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Extract

To the Editor:

Since the discovery of NOD2 as a Crohn's disease (CD) susceptibility gene, more recent genomewide association scans (GWAS), detecting loci conferring odds ratios (OR) of above 1.3–1.5, have uncovered a large number of further susceptibility loci and genes, including IL23R in the TH17 pathway, and the autophagy genes ATG16L1 and IRGM.1,2 By combining cohorts the power to detect lower ORs is further improved. A recent meta-analysis,3 combining British, North American, and Belgian-French GWAS, has led to the discovery of several new loci involved in CD susceptibility, with OR 1.1–1.5. Even so, the determinants identified to date account for only ≈20% of the estimated heritability of CD.

The strongest novel locus identified in this study was tagged by the rs11175593 variant, and estimated to confer an OR of 1.54 for CD susceptibility. This variant lies within the chromosome 12q12 locus and is within 40 kbp (kilobasepairs) of the leucine-rich repeat kinase 2 (LRRK2) gene and 360 kbp of the MUC19 gene (Fig. 1). Both these genes are extremely plausible biological candidates for CD susceptibility genes. The family of MUC genes encode for mucins, heavily glycosylated proteins forming an important part of barrier protection of epithelial cell surfaces.4 LRRK2 is involved in autophagy, which is increasingly recognized as being implicated in CD pathogenesis.5

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Letters to the Editor
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