Genetic variation in autophagy-related genes influences the risk and phenotype of Buruli ulcer
| Autor: | Fernando Rodrigues, Cristina Cunha, Jorge Pedrosa, Carlos Capela, Ange Dodji Dossou, Ghislain Emmanuel Sopoh, Rita Silva-Gomes, João F. Menino, Michel Makoutodé, Agostinho Carvalho, Alexandra G. Fraga |
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| Přispěvatelé: | Universidade do Minho |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Bacterial Diseases 0301 basic medicine Heredity Genotyping Techniques Nod2 Signaling Adaptor Protein Autophagy-Related Proteins Health services Medicine and Health Sciences Medicine Child Buruli Ulcer Cell Death lcsh:Public aspects of medicine Fungal genetics 3. Good health Actinobacteria Phenotypes Genetic Mapping Infectious Diseases Cell Processes Host-Pathogen Interactions Female Research Article Neglected Tropical Diseases Adult medicine.medical_specialty lcsh:Arctic medicine. Tropical medicine Adolescent Ciências Médicas::Ciências da Saúde Ciências da Saúde [Ciências Médicas] lcsh:RC955-962 Ubiquitin-Protein Ligases Autophagic Cell Death Variant Genotypes Mycology Genetic Predisposition Polymorphism Single Nucleotide Risk Assessment Young Adult 03 medical and health sciences Genetic variation Autophagy Genetics Humans Genetic Predisposition to Disease Fungal Genetics Gynecology Science & Technology Mycobacterium ulcerans Bacteria business.industry Organisms Public Health Environmental and Occupational Health Biology and Life Sciences Human Genetics lcsh:RA1-1270 Cell Biology Tropical Diseases Surgery 030104 developmental biology Genetics of Disease Carrier Proteins business |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP PLoS Neglected Tropical Diseases, Vol 10, Iss 4, p e0004671 (2016) ResearcherID PLoS Neglected Tropical Diseases |
| Popis: | Introduction Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. Objective Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. Methods Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. Results The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). Conclusion Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes. Author Summary Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. Because the exact trigger is still under investigation, current treatment options rely mostly on the surgical excision of the affected site. There is therefore a pressing demand for improved risk prediction and tailored treatment as well as for new drug targets. By resorting to the largest case-control study reported to date, we show that genetic variation in the autophagy-related genes NOD2, PARK2 and ATG16L1 influence the risk and course of BU disease. Thus, our results provide crucial insights into the role of autophagy in the pathogenesis of BU. |
| Databáze: | OpenAIRE |
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