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Autophagy as an important process in gut homeostasis and Crohn’s disease pathogenesis
  1. Ramnik J Xavier1,
  2. Alan Huett1,
  3. John D Rioux2
  1. 1
    Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  2. 2
    Université de Montréal and the Montreal Heart Institute, Research Center, Montreal, Quebec, Canada
  1. Dr J D Rioux, Université de Montréal and the Montreal Heart Institute, Research Center, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada; john.rioux{at}inflammgen.org

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Crohns disease (CD) is a complex polygenic trait whereby multiple genetic and non-genetic risk factors contribute to disease susceptibility. Association testing is a statistical approach commonly used for identifying genetic risk factors for complex/multigenic disease, which typically compares the allele frequency of a selected marker, most often a bi-allelic single nucleotide polymorphism (SNP), for differences between patient and control populations. SNPs represent most of the common genetic variation, with an estimated 10 million SNPs found in the human genome.1 Although a powerful statistical approach, until recently the majority of association studies were limited to the examination of a small number of candidate genes, the selection of which will inevitably be biased by the current knowledge of disease pathogenesis. Following some key developments in our understanding of genetic variation within the human genome, as well as technological advances that have enabled affordable genotyping of 300 000–1 000 000 SNPs per study subject (and, therefore, ∼1 billion genotypes or more per genetic study), association testing can now be applied genome wide in order to search for genetic risk factors in an unbiased manner.24

In one of the first genome-wide association studies (GWAS), we and our colleagues of the NIDDK IBD Genetics Consortium tested approximately 300 000 SNPs in 1000 patients with CD and in 1000 healthy individuals, and identified association with variants in the autophagy-related 16-like 1 (Saccharomyces cerevisiae) or ATG16L1 gene.5 The ATG16 gene product is part of a multimeric protein complex that is essential for autophagy, a biological process that mediates the bulk degradation of cytoplasmic components in lysosomes and vacuoles.6 This recent GWAS specifically identified an associated SNP that encodes a non-synonymous amino acid change—an alanine to threonine substitution in exon 8 (also known as Ala197Thr)—in the human equivalent of the ATG16 gene. In all of the …

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