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To the Editor:

The identification of a large number of genetic loci associated with susceptibility to inflammatory bowel disease (IBD) has implicated a wide range of biological processes in IBD pathogenesis.1 Genetic association studies to date have fallen short of explaining the total heritability of IBD. The “heritability gap” may be the result of a combination of low-frequency exonic alleles, as yet undefined intronic variants, copy number variation, epistasis, gene–environmental interaction or epigenetic changes.2

The IL12/23 pathway is critical in determining the genetic susceptibility to Crohn’s disease (CD) and deep sequencing analyses of the interleukin 23 receptor gene (IL23R) have identified several low-frequency exonic variants, particularly in individuals who are wild-type for the 3 common NOD2− polymorphisms.3,–5

The functional investigation of the genomic locus containing IL23R is hampered by the fact that, in addition to the widely replicated association of the Arg381Gln variant with CD, multiple additional association signals throughout the IL23R gene have been identified in adult onset CD.3,–7 To assess the extent of gene-wide association of IL23R to childhood IBD susceptibility without any bias toward putative function of the variants and to investigate gene–gene interaction with NOD2, we performed a haplotype-tagging investigation in 709 subjects, consisting of 357 childhood patients with IBD (233 CD, 86 ulcerative colitis, 38 IBD-type unspecified) and 352 population-matched controls. Detailed phenotypic data of the childhood IBD cohort were previously published.8

Issue Section:
Letters to the Editor
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