Faculty Collaboration Database

Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping. PLoS One 2015;10(6):e0128074

Date

06/23/2015

Pubmed ID

26098103

Pubmed Central ID

PMC4476779

DOI

10.1371/journal.pone.0128074

Scopus ID

2-s2.0-84939133461 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

BACKGROUND: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.

METHODS: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.

CONCLUSIONS: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

Author List

Cutler DJ, Zwick ME, Okou DT, Prahalad S, Walters T, Guthery SL, Dubinsky M, Baldassano R, Crandall WV, Rosh J, Markowitz J, Stephens M, Kellermayer R, Pfefferkorn M, Heyman MB, LeLeiko N, Mack D, Moulton D, Kappelman MD, Kumar A, Prince J, Bose P, Mondal K, Ramachandran D, Bohnsack JF, Griffiths AM, Haberman Y, Essers J, Thompson SD, Aronow B, Keljo DJ, Hyams JS, Denson LA, PRO-KIIDS Research Group, Kugathasan S

Author

Joshua D. Noe MD Associate Dean, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Age of Onset
Alleles
Base Sequence
Child
Colitis, Ulcerative
Crohn Disease
Female
Genetic Predisposition to Disease
Genotype
Humans
Male
Nod2 Signaling Adaptor Protein
Polymorphism, Single Nucleotide
Receptors, Interleukin
Sequence Analysis, DNA