Table 1. Examples of autophagy genetic variants associated with chronic inflammatory disorders.
| Disease | Variant | Proposed mechanism | Refs |
|---|---|---|---|
| Crohn disease | T300A coding variant of ATG16L1 (rs2241880) |
Destabilization of ATG16L1: • increased inflammasome activation • defects in secretory lineages of the intestinal epithelium • impaired xenophagy • failure to induce Treg cell differentiation • imbalanced relationship with the gut microbiota |
48,49,52,139,140,166 |
| Graft-versus-host disease | T300A coding variant of ATG16L1 (rs2241880) | Hyperactive autophagy-deficient DCs induce enhanced proliferation of donor-derived T cells in allogeneic HSCT recipients | 144 |
| Systemic lupus erythematosus | Polymorphism in a non-coding region proximal to ATG5 (rs548234) |
Increased ATG5 expression: • enhanced autophagy or LAP • increased TLR-mediated responses to nucleic acidsDecreased ATG5 expression: • impaired clearance of dead cells, which can increase systemic cytokine levels downstream of LAP deficiency |
62,146,148,150,151 |
| Asthma | Polymorphism in ATG5 promoter region (rs12201458, rs510432) |
Increased ATG5 promoter activity: • augmented goblet cell differentiation and mucus production |
145,147 |
| Vici syndrome | Loss-of-function mutations in EPG5 (recessive coding variants) |
EPG5* deficiency: • increased inflammation • immune dysfunction observed in some patients |
26,167 |
| Rheumatoid arthritis, type 1 diabetes, multiple sclerosis, Crohn disease, systemic lupus erythematosus, coeliac disease and primary biliary cirrhosis | Non-coding variants of PTPN22 (rs6679677, rs2476601 and rs1893217) and CLEC16A (rs2903692, rs725613 and rs17673553) |
Loss of PTPN22‡ and CLEC16A§ function: • inhibited degradation of autophagy substrates • impaired antigen presentation by thymic epithelial cells and generation of autoreactive T cells • loss of pancreatic β-cell function through reduced mitophagy (CLEC16A mutant) • it is unclear how these findings fit with the requirement of autophagy for generating citrullinated peptides recognized by T cells in rheumatoid arthritis |
129,166,168,169,170,171,172,173,174 |
CLEC16A, C-type lectin domain family 16 member A; DC, dendritic cell; EPG5, ectopic P granules protein 5 homologue; HSCT, haematopoietic stem cell transplant; LAP, LC3-associated phagocytosis; PTPN22, tyrosine-protein phosphatase non-receptor type 22; TLR, Toll-like receptor; Treg cell, regulatory T cell.
*EPG5 mediates the degradative function of autophagy, which is necessary to prevent myopathies.
‡PTPN22 regulated NOD2-induced autophagy.
§CLEC16A is a regulator of mitophagy.