Family-based genome-wide association study of leprosy in Vietnam

Gzara, Chaima; Dallmann-Sauer, Monica; Orlova, Marianna; Thuc, Nguyen Van; Thai, Vu Hong; Fava, Vinicius M.; Boland, Anne; Abel, Laurent; Alcaïs, Alexandre; Schurr, Erwin; Cobat, Aurélie

doi:10.1101/2020.01.30.20018432

Cited by 3 publications

(10 citation statements)

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“…These two alleles are tagging an extended haplotype which spans from HLA-A to HLA-DPB1 , a distance of approximately 3.15 Mb (signal #1 in Fig 1 ). These findings are strongly supported by a study of three Indian leprosy cohorts and our family-based leprosy GWAS in Vietnam [ 5 , 7 ]. In the Indian population samples, the authors reported a strong risk effect for leprosy of MHC class II SNP rs1071630 in two case-control samples from New Delhi and Kolkata [ 5 ].…”

Section: Discussionsupporting

confidence: 86%

“…The MHC region has been consistently identified as chromosomal location of strong genetic leprosy risk factors, including in our recent Vietnamese GWAS where three independent association signals were identified in the MHC region [ 7 ]. While genetic studies have implicated non-classical MHC genes like LTA and MICA in leprosy susceptibility, the main effects have been assigned to classical class I and class II HLA genes [ 11 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…For the present study, we enrolled 1,164 Vietnamese individuals recruited from Ho Chi Minh City in Vietnam, as previously described [ 7 , 13 , 14 ]. After quality control, 1,155 participants were included in the association study for leprosy per se , corresponding to 687 leprosy cases and 468 healthy controls ( Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…After quality control, 1,155 participants were included in the association study for leprosy per se , corresponding to 687 leprosy cases and 468 healthy controls ( Table 1 ). Healthy controls were subjects living in the same districts as leprosy cases with no family history of leprosy up to third-degree relatives [ 7 ]. Due to low prevalence of leprosy, it is possible that the inclusion of genetically susceptible subjects into the group of controls will result in an underestimate of the strength of the genetic effect.…”

Section: Methodsmentioning

confidence: 99%

“…Human genetic factors strongly influence susceptibility to leprosy and more than 30 loci throughout the genome have been associated with leprosy phenotypes (rev in [ 1 ]). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) within the Major Histocompatibility Complex (MHC) on chromosome 6p21 as the most significantly leprosy-associated genetic variants [ 2 – 7 ]. Divided into three classes, the MHC region harbors hundreds of genes including the classical Human Leukocyte Antigen (HLA) genes of the MHC class I and class II regions.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

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Human genetics of Buruli ulcer

Manry

2020

Hum Genet

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ACTR1Ahas pleiotropic effects on risk of leprosy, inflammatory bowel disease and atopy

Gilchrist

Auckland

Parks

et al. 2022

Preprint

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Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated five risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 (2 independent loci) and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583: combined p=8.81x10-9; OR=0.51 [95% CI 0.40-0.64]). The leprosy risk locus is a determinant of ACTR1A RNA expression in CD4+ T cells (posterior probability of colocalization - PP=0.96). Furthermore, it demonstrates pleiotropy with established risk loci for inflammatory bowel disease and atopic disease. Reduced ACTR1A expression decreases susceptibility to leprosy and atopy but increases risk of inflammatory bowel disease. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the evidence that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.

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Family-based genome-wide association study of leprosy in Vietnam

Cited by 3 publications

References 59 publications

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

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

Human genetics of Buruli ulcer

ACTR1Ahas pleiotropic effects on risk of leprosy, inflammatory bowel disease and atopy

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