The complex pattern of genetic associations of leprosy with HLA class I and class II alleles can be reduced to four amino acid positions

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.

Deep resequencing identifies candidate functional genes in leprosy GWAS loci

“…A recent GWAS in the Vietnamese population identified three independent association signals for leprosy in the MHC region [ 18 ]. Two of these signals tagged classical HLA alleles identified by HLA sequencing [ 32 ], while the third signal located near a major risk locus for psoriasis that encompassed CDSN , PSORS1C1 / PSORS1C2 and C6orf15 [ 18 , 33 ]. Here, we identified two low-frequency variants in high LD (p.G36S–p.P94fs) altering both CDSN – PSORS1C2 as being protective from leprosy independent of the GWAS leading SNP [ 18 ].…”

Host-Related Laboratory Parameters for Leprosy Reactions

“…The I602S SNP of TLR1 inhibits surface trafficking of the TLR1/TLR2 dimer, resulting in hyporesponsiveness to mycobacteria, suggesting a potential protective mechanism against M. leprae (58, 59). In addition, the MHC gene region carries major susceptibility for leprosy and LRs in different populations, with both protective and risk alleles (60,61).…”

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“…Genes 208 associated with leprosy include HLA (human leukocyte antigen) proteins. Analysis of eleven HLA genes in 1155 Vietnamese individuals revealed 4 leprosy-associated independent amino acid variants [HLA-DRβ1 positions 57 (D) and 13 (F), HLA-B position 63 (E) and HLA-A position 19 (K)] which comprised 2 pairs of linked genes, with one set conferring susceptibility [HLA-DRβ1 and HLA-A] and one being protective 209 .…”