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Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.

ABSTRACT: Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

SUBMITTER: Kugathasan S

PROVIDER: S-EPMC2770437 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.

Kugathasan Subra S Baldassano Robert N RN Bradfield Jonathan P JP Sleiman Patrick M A PM Imielinski Marcin M Guthery Stephen L SL Cucchiara Salvatore S Kim Cecilia E CE Frackelton Edward C EC Annaiah Kiran K Glessner Joseph T JT Santa Erin E Willson Tara T Eckert Andrew W AW Bonkowski Erin E Shaner Julie L JL Smith Ryan M RM Otieno F George FG Peterson Nicholas N Abrams Debra J DJ Chiavacci Rosetta M RM Grundmeier Robert R Mamula Petar P Tomer Gitit G Piccoli David A DA Monos Dimitri S DS Annese Vito V Denson Lee A LA Grant Struan F A SF Hakonarson Hakon H

Nature genetics 20080831 10

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a s ...[more]

PMID: 18758464

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Project description:BackgroundThe incidence of pediatric inflammatory bowel disease (PIBD) has increased dramatically during the past decades. This implies involvement of environmental factors in etiology but lends no clues about specific agents. We evaluated clustering in time and place of residence at PIBD onset using a case-control setting with comprehensive nationwide register data.MethodsWe included all PIBD cases diagnosed at ages < 18 years during 1992-2017 (3748 cases; median age of 14.6; 2316 (58%) with ulcerative colitis (UC), 1432 with Crohn's, and 18,740 age- and sex-matched controls) and constructed complete residential histories (including coordinates) from the national database until the date of the diagnosis of the case assigned as index date for the controls. Using the coordinates of the addresses of the subjects and the diagnosis/index dates, we evaluated clustering in time and place using the Knox test. Four temporal (2, 4, 6, 12 months) and four distance (0.25, 0.5, 1, 5 km) thresholds were used, and results were calculated separately for Crohn´s disease and UC. Similar analyses were conducted using the addresses at birth and the addresses five years before the diagnosis or index date. Based on the threshold values displaying the most clustering in the Knox test, logistic regression models were built to identify whether sex, age at diagnosis or the year of diagnosis affected the probability of belonging to a cluster. To analyze clustering in time and place throughout the residential histories, we used Jacquez's Q with an open-access python program pyjacqQ.ResultsThe mean number of residencies until the index date was 2.91 for cases and 3.05 for controls (p = 0.0003). Knox test indicated residential clustering for UC with thresholds of 500 m between locations and time-period of four months (p = 0.004). In the regression analysis, sex, age at diagnosis or year of UC diagnosis did not show differences between the clustered and other cases. Jacquez Q analyses showed higher than expected frequency of clustered cases throughout residential histories (p < 10- 8).ConclusionOur findings suggest that the incidence of PIBD, especially of UC, exhibits clustering in locations of residencies over time. For the clustered cases, environmental triggers warrant future studies.

Dataset Information

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.

Publications

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.

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