Regulation of mammalian autophagy in physiology and pathophysiology.

(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.

Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship.

BACKGROUND & AIMS: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. METHODS: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. RESULTS: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. CONCLUSIONS: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.

Genetic association between NLRP3 variants and Crohn's disease does not replicate in a large UK panel.

BACKGROUND: NLRP3 (formerly known as CIAS1 or NALP3) encodes a key component of the inflammasome and is a strong candidate gene for Crohn's disease (CD) susceptibility. A recent study reported significant and internally replicated association between CD and six single nucleotide polymorphisms (SNPs) in a regulatory region 5.3 kb downstream of NLRP3. Independent replication is required to verify these findings. METHODS: In all, 1298 CD cases and 1244 healthy controls were genotyped for the six SNPs using Taqman. Single locus, haplotype, and subphenotype analyses were conducted using logistic regression-based methods and PLINK, respectively. RESULTS: No significant associations were found, either on single locus, subphenotype, or haplotype analysis. CONCLUSIONS: Given our high (>90%) power to replicate findings from the index study, our data suggest either a much smaller effect size for the association between NLRP3 and CD susceptibility than previously reported or the possibility of a false-positive result in the index study. Further studies in other populations are required to determine what role, if any, NLRP3 variants play in CD susceptibility.

Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease.

The era of genome-wide association (GWA) scanning has shed new light on the genetic basis of common disease and nowhere is this better illustrated than Crohn's disease (CD). CD is a chronic debilitating inflammatory bowel disease characterized by stricturing and fistula formation. Mainstays of current therapy are immune suppression and surgery. The pathogenesis of CD is poorly understood, but it has long been recognized that both genetic susceptibility and bacterial antigens play important roles. A variety of intracellular bacteria have been postulated to trigger CD, but the evidence for any one organism is equivocal. The current consensus is that commensal gut bacteria provide the drive for CD-related inflammation. Three GWA scans undertaken in the last 6 months have identified 10 new loci demonstrating highly significant and replicated association with CD. Two of the strongest hits implicate genes IRGM and ATG16L1, which encode proteins thought to be critical to the autophagy pathway. The critical next step is functional characterization of the CD-associated genetic variants in IRGM and ATG16L. It seems highly plausible that variation in these genes holds the key to understanding exactly which bacteria drive the intestinal inflammation of CD and the mechanism by which they do this.