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Possible host genetic factors influencing leprosy susceptibility in a multiplex family from Anjouan, Comoros

L Kraußer(1,2,3) D Ahmed(5) W Abdou(5) M Orlova(6,7) M Dallmann-Sauer(6,7) M Ronse(2) I S Ali(5) Z Salim(6) Y Assoumani(4) B C de Jong(2) E Schurr(6,7) V M Fava(6,7)

1:University of Antwerp; 2:Institute of Tropical Medicine (ITM), Antwerp, Belgium; 3:Research Foundation Flanders (FWO), Brussels, Belgium; 4:Damien Foundation, Brussels, Belgium; 5:National Tuberculosis and Leprosy Control Program, Moroni, Union of the Comoros; 6:Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1; 7:McGill International TB Centre, Montreal, QC, Canada H4A 3J1

Leprosy remains hyperendemic in the Comoros, specifically on Anjouan, despite continuous efforts in disease control by the National Tuberculosis and Leprosy Control Programme. The continued prevalence of leprosy led to the hypothesis that host genetic factors may contribute to an increased susceptibility to Mycobacterium leprae in this area. In a pilot study we recruited eight members of a multiplex leprosy family, including seven multibacillary leprosy patients, who donated whole blood for genomic DNA extraction. Employing whole genome sequencing analysis, we searched for candidate mutations with strong impact on leprosy susceptibility. 

We prioritized our search on protein-altering variants with predicted functional or regulatory impact at the protein level. Further, we assumed recessive and dominant models of inheritance of variants to identify three candidate leprosy susceptibility genes: IL12RB1HLA-A and MALT1. All affected family members were homozygous for p.P40L, an expression quantitative trait locus (eQTL) downregulating the IL12RB1 expression. This might lead to an IL12RB deficiency, impairing Th1-mediated immunity and reducing control of M. leprae. Additionally, all affected participants were heterozygous for p.I641V in MALT1, while the healthy control did not have the variant. MALT1 is involved in the formation of the noncanonical inflammasome and IL1-beta processing. By inferring the HLA-A alleles, we found that 6/7 affected family members were homozygous for the HLA-A*30:02 allele, with a potentially altered  M. leprae antigen recognition mechanism.

These promising candidates have to undergo additional investigations, including wider genomic analyses of the population in the endemic areas and functional confirmation of their influence on leprosy susceptibility. 

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