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

Jeremy Manry,Marie-Françoise Ardant,Ioannis Theodorou,Laurent Marsollier,Annick Chauty,Maya Chrabieh,Estelle Marion,Christian Johnson,Lazaro Lorenzo,Alexandre Alcaïs,Quentin B Vincent,Laurent Abel

doi:10.1038/s42003-020-0920-6

Abstract

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.

Highlights

Buruli ulcer, caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions, is the third mycobacterial disease worldwide
The most significant signal for association was observed for an imputed SNP located on chromosome 19 with a P value = 2.80 × 10−7, a minor allele frequency (MAF) of 0.09 and an odds ratio (OR) estimated at 2.33 [95%confidence interval (CI): 1.62–3.34] for developing Buruli ulcer for TT vs. CT or CT vs. CC carriers
The lowest P value (0.017) was obtained for rs2269497, a missense variant of RGS12 identified in a Genome-wide association studies (GWAS) on tuberculosis in a Chinese population[30], for which the minor G allele was found to be associated with a risk of tuberculosis, whereas we found it to have a protective effect in Buruli ulcer

Summary

Introduction

Buruli ulcer, caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions, is the third mycobacterial disease worldwide. 4 Centre Interfacultaire de Formation et de Buruli ulcer is a chronic infectious disease caused by Mycobacterium ulcerans It received little attention until about 15 years ago, despite being more prevalent than tuberculosis or leprosy in some areas[1]. Considerable variability has been reported in the clinical presentation of Buruli ulcer, including spontaneous healing in both humans[10,11] and specific mouse strains[11] This observation, together with the familial clustering of cases[12,13], support the view of a substantial contribution of host genetic factors to the response to infection with M. ulcerans. Our analysis identifies two novel variants independently associated with the onset of Buruli ulcer and confirms the protective effect of a missense variant in the bacterial autophagy gene ATG16L1

Methods

Results

Conclusion