Endocrine Abstracts

Background: Loss of autophagy protein ATG16L1 enhances endotoxin-induced interleukin 1β (IL1β) production. IL1β has been found to have antineoplastic effects in thyroid malignancies. We hypothesized that a missense polymorphism in ATG16L1 autophagy gene (Thr300Ala) results in changes in the function of the molecule and influences susceptibility to and prognosis of epithelial cell derived thyroid carcinoma (TC).

Objective: i) To assess the functional differences between the 300Thr (A) and 300Ala (G) allele of ATG16L1; and ii) to assess whether ATG16L1 Thr300Ala polymorphism influences the susceptibility to and the prognosis of TC.

Patients and methods: The ATG16L1 genotype was analyzed by PCR in 139 TC patients and 136 healthy controls. In the control group peripheral blood mononuclear cells were stimulated with the NOD2 ligand muramyl dipeptide (MDP). The ATG16L1 function was assessed by measuring IL1β 24 h later. Within the patients group we analyzed the genotype-phenotype associations.

Results: MDP-stimulated IL1β production was significantly higher in individuals bearing the GG/GA allele compared to those bearing AA allele, supporting a gene-dosage or a dominant effect of the 300Ala variant on the function of the molecule. The difference in genotype frequencies between the patients and control groups were analyzed in a gene dosage dependent model using logistic regression and in a dominant model using χ² analysis. The G allele of ATG16L1 is associated with decreased risk for TC (OR=0.46, P=0.041 in the gene dose dependent model, and OR=0.51, P=0.025 in a dominant model). Furthermore, patients carrying the AG/GG genotype had a higher chance of successful I¹³¹ ablation (P=0.017) and required a lower cumulative I¹³¹ dose to achieve remission (P=0.014) than patients carrying the AA genotype.

Conclusions: The Thr300Ala ATG16L1 polymorphism has important functional consequences, with significantly higher IL1β release in individuals bearing the 300Ala variant. The 300Ala allele was associated with both a lower susceptibility for TC and lower I¹³¹ dose required to achieve remission.