Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer

Abstract

IntroductionBuruli 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.ObjectiveGenetic 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.MethodsGenetic 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.ResultsThe 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).ConclusionOur findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes.

Genome-wide association study of Buruli ulcer in rural Benin highlights role of two LncRNAs and the autophagy pathway

“…This variant is not in LD with variants of the PRKN (a.k.a. PARK2)/PACRG cluster associated with leprosy, including that reported to be associated with Buruli ulcer by Capela et al 26 (r² = 0.007) ( Table 3). We then looked at the 35 SNPs reaching genome-wide significance in the GWAS performed on tuberculosis (eight independent variants in eight different chromosomal regions; Supplementary Data 3a) or leprosy (27 variants in 19 different chromosomal regions; Supplementary Data 3b).…”

“…No enrichment in P values either <0.01 or <0.001 was observed among these variants in our discovery sample, the best hit being rs58925751, located in the DEFB123 gene on chromosome 20 (P value = 4.13 × 10 −4 ). We then checked the evidence of association in our GWAS for the six variants displaying significant association with Buruli ulcer in the three candidate-gene association studies on Buruli ulcer performed to date [25][26][27] ( Table 3). Only one of these variants-rs2241880, a missense T300A variant located in the ATG16L1 gene-had a P value < 0.05 in our GWAS under the additive model with the same allelic effect (one-tailed P value = 0.015).…”

“…These studies explored a total of seven genes selected on the basis of their involvement in MSMD, leprosy or tuberculosis. Significant association with Buruli ulcer was reported for common variants of six of these genes: SLC11A1 25 , PRKN, NOD2, and ATG16L1 26 and iNOS and IFNG 27 . We performed a two-stage case-control GWAS, to investigate comprehensively the role of common variants in the development of Buruli ulcer, on a sample of 1524 individuals recruited at the Centre de Dépistage et de Traitement de la Lèpre et de l'Ulcère de Buruli (CDTLUB) of Pobè, Benin.…”

Genome-wide association study of Buruli ulcer in rural Benin

“…Furthermore, in the previous study 27 , GG homozygotes were found to be protected against the ulcerative clinical form of Buruli ulcer, with an OR of 0.35 [0.13-0.90]. Strikingly, when focusing only on ulcerative cases of our discovery sample (255 ulcerative cases vs. 401 controls), the association was more significant (P value = 0.003), with an OR of 0.31 [0.14-0.68] (Table 4).…”

“…These studies explored a total of seven genes selected on the basis of their involvement in MSMD, tuberculosis or leprosy. Significant association with Buruli ulcer was reported for common variants of six of these genes: SLC11A1 26 , PRKN, NOD2, and ATG16L1 27 and iNOS and IFNG 28 . We performed a two-stage case-control GWAS, to investigate…”