Genetic variation in autophagy-related genes influences the risk and phenotype of Buruli ulcer

• Published in: PLoS neglected tropical diseases 2016-04, Vol.10 (4), p.e0004671-e0004671
• Main Authors: Capela, C., Dossou, A. D., Silva-Gomes, Rita, Sopoh, G. E., Makoutode, M., Menino, João Filipe Marques Almeida Ferreira, Fraga, Alexandra Gabriel, Cunha,Cristina, Carvalho, Agostinho, Rodrigues, Fernando, Pedrosa, Jorge
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Analysis; Autophagy; Autophagy (Cytology); Autophagy-Related Proteins; Biology and Life Sciences; Buruli ulcer; Buruli Ulcer - epidemiology; Buruli Ulcer - genetics; Buruli Ulcer - pathology; Carrier Proteins - genetics; Child; Ciências da Saúde; Ciências Médicas; Cytoskeleton; Development and progression; Disease; Female; Funding; Gender; Genes; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic variation; Genomics; Genotyping Techniques; Haplotypes; Health care; Host-Pathogen Interactions; Humans; Infections; Influence; Male; Medicine and Health Sciences; Mycobacterium ulcerans - immunology; Nod2 Signaling Adaptor Protein - genetics; Pathogens; Polymorphism, Single Nucleotide; Risk Assessment; Risk factors; Science & Technology; Skin diseases; Tropical diseases; Ubiquitin-Protein Ligases - genetics; Ulcers; Young Adult
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0004671

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. The research leading to these results received funding from the Health Services of the Fundação Calouste Gulbenkian under the grant Proc.N°94776 LJ; from the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo 267 Norte); from the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). JFM received an individual QREN fellowship (UMINHO/BPD/14/2014); CCu and AGF received an individual FCT fellowship (SFRH/BPD/96176/2013 and SFRH/BPD/68547/2010, respectively); and AC received an FCT contract (IF/00735/2014). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manus