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Low-Frequency IL23R Coding Variant Associated with Crohn's Disease Susceptibility in Japanese Subjects Identified by Personal Genomics Analysis.

ABSTRACT: BACKGROUND:The common disease-common variant hypothesis is insufficient to explain the complexities of Crohn's disease (CD) genetics; therefore, rare variants are expected to be important in the disease. We explored rare variants associated with susceptibility to CD in Japanese individuals by personal genomic analysis. METHODS:Two-step analyses were performed. The first step was a trio analysis with whole-exome sequence (WES) analysis and the second was a follow-up case-control association study. The WES analysis pipeline comprised Burrows-Wheeler Aligner, Picard, Genome Analysis Toolkit, and SAMTOOLS. Single nucleotide variants (SNVs)/indels were annotated and filtered by using programs implemented in ANNOVAR in combination with identity-by-descent (IBD), subsequently were subjected to the linkage based, and de novo based strategies. Finally, we conducted an association study that included 176 unrelated subjects with CD and 358 healthy control subjects. RESULTS:In family members, 234,067-297,523 SNVs/indels were detected and they were educed to 106-146 by annotation based filtering. Fifty-four CD variants common to both individuals of the affected sib pair were identified. The linkage based strategy detected five candidate variants whereas the de novo based strategy identified no variants. Consequently, five candidates were analyzed in the case-control association study. CD showed a significant association with one variant in exon 4 of IL23R, G149R [rs76418789, P = 3.9E-5, odds ratio (OR) 0.21, 95% confidence interval (CI) 0.09-0.47 for the dominant model (AA + AG versus GG), and P = 7.3E-5, OR 0.21, 95% CI 0.10-0.48 for AG versus GG, and P = 7.2E-5, OR 0.23, 95% CI 0.10-0.50 for the allele model]. CONCLUSIONS:The present study, using personal genomics analysis of a small CD pedigree, is the first to show that the low-frequency non-synonymous variant of IL23R, rs76418789, protects against CD development in Japanese subjects.

SUBMITTER: Onodera K

PROVIDER: S-EPMC4574159 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Low-Frequency IL23R Coding Variant Associated with Crohn's Disease Susceptibility in Japanese Subjects Identified by Personal Genomics Analysis.

Onodera Kei K Arimura Yoshiaki Y Isshiki Hiroyuki H Kawakami Kentaro K Nagaishi Kanna K Yamashita Kentaro K Yamamoto Eiichiro E Niinuma Takeshi T Naishiro Yasuyoshi Y Suzuki Hiromu H Imai Kohzoh K Shinomura Yasuhisa Y

PloS one 20150916 9

<h4>Background</h4>The common disease-common variant hypothesis is insufficient to explain the complexities of Crohn's disease (CD) genetics; therefore, rare variants are expected to be important in the disease. We explored rare variants associated with susceptibility to CD in Japanese individuals by personal genomic analysis.<h4>Methods</h4>Two-step analyses were performed. The first step was a trio analysis with whole-exome sequence (WES) analysis and the second was a follow-up case-control as ...[more]

PMID: 26375822

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Project description:AimTo assess whether the polymorphisms of NOD2/CARD15, autophagy-related 16-like 1 (ATG16L1), and interleukin-23 receptor (IL23R) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn's disease (CD).MethodsPolymorphisms R702W, G908R, and 3020insC of NOD2/CARD15; rs2241880 A/G of ATG16L1, and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymorphism analysis. The polymorphisms rs2241880 A/G of the ATG16L1, and rs11209026 (R381Q) of the IL23R gene in the children's cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K).ResultsThe 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without colonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to controls (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype.ConclusionPolymorphism 3020insC in NOD2/CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not early-onset disease.

Dataset Information

Low-Frequency IL23R Coding Variant Associated with Crohn's Disease Susceptibility in Japanese Subjects Identified by Personal Genomics Analysis.

Publications

Low-Frequency IL23R Coding Variant Associated with Crohn's Disease Susceptibility in Japanese Subjects Identified by Personal Genomics Analysis.

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