PDF《Autophagy》

ATG16L1, autophagy-related 16-like

1 (S. cerevisiae);

c., coding sequence;

CD, Crohn disease;

ER, endoplasmic reticulum;

GWAS, genome-wide association studies;

IBD, inflammatory bowel disease;

IRGM, immunity-related GTPase family, M;

LPS, lipopolysaccharide;

LRRK2, leucine-rich repeat kinase 2;

MB-MDR, model- based multifactor dimensionality reduction;

MTMR3, myotubularin-related protein 3;

NOD2, nucleotide-binding oligomerization domain-containing 2;

ORMDL3, ORM1-like

3 (S. cerevisiae);

p., protein position;

rs, reference SNP;

SNP, single nucleotide polymorphism;

UC, ulcerative colitis;

ULK1, unc-51 like autophagy activating kinase 1;

UPR, unfolded protein response;

XBP1, X-box binding protein

1 Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress (XBP1 and ORMDL3) to be associated with Crohn disease (CD). We studied the known CD-associated variants in these genes in a large cohort of

3451 individuals (1744 CD patients,

793 ulcerative colitis (UC) patients and

914 healthy controls). We also investigated the functional phenotype linked to these genetic variants. Association with CD was confirmed for NOD2, ATG16L1, IRGM, MTMR3, and ORMDL3. The risk for developing CD increased with an increasing number of risk alleles for these genes (P <

0.001, OR 1.26 [1.20 to 1.32]). Three times as many (34.8%) CD patients carried a risk allele in all three pathways, in contrast to 13.3% of the controls (P <

0.0001, OR = 3.46 [2.77 to 4.32]). For UC, no significant association for one single nucleotide polymorphism (SNP) was found, but the risk for development of UC increased with an increasing total number of risk alleles (P = 0.001, OR = 1.10 [1.04 to 1.17]). We found a genetic interaction between reference SNP (rs)2241880 (ATG16L1) and rs10065172 (IRGM) in CD. Functional experiments hinted toward an association between an increased genetic risk and an augmented inflammatory status, highlighting the relevance of the genetic findings. www.landesbioscience.com Autophagy

2047 Basic Research Paper Basic Research Paper From the CD GWAS and meta-analyses three major pathways emerged that seem primarily important for CD pathogenesis: microbial sensing, autophagy, and endoplasmic reticulum (ER) stress. The first CD susceptibility gene identified was NOD2.4 NOD2 is expressed intracellularly, particularly in monocytes and Panethcells,andencodesNOD2,areceptorformuramyldipeptide, a component of peptidoglycan present in bacterial cell walls. NOD2 plays an important role in innate immunity in modulating signaling through oll-like receptor pathways and activating NFKB.5 The three NOD2 variants most commonly associated with CD are two missense mutations, arginine

702 to tryptophan (p.R702W, rs2066844), and glycine

908 to arginine (p.G908R, rs2066845), as well as a frameshift mutation resulting from a cytosine insertion after amino acid

1007 (p.L1007fs [frameshift], rs2066847). These variants are located in or near the leucine- rich repeat region of NOD2, the ligand-binding domain of this receptor, each impairing responses to peptidoglycan stimulation. The identification of NOD2 as a susceptibility gene indicated for the first time the importance of defects in microbial sensing as a key pathogenic mechanism in IBD. In two GWAS published in 2007, two of the strongest associations occur with ATG16L1 and IRGM, genes encoding for proteins essential for the autophagy process.6,7 Autophagy is a cellular lysosomal pathway for the removal of damaged or excessive cytoplasmic components, including proteins and entire organelles, performing major homeostatic functions such as nutrient provision and quality control.8 It also plays a crucial role in the immune system for elimination of intracellular pathogens, presentation of endogenous antigens and shaping B- and T-cell function. The ATG16L1 variant (rs2241880), encoding an amino acid changing polymorphism (T300A), results in abnormal Paneth cell structure and function, and impaired bacterial handling.9 IRGM, for which rs10065172 and rs4958847 are the known CD-associated variants, is critical for both the initiation and the maturation of xenophagy.10 Rs10065172 (c.313C >