Genetics of leprosy: Expected and unexpected developments and perspectives

Sauer, Monica E.D.; Salomão, Heloisa; Ramos, Geovana Brotto; D’Espindula, Helena R.S.; Rodrigues, Rafael S.A.; Macedo, Wilian C.; Sindeaux, Renata H.M.; Mira, Marcelo Távora

doi:10.1016/j.clindermatol.2014.10.001

Cited by 36 publications

(27 citation statements)

References 99 publications

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“…Leprosy, an ancient dermatosis, is caused by infection with Mycobacterium leprae or Mycobacterium lepromatosis and primarily affects the skin and peripheral nerves of patients . Linkage analyses, genome‐wide association studies (GWAS) and candidate gene association analyses have confirmed the involvement of host genetic factors in the susceptibility of leprosy and identified several leprosy risk loci, most of which are located in noncoding genomic regions. More recently, a large‐scale exome‐wide association study (EWAS) identified 7 new risk coding variants using the Infinium HumanExome BeadChip (Illumine, San Diego, California).…”

Section: Introductionmentioning

confidence: 99%

Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy

Wang

et al. 2018

Clinical Genetics

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Seven new risk coding variants have been identified through an exome-wide association study (EWAS), which studied the contributions of protein-coding variants to leprosy susceptibility. But some potential susceptibility loci were not studied in the previous EWAS study because of the project consideration. Seventeen unstudied potential susceptibility loci of the previous EWAS were validated in 3169 cases and 9814 controls in this study. Four disease-associated exonic loci were identified: rs671 in ALDH2 (P = 2.0 × 10 , odds ratio [OR] = 1.35), rs13259978 in SLC7A2 (P = 1.74 × 10 , OR = 1.28), rs925368 in GIT2 (P = 9.18 × 10 , OR = 1.44), and rs75680863 in TCN2 (P = 8.37 × 10 , OR = 0.74). Potentially implicating ZFP36L1 as a new susceptibility gene, 1 intergenic single nucleotide polymorphism (SNP), rs1465788 (P = 7.81 × 10 , OR = 0.88), was also suggested to be associated with leprosy. A luciferase reporter assay showed that the rs1465788 risk allele notably decreased the transcription activity of the flanking sequence. These findings suggest the possible involvement of lipid metabolism, NF-κB homeostasis and macrophage antimicrobial pathways in leprosy pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy

Wang

et al. 2018

Clinical Genetics

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“…Host genetics accounts for a great proportion of disease heritability in leprosy and many genes were already identified with substantial evidences in support of their association with leprosy 9 . Among them, genes HLA-DR-DQ (major histocompatibility complex, class II, DR -class II DQ) 10 , LTA (lymphotoxin alpha) 11 , IL10 (interleukin 10) 12 , PRKN/PACRG (parkin RBR E3 ubiquitin protein ligase/parkin coregulated gene) 13 , NOD2 (nucleotide binding oligomerization domain containing 2) 14 , LACC1/CCDC122 (laccase domain containing 1/coiled-coil domain containing 122) 14 , SOD2 (superoxide dismutase 2) 15 , NEBL (nebulette) (unpublished data), GATA3 (GATA binding protein 3) 16 , IFNG (interferon gamma) 17 and TLR1 (toll like receptor 1) 18 have been associated with leprosy in Brazilian population samples, the majority of them playing important roles related to the host immune system.…”

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confidence: 99%

Human Genetic Susceptibility of Leprosy Recurrence

Sartori

Penna

Bührer-Sékula

et al. 2020

Sci Rep

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Host genetic susceptibility to leprosy has been intensively investigated over the last decades; however, there are no studies on the role of genetic variants in disease recurrence. A previous initiative identified three recurrent cases of leprosy for which none of the M. leprae strains, as obtained in the first and the second diagnosis, had any known genomic variants associated to resistance to Multidrug therapy; in addition, whole genome sequencing indicated that the same M. leprae was causing two out of the three recurrences. thus, these individuals were suspected of being particularly susceptible to M. leprae infection, either as relapse or reinfection. To verify this hypothesis, 19 genetic markers distributed across 11 loci (14 genes) classically associated with leprosy were genotyped in the recurrent and in three matching non-recurrent leprosy cases. An enrichment of risk alleles was observed in the recurrent cases, suggesting the existence of a particularly high susceptibility genetic profile among leprosy patients predisposing to disease recurrence.Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an obligatory intracellular, slow growing, alcohol-acid resistant bacillus with tropism for skin macrophages and Schwann cells of the peripheral nervous system 1 . The disease affects more than 200.000 people every year globally, with high incidence and prevalence concentrating in India and Brazil 2 . Leprosy presents a large spectrum of clinical manifestations that varies depending on the host's immune response, ranging from the localized tuberculoid to the systemic lepromatous forms as defined in the classic Ridley & Jopling classification system 3 . Alternative, the World Health Organization (WHO) classification protocol distributes leprosy cases as paucibacillary (PB) or multibacillary (MB) for treatment purposes 4 .Leprosy is treated by a multidrug therapy (MDT) consisting of rifampicin, dapsone and clofazimine carried out for six monthly doses for PB patients and for 12 monthly doses for MB patients 5 ; treatment is distributed for free in endemic countries since 1995 6 . Currently, there is the proposal for a uniform multidrug therapy regimen for leprosy patients that consists of six doses of MDT prescribed regardless of any clinical classification criteria. A Clinical Trial for Uniform Multidrug Therapy Regimen for Leprosy Patients in Brazil, (U-MDT/CT-BR) was recently conducted to compare outcomes of regular 12 doses MDT (R-MDT) and the uniform six doses MDT (U-MDT). The study included results from laboratory tests (bacilloscopic index, serology and histopathology) and clinical evaluation during long term follow-up 7 . Among the recurrent cases of leprosy identified in the U-MDT/CT-BR trial; for three of them, M. leprae isolates obtained in the first and second diagnosis were submitted to whole genome sequencing (WGS); analyses did not show any mutations associated with drug resistance.

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“…Cerca de 0,5% de los contactos de la forma paucibacilar y un 3% de la forma multibacilar desarrollará lepra en los años siguientes (rango: seis meses-20 años; promedio dos a cuatro años) 12 . El riesgo de desarrollar la enfermedad depende no solo de la forma bacilar del caso índice ya comentada, sino que también de la cercanía con él, ya que el riesgo aumenta en los contactos domiciliarios y la consanguineidad con el paciente índice, debido a una susceptibilidad genética para desarrollar EH 9,12,13 . Los largos períodos de incubación obligan a examinar anualmente a los contactos por al menos 10 años.…”

Section: Discussionunclassified

Enfermedad de Hansen. Una condición emergente en Chile

San-Martín

Carrasco

Fíca

et al. 2018

Rev. chil. infectol.

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Hansen disease, an emergent condition in Chile Hansen's disease (HD) is caused by Mycobacterium leprae. It has a chronic course and preferentially affects the skin and the peripheral nerves. It´s an emergent infection in Chile due to migration waves. This case report affecting a migrant worker from Haiti that presented several compatible skin lesions, with hypoesthesia and unilateral madarosis that appeared before arrival. The diagnosis of a multibacillary form was established by clinical findings, presence of fast acid bacilli on a direct skin smear, and inflammatory cell surrounding nerve endings and granulomas on skin biopsy. Besides, specific rpoB and hsp65 gene segments from M. leprae were amplified from skin samples. Patient was treated with the WHO standard combined regimen for multibacillary forms during one year showing partial regression of skin lesions. Nasopharyngeal samples showed the presence of M. leprae rpoB copies detected by PCR decreasing until six months of therapy. Notifiable diseases databases showed a recent increment of cases, all related to migrant population. Hansen´s disease is a new condition in Chile and clinicians should be aware of this possibility. Molecular tools may facilitate diagnosis and follow up.

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Genetics of leprosy: Expected and unexpected developments and perspectives

Cited by 36 publications

References 99 publications

Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy

Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy

Human Genetic Susceptibility of Leprosy Recurrence

Enfermedad de Hansen. Una condición emergente en Chile

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