. Relationship between genome and epigenome--challenges and requirements for future research. BMC Genomics. 2014 Jun 18;15:487. doi: 10.1186/1471-2164-15-487. [COBISS.SI-ID 512412216]
COBISS.SI-ID: 512723768
Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34819 patients (19713 with Crohn's disease, 14683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29838 patients (16902 with Crohn's disease, 12597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10-5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1 65X1078), even after exclusion of NOD2, MHC, and 3p21 (p=9 23 x 10 18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6%8%%%10%4). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Our additional papers associated with deliverable 3: genotype/clinical correlations 19. DNA polymorphisms predict time to progression from uncomplicated to complicated Crohn's disease. Eur J Gastroenterol Hepatol. 2018 Apr;30(4):447-455. [COBISS.SI-ID 6215999] 20. Crohn's disease candidate gene alleles predict time to progression from inflammatory B1 to stricturing B2, or penetrating B3 phenotype. Genet Test Mol Biomarkers. 2018 Feb 15. doi: 10.1089/gtmb.2017.0210. [COBISS.SI-ID 6250047]
COBISS.SI-ID: 512567352
Aim: To see if SNPs could help predict response to biological therapy using adalimumab (ADA) in Crohn's disease (CD). Materials & methods: IBDQ index and CRP levels were used to monitor therapy response. We genotyped 31 CD-associated genes in 102 Slovenian CD patients. Results: The strongest association for treatment response defined as decrease in CRP levels was found for ATG16L1 SNP rs10210302. Additional SNPs in 7 out of 31 tested CD-associated genes (PTGER4, CASP9, IL27, C11orf30, CCNY, IL13, NR1I2) showed suggestive association with ADA response. Conclusion: Our results suggest ADA response in CD patients is genetically predisposed by SNPs in CD risk genes and suggest ATG16L1 as most promising candidate gene for drug response in ADA treatment. Our results have been recently replicated in large USA study, Am J Gastroenterol, 2016 doi: 10.1038/ajg.2016.408). Additional papers with impact factor associated with project deliverable 3: pharmacogenomics biomarkers: 22. A Prospective Pharmacogenomic Study of Crohn's Disease Patients during Routine Therapy with Anti-TNF-α Drug Adalimumab: Contribution of ATG5, NFKB1, and CRP Genes to Pharmacodynamic Variability. OMICS. 2016 May;20(5):296-309. doi: 10.1089/omi.2016.0005. [COBISS.SI-ID 512594744] 24. Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn's Disease Patients. Biochem Genet. 2016 Aug;54(4):476-486. doi: 10.1007/s10528-016-9734-0. [COBISS.SI-ID 5689919]
COBISS.SI-ID: 512474168
Aim: To develop a risk model for Crohn's disease (CD) based on homogeneous population. Methods: In our study were included 160 CD patients and 209 healthy individuals from Slovenia. The association study was performed for 112 single nucleotide polymorphisms (SNPs). We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC). For risk evaluation, we divided individuals according to positive and negative likelihood ratios (LR) of a test, with LR ) 5 for high risk group and LR ( 0.20 for low risk group. Results: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. Individuals with the highest risk (GRS ) 5.54) showed significantly increased odds of developing CD (OR = 26.65, 95%CI: 11.25-63.15) compared to the individuals with the lowest risk (GRS ( 4.57) which is a considerably greater risk captured than in one SNP with the highest effect size (OR = 3.24). When more than 33 SNPs were included in GRS, discriminatory ability was not improved significantly; AUC of all 74 SNPs was 0.76. Conclusion: The authors proved the possibility of building accurate genetic risk score based on 33 risk variants on Slovenian CD patients which may serve as a screening tool in the targeted population.
COBISS.SI-ID: 5648447
Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules1. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles2, 3. To address this, we performed high-density SNP typing of the MHC in )32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD. Other papers with impact factor associated with c Deliverable 1: genome wide association study, genetics architecture of disease; : 2. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. [COBISS.SI-ID 512567608] 3. Albumin level is associated with CCNY gene polymorphism and response to anti-TNF treatment with adalimumab in Crohn’s disease patients. Research journal of life sciences, ISSN 2052-5176, 2015, vol. 2, iss. 1, str. 1-6. [COBISS.SI-ID 512560184] 4. Polymorphisms in recent GWA identified asthma genes CA10, SGK493, and CTNNA3 are associated with disease severity and treatment response in childhood asthma. Immunogenetics. 2014 Mar;66(3):143-51. doi: 10.1007/s00251-013-0755-0. [COBISS.SI-ID 17472790] 5. Rationale and design of the multiethnic pharmacogenomics in childhood asthma consortium. Pharmacogenomics. 2017 Jul;18(10):931-943. doi: 10.2217/pgs-2017-0035. [COBISS.SI-ID 512723512] 6. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. 2017 Feb;49(2):269-273. doi: 10.1038/ng.3745. [COBISS.SI-ID 512682296] 7. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. [COBISS.SI-ID 512606264]
COBISS.SI-ID: 512464184