Polymorphisms in Autophagy Genes Are Associated with Paget Disease of Bone

Abstract

Paget disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The main alteration resides in osteoclasts that increase in size, number and activity. Many osteoclasts have cytoplasmic inclusions that have been associated with protein aggregates, increasing the evidences of a possible deregulation of autophagy in the development of the PDB. Autophagy starts with encapsulation of the target into a double-membrane-bound structure called an “autophagosome.” It has been reported that at least 18 ATG genes (autophagy-related genes) are involved in autophagosome formation. We have studied the distribution of genotypes of the ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183 and ATG5 rs2245214 polymorphisms in a Spanish cohort of subjects with PDB and compared with healthy subjects. Our results show that being a carrier of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing PDB, whereas being a carrier of the T allele of ATG10 rs1864183 polymorphism decreased the risk of suffering the disease in our series. This is the first report that shows an association between autophagy and Paget Disease of Bone and requires further confirmation in other series.

Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non–Small Cell Lung Cancer after Definitive Radiotherapy

“…29 In contrast, in another study of 238 patients with paget disease of bone (PDB) and 264 sex-matched controls, Usategui-Martin et al found that genotype frequencies did not significantly differ between PDB patients and healthy subjects. 45 In the present study, we observed that ATG2B rs17784271 variant G allele was associated with a poor LRFS and PFS, but we did not find an association of the variant genotypes with risk of severe RP and OS in patients with NSCLC, suggesting that the ATGB2 rs17784271 variant G allele may play a role in the LRF and PFS of NSCLC after definitive radiotherapy.…”

Association of single nucleotide autophagy‐related protein 5 gene polymorphism rs2245214 with susceptibility to non–small cell lung cancer

“…In contrast, the C‐allele did not affect morbidity risk of this disease . Unlike our study, previous findings indicated that the GG genotype of this polymorphism increases morbidity of thyroid carcinoma and that the ATG5 G‐allele increases the risk of morbidity, whereas in the current study C‐allele improves the risk of morbidity of lung cancer. Others showed that the frequency distribution of genotypes in myeloma disease was not significantly different between patients and healthy controls .…”

“…In our study, it was shown that GG genotype of the intronic polymorphism rs2245214 can be a protective factor for NSCLC, which may be due to regulatory effects by this polymorphism on ATG5 function; future in-depth studies are warranted. In a study by Usatequi-Martin et al, 30 no significant relationship between genotype of the rs2245214 ATG5 gene polymorphism and risk of morbidity of Paget's disease was observed. This finding is different from ours, which may be due to a distinct disease nature of Paget's disease and lung cancer.…”

“…Defects in the autophagy pathway or variations in the genes associated with this pathway have been identified in different kinds of human diseases, such as neurodegenerative and lysosomal disorders, and also in various cancers . On the basis of many recent investigations, the relationship between autophagy and different types of diseases including Paget’s disease; lupus erythematosus; and breast, thyroid, colorectal, cerebrocervical, and lung cancers have been recognized for having single‐nucleotide polymorphisms (SNPs) in ATG genes …”

Nuevas aproximaciones en el estudio de la ruta autofágica en cáncer colorrectal

“…El polimorfismo de ATG5 rs2245214 genera un cambio intrónico y ha sido previamente estudiado en enfermedades como la tuberculosis, el lupus eritematoso, la enfermedad ósea de Paget, el cáncer de tiroides no medular y el melanoma (145)(146)(147)(148). En nuestro estudio no hemos encontrado diferencias significativas entre los pacientes con SL, PAF, CCR esporádico y el grupo control.…”