Abstract
Leprosy is a chronic disease caused by Mycobacterium leprae. Worldwide, more than 200,000 new patients are affected by leprosy annually, making it the second most common mycobacterial disease after tuberculosis. The MHC/HLA region has been consistently identified as carrying major leprosy susceptibility variants in different populations at times with inconsistent results. To establish the unambiguous molecular identity of classical HLA class I and class II leprosy susceptibility factors, we applied next-generation sequencing to genotype with high-resolution 11 HLA class I and class II genes in 1,155 individuals from a Vietnamese leprosy case-control sample. HLA alleles belonging to an extended haplotype from HLA-A to HLA-DPB1 were associated with risk to leprosy. This susceptibility signal could be reduced to the HLA-DRB1*10:01~ HLA-DQA1*01:05 alleles which were in complete linkage disequilibrium (LD). In addition, haplotypes containing HLA-DRB3~ HLA-DRB1*12:02 and HLA-C*07:06~ HLA-B*44:03~ HLA-DRB1*07:01 alleles were found as two independent protective factors for leprosy. Moreover, we replicated the previously associated HLA-DRB1*15:01 as leprosy risk factor and HLA-DRB1*04:05~HLA-DQA1*03:03 as protective alleles. When we narrowed the analysis to the single amino acid level, we found that the associations of the HLA alleles were largely captured by four independent amino acids at HLA-DRβ1 positions 57 (D) and 13 (F), HLA-B position 63 (E) and HLA-A position 19 (K). Hence, analyses at the amino acid level circumvented the ambiguity caused by strong LD of leprosy susceptibility HLA alleles and identified four distinct leprosy susceptibility factors.
Highlights
Leprosy is a chronic human disease of the skin and peripheral nerves that results from an infection with Mycobacterium leprae
The most significant susceptibility factors are located in the Major Histocompatibility Complex (MHC) region and likely involve classical Human Leukocyte Antigen (HLA) genes
By conducting a comprehensive sequenced-based analysis of HLA class I and class II genes, we are able to provide a unifying view of the complex relationship of leprosy susceptibility and HLA alleles
Summary
Leprosy is a chronic human disease of the skin and peripheral nerves that results from an infection with Mycobacterium leprae. The MHC region harbors hundreds of genes including the classical Human Leukocyte Antigen (HLA) genes of the MHC class I and class II regions. These genes encode transmembrane receptors that present short antigenic peptides to T-cells, and, in the case of class I molecules, to NK-cells and specialized cells of the monocyte lineage (rev in [8]). The highly polymorphic class I/II genes present several bi-allelic and multi-allelic amino acid variants that impact on the strength and specificity of peptide binding. Defined HLA alleles are, on the molecular level, multi-variant haplotypes of specific genes. Molecular defined HLA alleles are generally used for HLA genetics studies since they provide a higher resolution over immunologically–defined alleles
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