Imielinski, M., Baldassano, R. N., Griffiths, A., Russell, R. K., Annese, V., Dubinsky, M. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41, 1335-1340

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Nature Genetics (Impact Factor: 29.35). 11/2009; 41(12):1335-40. DOI: 10.1038/ng.489
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The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

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Available from: Richard Russell, Mar 03, 2014
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    • "Silverberg et al. [71] UC No proctitis North America 1052 UC 2571 1405 UC 1115 2009 Illumina 550k; Affymetrix custom 10k Asano et al. [72] UC Japan 749 UC 2031 635 UC 1026 2009 Affymetrix 1000k UKIBDGC [73] UC UK 2361 UC 5417 2321 UC 4818 2009 Illumina 550k Imielinski et al. [74] IBD "
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    ABSTRACT: Abstract The two major subtypes of inflammatory bowel disease (IBD), ulcerative colitis (UC, MIM#191390) and Crohn's disease (CD, MIM#266600), are chronic relapsing-remitting inflammatory disorders affecting primarily the gastrointestinal tract. Prevalence rates in North America and Europe range from 21 to 246 per 100,000 for UC and 8 to 214 per 100,000 for CD. Although CD and UC share some clinical and pathological features, they can be distinguished by localization, endoscopic appearance, histology and behavior, which suggest differences in the underlying pathophysiology. The importance of genetic risk factors in disease etiology is high and has been documented more clearly for CD than for UC (relative sibling risks λs: 15-35 for CD, 6-9 for UC). The most recent and largest genetic association study for IBD, which employed genome-wide association data for over 75,000 patients and controls, established the association of 163 susceptibility loci with IBD. Although the disease variance explained by the 163 loci only amounts to 13.6% for CD and 7.5% for UC, the identified loci and the candidate genes within yielded valuable insights into the pathogenesis of IBD and the relevant disease pathways. We here review the current research on the genetics of IBD and provide insights into on current efforts as well as suggest topics for future research.
    Scandinavian Journal of Gastroenterology 01/2015; 50(1):13-23. DOI:10.3109/00365521.2014.990507 · 2.36 Impact Factor
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    • "rs713875 is a C/G variant located downstream of the HORMAD2 and LIF genes that has been implicated in multiple diseases, including Crohn's disease [27], IgA nephropathy [28] and early-onset inflammatory bowel disease [29]. It is also an eQTL for MTMR3 [16] and a DNAse sensitive quantitative trait loci for the chr22:28922487–28922487 region [30]. "
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    ABSTRACT: We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results.
    PLoS ONE 06/2014; 9(6):e98464. DOI:10.1371/journal.pone.0098464 · 3.23 Impact Factor
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    • "A male genome-wide association dominance has been observed in children with CD, while females are more frequently affected in adulthood. Despite higher familial occurrence of IBD in children genomewide association studies showed that multiple genes conferring susceptibility are comparable [49, 50]. A key feature of pediatric-onset IBD is the potential impaired growth retardation and delayed puberty. "
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    ABSTRACT: New epidemiological data suggest that the incidence of inflammatory bowel disease (IBD) is increasing. As a result the burden of disease accounts for more strains to the health care system. The clinical variability queries whether disease characteristics are related to clinical outcome. Our aim was to delineate the latest results of incidence trends in pediatric IBD and to compare the first experiences with Paris Classification. Incidence of pediatric IBD has been increasing in Western Europe and in Eastern Europe. To better characterize IBD, Paris Classification was introduced and validated recently. Ileocolonic involvement is the most characteristic disease location in Crohn's disease (CD) based on applying Paris Classification. The rate of perianal disease and complicated behaviour in CD was similar. It is of interest that CD patients with colonic involvement were less likely to have stricturing disease compared with patients with ileal involvement. In addition, pancolitis dominated in ulcerative colitis (UC). However, most countries lack prospective, nationwide epidemiological studies to estimate incidence trends. This review emphasizes the importance of nationwide registries that enroll all pediatric IBD cases serving reliable data for "everyday practice." These first reports have shown that Paris Classification is a useful tool to determine the pediatric IBD phenotype.
    Gastroenterology Research and Practice 03/2014; 2014:904307. DOI:10.1155/2014/904307 · 1.75 Impact Factor
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