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Buruli ulcer, the third most common mycobacterial disease worldwide, is caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions. Susceptibility to Buruli ulcer is thought to depend on host genetics, but very few genetic studies have been performed. The identification of a microdeletion on chromosome 8 in a familial form of severe Buruli ulcer suggested a monogenic basis of susceptibility. The role of common host genetic variants in Buruli ulcer development has been investigated in only three candidate-gene studies targeting genes involved in mycobacterial diseases. A recent genome-wide association study suggested a probable role for long non-coding RNAs and strengthened the contribution of autophagy as a major defense mechanism against mycobacteria. In this review, we summarize the history, epidemiological and clinical aspects of Buruli ulcer, focusing particularly on genetic findings relating to susceptibility to this disease. Finally, we discuss exciting new genetic avenues arising, in particular, from studies of mouse models, and the need for different disciplines to work together, to benefit from the extensive work on other mycobacterial diseases, mostly tuberculosis and leprosy. We are convinced that such pooling of effort will lead to the development of efficient novel strategies for combatting Buruli ulcer.

Buruli ulcer, caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions, is the third mycobacterial disease worldwide. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a sample of 1524 well characterized patients and controls from rural Benin. Two-stage analyses identify two variants located within LncRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85 × 10 -7 ; odds ratio = 1.80 [1.43-2.27]), and rs76647377 in LINC01622 (P = 9.85 × 10 -8 ; hazard ratio = 0.41 [0.28-0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14-0.68]). Our results suggest LncRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer.

Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was the most severe of over 2,000 BU cases treated at the Centre de Dépistage et de Traitement de la Lèpre et de l'Ulcère de Buruli, Pobe, Benin, since its opening in 2003. The infection spread to all limbs with PCR-confirmed skin, bone and joint infections. Genome-wide linkage analysis of seven family members was performed and whole-exome sequencing of both patients was obtained. A 37 kilobases homozygous deletion confirmed by targeted resequencing and located within a linkage region on chromosome 8 was identified in both patients but was absent from unaffected siblings. We further assessed the presence of this deletion on genotyping data from 803 independent local individuals (402 BU cases and 401 BU-free controls). Two BU cases were predicted to be homozygous carriers while none was identified in the control group. The deleted region is located close to a cluster of beta-defensin coding genes and contains a long non-coding (linc) RNA gene previously shown to display highest expression values in the skin. This first report of a microdeletion co-segregating with severe BU in a large family supports the view of a key role of human genetics in the natural history of the disease.