ABSTRACT At a time when complex diseases affect globally 280 million people and claim 14 million lives every year, there is an urgent need to rapidly increase our knowledge into their underlying etiologies. Though critical in identifying the people at risk, the causal environmental factors (microbiome and/or pollutants) and the affected pathophysiological mechanisms are not well understood. Herein, we consider the variations of autophagy-related (ATG) genes at the heart of mechanisms of increased susceptibility to environmental stress. A comprehensive autophagy genomic resource is presented with 263 single nucleotide polymorphisms (SNPs) for 69 autophagy-related genes associated with 117 autoimmune, inflammatory, infectious, cardiovascular, neurological, respiratory, and endocrine diseases. We thus propose the term ‘autophagopathies’ to group together a class of complex human diseases the etiology of which lies in a genetic defect of the autophagy machinery, whether directly related or not to an abnormal flux in autophagy, LC3-associated phagocytosis, or any associated trafficking. The future of precision medicine for common diseases will lie in our ability to exploit these ATG SNP x environment relationships to develop new polygenetic risk scores, new management guidelines, and optimal therapies for afflicted patients. Abbreviations: ATG, autophagy‐related; ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementia; ccRCC, clear cell renal cell carcinoma; CD, Crohn disease; COPD, chronic obstructive pulmonary disease; eQTL, expression quantitative trait loci; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; GTEx, genotype-tissue expression; GWAS, genome-wide association studies; LAP, LC3-associated phagocytosis; LC3-II, phosphatidylethanolamine conjugated form of LC3; LD, linkage disequilibrium; LUAD, lung adenocarcinoma; MAF, minor allele frequency; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NSCLC, non-small cell lung cancer; OS, overall survival; PtdIns3K CIII, class III phosphatidylinositol 3 kinase; PtdIns3P, phosphatidylinositol-3-phosphate; SLE, systemic lupus erythematosus; SNPs, single-nucleotide polymorphisms; mQTL, methylation quantitative trait loci; ULK, unc-51 like autophagy activating kinase; UTRs, untranslated regions; WHO, World Health Organization.

https://figshare.com/articles/journal_contribution/Autophagopathies_from_autophagy_gene_polymorphisms_to_precision_medicine_for_human_diseases/19525315/1/files/34707841.pdf

Autophagopathies: from autophagy gene polymorphisms to precision medicine for human diseases

To unveil the role and regulatory mechanism of miR‐146a‐5p in sepsis. A sepsis cell model was established via lipopolysaccharide (LPS)‐induction in dendritic cells (DCs). The maturation of DCs was evaluated via flow cytometry. Gene expression was measured through reverse‐transcription quantitative polymerase chain reaction (RT‐qPCR). The concentrations of inflammation biomarkers were revealed via enzyme‐linked immunosorbent assay (ELISA). The pathological and histological changes in lungs in the sepsis mice model were analyzed via hematoxylin and eosin (H&E) staining. In this study, the miR‐146a‐5p level was elevated in the serum of sepsis patients and LPS‐induced DCs but decreased in the serums of cured sepsis patients. Furthermore, miR‐146a‐5p deletion alleviated the activation of T cells and attenuated the imbalance of Th17/Treg. Besides, ATG7 was validated as a target of miR‐146a‐5p. ATG7 elevation enhanced lactate production and glucose uptake in LPS‐triggered DCs. Additionally, upregulation of ATG7 suppressed the protein levels of phosphorylated adenosine monophosphate‐activated protein kinase (p‐AMPK), phospho protein kinase B (p‐AKT), and phosphorylated signal transducer and activator for transcription 3 (p‐STAT3). In addition, miR‐146a‐5p downregulation alleviated T‐cell activation, inflammation, lactate production, and glucose uptake in sepsis mice. Moreover, the lung injury due to sepsis was also attenuated as a result of miR‐146a‐5p silencing. MiR‐146a‐5p aggravates sepsis through DCs activation and glycolysis via targeting ATG7.

MiR‐146a‐5p accelerates sepsis through dendritic cell activation and glycolysis via targeting ATG7

Iris Grosjean *, Barnabé Roméo *, Marie-Angela Domdom , Nathalie Yazbeck , Grégoire D’Andréa , Amine Belaid , Olivier Camuzard, Olivia Vidal , Guillemette Crépeaux , Romain K Gherardi , François Jerome Authier , Jean Daniel Masson , Eric Gilson , Charles Hugo Marquette, Sylvie Leroy , Jérémie Roux 1, Patrick Brest , Martin Von Bergen , Gérard Milano , Daniel J. Klionsky , Paul Hofman , Baharia Mograbi 1#

An Atlas of the Genetic Variations Linking Dysregulation of Autophagy to Human Diseases: The Missing Environmental Link

Autophagy is a dynamic self-renovation biological process that maintains cell homeostasis and is responsible for the quality control of proteins, organelles, and energy metabolism. The E1-like ubiquitin-activating enzyme autophagy-related gene 7 (ATG7) is a critical factor that initiates classic autophagy reactions by promoting the formation and extension of autophagosome membranes. Recent studies have identified the key functions of ATG7 in regulating the cell cycle, apoptosis, and metabolism associated with the occurrence and development of multiple diseases. This review summarizes how ATG7 is precisely programmed by genetic, transcriptional, and epigenetic modifications in cells and the relationship between ATG7 and aging-related diseases. 

Insights on E1-like enzyme ATG7: functional regulation and relationships with aging-related diseases

Association analysis of single nucleotide polymorphisms in autophagy related 7 (ATG7) gene in patients with coronary artery disease

Objective
To investigate the correlation between late-onset sporadic parkinson's disease(PD)and single nucleotide polymorphism(SNP)of autophagy-related genes 7(Atg7)rs2606757(6+ 1196A/T)in Han Chinese population.


Methods
Totally 124 patients with late-onset sporadic PD(the PD group)and 105 age- and sex-matched healthy individuals(the control group)were enrolled in this study.The SNP of Atg7 rs2606757 was detected by the polymerase chain reaction and restriction fragment length polymorphism(PCR-RFLP). After gene sequencing for the detection of allele and genotype frequencies distribution and testing Hardy-Weinberg equilibrium, the differences in Atg7 rs2606757 genotype and allele frequency were compared between PD group and control group and between males and females.


Results
The frequency of AA genotype was statistically significantly lower in the PD group[34.7%(43/124)]than in the control group[53.3%(56/105)](χ2=8.063, P=0.005, OR=0.465, 95%CI: 0.273-0.791). In men's PD group versus men's control group, AA genotype of the Atg7 rs2606757 showed a lower frequency for late-onset sporadic PD[33.3%(23/69)vs.53.2%(33/62), χ2=5.280, P=0.022, OR=0.439, 95%CI: 0.217-0.891]. Logistic regression analysis indicated that the AA genotype frequency distribution of Atg7 rs2606757 showed a significant difference between PD and control groups(OR=2.210, 95%CI: 1.289-3.789, P=0.004).


Conclusions
The higher frequence of AA genotype at Atg7 rs2606757 only in males might be associated with the decreased risk of late-onset sporadic PD.


Key words: 
Autophagy; Atg7; Polymorphism single nucleotide; Parkinson's disease

Correlation between late-onset sporadic Parkinson's disease and single nucleotide polymorphism of Atg7 rs2606757

Objective
To investigate the association between rs14016(19+31C/T) polymorphisms of autophagy-related genes 7 (Atg7) and Parkinson's disease (PD) in Han population in China.


Methods
Totally 123 patients with Parkinson's disease (PD) (case group) and 101 synchronized health controls (control group) were selected from Chinese Han population between January 2013 and July 2016.A single nucleotide polymorphism (SNP) of rs14016 of Atg7 gene was detected by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.After gene sequencing for genotyping and detection of alleles, genotype and allele frequency distributions were analyzed in the two groups.


Results
The frequency distributions of TT genotype and T alleles were 17.9% (22/123) and 41.1% (101/246) in the case group, and 5.9% (6/101) and 31.2% (63/202) in the control group, respectively.The difference in genotype frequencies between the two groups was statistically significant (χ2=7.236, P=0.007, OR=3.01, 95% CI: 1.27-7.14). The frequencies of T and C alleles were 41.1% (101/246) and 58.9% (145/246) respectively in the case group, and 31.2% (63/202) and 68.8% (139/202) in the control group (χ2=4.655, P=0.031, OR=1.32, 95%CI: 1.02-1.70), with the statistically significant difference in the allele.The TT genotype of rs14016 showed statistical significance between the two groups by logistic regression analysis (OR=3.40, 95%CI: 1.32-8.80, P=0.012).


Conclusions
The T allele and TT genotype at the rs14016 of Atg7 gene might be associated with PD, and might increase the risk for suffering from PD, which is worthy of further fully researches.


Key words: 
Autophagy-related genes 7; Polymorphism, single nucleotide; Parkinson disease; Autophagy

The analysis of correlation between single nucleotide polymorphism at Atg7 rs14016 and Parkinson's disease

Background: Autophagy-related gene 7 (ATG7) plays a key role in autophagy and is strongly implicated in Parkinson’s disease (PD). This study investigated the associations of rs1375206 polymorphism ...

Associations of ATG7 rs1375206 polymorphism and elevated plasma ATG7 levels with late-onset sporadic Parkinson's disease in a cohort of Han Chinese from southern China.

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Correlation between late-onset sporadic Parkinson's disease and single nucleotide polymorphism of Atg7 rs2606757

The analysis of correlation between single nucleotide polymorphism at Atg7 rs14016 and Parkinson's disease

Associations of ATG7 rs1375206 polymorphism and elevated plasma ATG7 levels with late-onset sporadic Parkinson's disease in a cohort of Han Chinese from southern China.