Detailed Haplotype-Tagging Study of Germline Variation of MUC19 in Inflammatory Bowel Disease

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 Haploview diagram of selected SNPs in the region of LRRK2 and MUC19. Red box on left = rs11175593 (WTCCC SNP), 3 red boxes on right = MUC19 SNPs genotyped in our cohort. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] In order to narrow down the signal at this locus we genotyped tagging single nucleotide polymorphisms (SNPs) across the MUC19 gene in a cohort of Scottish inflammatory bowel disease (IBD) patients and controls. MUC19 SNPs were chosen using solid spine of linkage disequilibrium (LD) to tag haplotypic variation of the MUC19 gene including the extended 5′ and 3′ regions (haplotype frequency >5%), and required 3 SNPs. These SNPs were genotyped on the Taqman genotyping platform (Applied Biosystems, Foster City, CA) in a cohort of Scottish IBD patients and controls consisting of 437 CD patients, 451 ulcerative colitis (UC) patients, and 428 population controls. All IBD cases were phenotyped according to the Montreal Classification.6 Given that the case–control OR of association of rs11175593 with CD was 1.54, our study had more than 95% power to detect an association with CD for each of the 3 tagging variants, allowing for an OR of greater than 1.2. Single marker and haplotype susceptibility analyses did not show an association with any of the MUC19 haplotype-tagging variants, in IBD overall, or CD or UC separately (Table 1). In addition, a detailed genotype–phenotype analysis for both CD and UC according to the Montreal Classification was also negative (Tables 2, 3). Allelic Frequencies in CD, UC, and Controls and Associated P Values Allelic Frequencies in CD, UC, and Controls and Associated P Values CD Subphenotypic Analysis: Allelic Frequencies and Associated P Values CD Subphenotypic Analysis: Allelic Frequencies and Associated P Values UC Subphenotypic Analysis: Allelic Frequencies and Associated P Values UC Subphenotypic Analysis: Allelic Frequencies and Associated P Values Further detailed analysis of available HapMap data showed a complete lack of LD between rs11175593 and the three MUC19 tagging variants (r2 = 0). Our data suggest that the genomewide significant association of the 12q12 locus with CD is not attributable to germline variation of the MUC19 gene. In fact, looking across all known SNPs in the MUC19 gene on available HapMap data, only 1 SNP has any LD with rs11175593. Multiple SNPs within the LRRK2 gene, however, have D′ and r2 of 1 with rs11175593. Overall, the data would suggest that LRRK2 is likely to represent the susceptibility gene at this region. Until now, interest in LRRK2 has been in the context of the neurodegenerative disorder Parkinson's disease, as LRRK2 mutations are closely associated with some cases of genetically inherited Parkinson's.7 Autophagy plays an active role in neurite degeneration in cell lines that express mutant LRRK2,8 making it likely that autophagy is a key player in Parkinson's disease pathogenesis. Defective autophagy in CD is being increasingly recognized as important in disease pathogenesis, probably through dysregulated autophagy preventing the breakdown of intracellular pathogens. Although the LRRK2 gene has a complicated haplotypic structure requiring a large number of SNPs to cover the gene, it is potentially an important player in the rapidly evolving story of autophagy in IBD.

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