title: Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer.
abstract: BACKGROUND
  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).
  
  
  CONCLUSIONS
  Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Capela
authors.affiliation: Buruli Ulcer Treatment Center of Allada, Allada, Benin.
authors.forename: Ange Dodji
authors.initials: AD
authors.lastname: Dossou
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Silva-Gomes
authors.affiliation: Buruli Ulcer Treatment Center of Allada, Allada, Benin.|Regional Institute for Public Health, Ouidah, Benin.
authors.forename: Ghislain Emmanuel
authors.initials: GE
authors.lastname: Sopoh
authors.affiliation: Regional Institute for Public Health, Ouidah, Benin.
authors.forename: Michel
authors.initials: M
authors.lastname: Makoutode
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: João Filipe
authors.initials: JF
authors.lastname: Menino
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Alexandra Gabriel
authors.initials: AG
authors.lastname: Fraga
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Pedrosa
mesh_terms: D000293:Adolescent; D000328:Adult; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D054312:Buruli Ulcer / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D019911:Mycobacterium ulcerans / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein