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1.
PLoS Negl Trop Dis ; 15(12): e0010029, 2021 12.
Article in English | MEDLINE | ID: mdl-34879060

ABSTRACT

Leprosy is the second most prevalent mycobacterial disease globally. Despite the existence of an effective therapy, leprosy incidence has consistently remained above 200,000 cases per year since 2010. Numerous host genetic factors have been identified for leprosy that contribute to the persistently high case numbers. In the past decade, genetic epidemiology approaches, including genome-wide association studies (GWAS), identified more than 30 loci contributing to leprosy susceptibility. However, GWAS loci commonly encompass multiple genes, which poses a challenge to define causal candidates for each locus. To address this problem, we hypothesized that genes contributing to leprosy susceptibility differ in their frequencies of rare protein-altering variants between cases and controls. Using deep resequencing we assessed protein-coding variants for 34 genes located in GWAS or linkage loci in 555 Vietnamese leprosy cases and 500 healthy controls. We observed 234 nonsynonymous mutations in the targeted genes. A significant depletion of protein-altering variants was detected for the IL18R1 and BCL10 genes in leprosy cases. The IL18R1 gene is clustered with IL18RAP and IL1RL1 in the leprosy GWAS locus on chromosome 2q12.1. Moreover, in a recent GWAS we identified an HLA-independent signal of association with leprosy on chromosome 6p21. Here, we report amino acid changes in the CDSN and PSORS1C2 genes depleted in leprosy cases, indicating them as candidate genes in the chromosome 6p21 locus. Our results show that deep resequencing can identify leprosy candidate susceptibility genes that had been missed by classic linkage and association approaches.


Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Leprosy/genetics , Adolescent , Adult , B-Cell CLL-Lymphoma 10 Protein/genetics , Female , Genetic Linkage , High-Throughput Nucleotide Sequencing , Humans , Interleukin-18 Receptor alpha Subunit/genetics , Interleukin-18 Receptor beta Subunit/genetics , Male , Young Adult
2.
PLoS Pathog ; 16(8): e1008818, 2020 08.
Article in English | MEDLINE | ID: mdl-32776973

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-DRß1 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.


Subject(s)
Amino Acids/genetics , Genetic Predisposition to Disease , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class I/genetics , Leprosy/pathology , Mutation , Adolescent , Adult , Female , Haplotypes , Humans , Leprosy/genetics , Male , Young Adult
3.
PLoS Pathog ; 16(5): e1008565, 2020 05.
Article in English | MEDLINE | ID: mdl-32421744

ABSTRACT

Leprosy is a chronic infectious disease of the skin and peripheral nerves with a strong genetic predisposition. Recent genome-wide approaches have identified numerous common variants associated with leprosy, almost all in the Chinese population. We conducted the first family-based genome-wide association study of leprosy in 622 affected offspring from Vietnam, followed by replication in an independent sample of 1181 leprosy cases and 668 controls of the same ethnic origin. The most significant results were observed within the HLA region, in which six SNPs displayed genome-wide significant associations, all of which were replicated in the independent case/control sample. We investigated the signal in the HLA region in more detail, by conducting a multivariate analysis on the case/control sample of 319 GWAS-suggestive HLA hits for which evidence for replication was obtained. We identified three independently associated SNPs, two located in the HLA class I region (rs1265048: OR = 0.69 [0.58-0.80], combined p-value = 5.53x10-11; and rs114598080: OR = 1.47 [1.46-1.48], combined p-value = 8.77x10-13), and one located in the HLA class II region (rs3187964 (OR = 1.67 [1.55-1.80], combined p-value = 8.35x10-16). We also validated two previously identified risk factors for leprosy: the missense variant rs3764147 in the LACC1 gene (OR = 1.52 [1.41-1.63], combined p-value = 5.06x10-14), and the intergenic variant rs6871626 located close to the IL12B gene (OR = 0.73 [0.61-0.84], combined p-value = 6.44x10-8). These results shed new light on the genetic control of leprosy, by dissecting the influence of HLA SNPs, and validating the independent role of two additional variants in a large Vietnamese sample.


Subject(s)
Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class I/genetics , Leprosy/genetics , Polymorphism, Single Nucleotide , Female , Genome-Wide Association Study , Humans , Interleukin-12 Subunit p40/genetics , Intracellular Signaling Peptides and Proteins/genetics , Leprosy/epidemiology , Male
4.
Proc Natl Acad Sci U S A ; 116(31): 15616-15624, 2019 07 30.
Article in English | MEDLINE | ID: mdl-31308240

ABSTRACT

Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (PSKAT-O = 1.6 × 10-4). This genewise association was driven almost entirely by the gain-of-function variant R1628P (P = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene PRKN (formerly PARK2) where 7 rare variants were enriched in T1R-affected cases (PSKAT-O = 7.4 × 10-5). Mutations in both PRKN and LRRK2 are known causes of Parkinson's disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD (P = 1.5 × 10-4). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.


Subject(s)
Leprosy , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Mutation , Parkinson Disease , Ubiquitin-Protein Ligases , Female , Humans , Leprosy/genetics , Leprosy/metabolism , Leprosy/pathology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Male , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
5.
PLoS Genet ; 13(2): e1006637, 2017 02.
Article in English | MEDLINE | ID: mdl-28222097

ABSTRACT

Leprosy Type-1 Reactions (T1Rs) are pathological inflammatory responses that afflict a sub-group of leprosy patients and result in peripheral nerve damage. Here, we employed a family-based GWAS in 221 families with 229 T1R-affect offspring with stepwise replication to identify risk factors for T1R. We discovered, replicated and validated T1R-specific associations with SNPs located in chromosome region 10p21.2. Combined analysis across the three independent samples resulted in strong evidence of association of rs1875147 with T1R (p = 4.5x10-8; OR = 1.54, 95% CI = 1.32-1.80). The T1R-risk locus was restricted to a lncRNA-encoding genomic interval with rs1875147 being an eQTL for the lncRNA. Since a genetic overlap between leprosy and inflammatory bowel disease (IBD) has been detected, we evaluated if the shared genetic control could be traced to the T1R endophenotype. Employing the results of a recent IBD GWAS meta-analysis we found that 10.6% of IBD SNPs available in our dataset shared a common risk-allele with T1R (p = 2.4x10-4). This finding points to a substantial overlap in the genetic control of clinically diverse inflammatory disorders.


Subject(s)
Genetic Predisposition to Disease , Inflammatory Bowel Diseases/genetics , Leprosy/genetics , RNA, Long Noncoding/genetics , Female , Gene Expression Regulation , Genome-Wide Association Study , Humans , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/pathology , Leprosy/complications , Leprosy/pathology , Male , Nerve Degeneration/complications , Nerve Degeneration/genetics , Nerve Degeneration/pathology , Polymorphism, Single Nucleotide , Quantitative Trait Loci/genetics , RNA, Long Noncoding/biosynthesis , Risk Factors , Vietnam
6.
s.l; s.n; 2017. 16 p. ilus, tab, graf.
Non-conventional in English | Sec. Est. Saúde SP, HANSEN, Hanseníase Leprosy, SESSP-ILSLPROD, Sec. Est. Saúde SP, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1087674

ABSTRACT

Leprosy Type-1 Reactions (T1Rs) are pathological inflammatory responses that afflict a sub-group of leprosy patients and result in peripheral nerve damage. Here, we employed a family-based GWAS in 221 families with 229 T1R-affect offspring with stepwise replication to identify risk factors for T1R. We discovered, replicated and validated T1R-specific associations with SNPs located in chromosome region 10p21.2. Combined analysis across the three independent samples resulted in strong evidence of association of rs1875147 with T1R (p = 4.5x10-8; OR = 1.54, 95% CI = 1.32-1.80). The T1R-risk locus was restricted to a lncRNA-encoding genomic interval with rs1875147 being an eQTL for the lncRNA. Since a genetic overlap between leprosy and inflammatory bowel disease (IBD) has been detected, we evaluated if the shared genetic control could be traced to the T1R endophenotype. Employing the results of a recent IBD GWAS meta-analysis we found that 10.6% of IBD SNPs available in our dataset shared a common risk-allele with T1R (p = 2.4x10-4). This finding points to a substantial overlap in the genetic control of clinically diverse inflammatory disorders.


Subject(s)
Humans , Male , Female , Genome-Wide Association Study , Leprosy/genetics , Leprosy/pathology , Genetic Predisposition to Disease , RNA, Long Noncoding/genetics
7.
PLoS Negl Trop Dis ; 10(2): e0004412, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26844546

ABSTRACT

BACKGROUND: Depending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R). The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LRRK2 gene have been associated with leprosy in some but not in other studies. We hypothesized that LRRK2 was a T1R susceptibility gene and that inconsistent association results might reflect different proportions of patients with T1R in the different sample settings. Hence, we evaluated the association of LRRK2 variants with T1R susceptibility. METHODOLOGY: An association scan of the LRRK2 locus was performed using 156 single-nucleotide polymorphisms (SNPs). Evidence of association was evaluated in two family-based samples: A set of T1R-affected and a second set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to T1R-free families were considered T1R-specific. An expression quantitative trait locus (eQTL) analysis was applied to evaluate the impact of T1R-specific SNPs on LRRK2 gene transcriptional levels. PRINCIPAL FINDINGS: A total of 18 T1R-specific variants organized in four bins were detected. The core SNP capturing the T1R association was the LRRK2 missense variant M2397T (rs3761863) that affects LRRK2 protein turnover. Additionally, a bin of nine SNPs associated with T1R were eQTLs for LRRK2 in unstimulated whole blood cells but not after exposure to Mycobacterium leprae antigen. SIGNIFICANCE: The results support a preferential association of LRRK2 variants with T1R. LRRK2 involvement in T1R is likely due to a pathological pro-inflammatory loop modulated by LRRK2 availability. Interestingly, the M2397T variant was reported in association with Crohn's disease with the same risk allele as in T1R suggesting common inflammatory mechanism in these two distinct diseases.


Subject(s)
Disease Susceptibility , Inflammation/genetics , Inflammation/pathology , Leprosy/genetics , Leprosy/pathology , Mutation, Missense , Protein Serine-Threonine Kinases/genetics , Adult , Female , Genetic Association Studies , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Polymorphism, Single Nucleotide , Young Adult
8.
J Infect Dis ; 211(6): 968-77, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25320285

ABSTRACT

BACKGROUND: Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R. METHODS: We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects. RESULTS: In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R. CONCLUSIONS: Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response.


Subject(s)
CD30 Ligand/genetics , Leprosy/genetics , Chromosome Mapping , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Leprosy/immunology , Polymorphism, Single Nucleotide , Tumor Necrosis Factor Ligand Superfamily Member 15/genetics
9.
Hum Genet ; 133(7): 883-93, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24563210

ABSTRACT

Leprosy is caused by infection with Mycobacterium leprae and is classified clinically into paucibacillary (PB) or multibacillary (MB) subtypes based on the number of skin lesions and the bacillary index detected in skin smears. We previously identified a major PB susceptibility locus on chromosome region 10p13 in Vietnamese families by linkage analysis. In the current study, we conducted high-density association mapping of the 9.5 Mb linkage peak on chromosome region 10p13 covering 39 genes. Using leprosy per se and leprosy subtypes as phenotypes, we employed 294 nuclear families (303 leprosy cases, 63 % MB, 37 % PB) as a discovery sample and 192 nuclear families (192 cases, 55 % MB, 45 % PB) as a replication sample. Replicated significant association signals were revealed in the genes for cubilin (CUBN) and nebulette (NEBL). In the combined sample, the C allele (frequency 0.26) at CUBN SNP rs10904831 showed association [p = 1 × 10(-5); OR 0.52 (0.38-0.7)] with MB leprosy only. Likewise, allele T (frequency 0.42) at NEBL SNP rs11012461 showed association [p = 4.2 × 10(-5); OR 2.51 (1.6-4)] with MB leprosy only. These associations remained valid for the CUBN signal when taking into account the effective number of tests performed (type I error significance threshold = 2.4 × 10(-5)). We used the results of our analyses to propose a new model for the genetic control of polarization of clinical leprosy.


Subject(s)
Carrier Proteins/genetics , Chromosomes, Human, Pair 10/genetics , Cytoskeletal Proteins/genetics , Genetic Linkage , Genetic Predisposition to Disease , LIM Domain Proteins/genetics , Leprosy, Multibacillary/genetics , Receptors, Cell Surface/genetics , Alleles , Asian People/genetics , Chromosome Mapping , Female , Gene Frequency , Genetics, Population , Genotype , Humans , Male , Mycobacterium leprae , Polymorphism, Single Nucleotide , Vietnam
10.
PLoS Genet ; 9(7): e1003624, 2013.
Article in English | MEDLINE | ID: mdl-23874223

ABSTRACT

Leprosy reversal reactions type 1 (T1R) are acute immune episodes that affect a subset of leprosy patients and remain a major cause of nerve damage. Little is known about the relative importance of innate versus environmental factors in the pathogenesis of T1R. In a retrospective design, we evaluated innate differences in response to Mycobacterium leprae between healthy individuals and former leprosy patients affected or free of T1R by analyzing the transcriptome response of whole blood to M. leprae sonicate. Validation of results was conducted in a subsequent prospective study. We observed the differential expression of 581 genes upon exposure of whole blood to M. leprae sonicate in the retrospective study. We defined a 44 T1R gene set signature of differentially regulated genes. The majority of the T1R set genes were represented by three functional groups: i) pro-inflammatory regulators; ii) arachidonic acid metabolism mediators; and iii) regulators of anti-inflammation. The validity of the T1R gene set signature was replicated in the prospective arm of the study. The T1R genetic signature encompasses genes encoding pro- and anti-inflammatory mediators of innate immunity. This suggests an innate defect in the regulation of the inflammatory response to M. leprae antigens. The identified T1R gene set represents a critical first step towards a genetic profile of leprosy patients who are at increased risk of T1R and concomitant nerve damage.


Subject(s)
Antigens, Bacterial/blood , Gene Expression Profiling , Leprosy/genetics , Mycobacterium leprae/genetics , Nerve Degeneration/genetics , Adolescent , Adult , Antigens, Bacterial/isolation & purification , Child , Female , Gene Expression Regulation , Humans , Immunity, Innate/genetics , Interferon-gamma/blood , Leprosy/microbiology , Leprosy/physiopathology , Male , Mycobacterium leprae/pathogenicity , Nerve Degeneration/microbiology , Nerve Degeneration/physiopathology , Retrospective Studies
11.
Hum Genet ; 132(1): 107-16, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23052943

ABSTRACT

One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 × 10(-5)) for association among Vietnamese patients. Next, we enrolled a case-control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture >80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10(-8)). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.


Subject(s)
Ethnicity/genetics , Leprosy/genetics , Molecular Chaperones/genetics , Ubiquitin-Protein Ligases/genetics , Adolescent , Adult , Age of Onset , Asian People/genetics , Case-Control Studies , Child , Female , Genetic Association Studies , Humans , India , Introns , Leprosy/diagnosis , Linkage Disequilibrium , Male , Microfilament Proteins , Middle Aged , Multivariate Analysis , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Vietnam , White People/genetics , Young Adult
12.
J Infect Dis ; 206(11): 1763-7, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-22984114

ABSTRACT

A genomewide association study in Chinese patients with leprosy detected association signals in 16 single-nucleotide polymorphisms (SNPs) belonging to 6 loci, of which 4 are related to the NOD2 signaling pathway and are Crohn's disease susceptibility loci. Here, we studied these 16 SNPs as potential leprosy susceptibility factors in 474 Vietnamese leprosy simplex families. We replicated SNPs at HLA-DR-DQ, RIPK2, CCDC122-LACC1, and NOD2 as leprosy susceptibility factors in Vietnam. These results validated the striking overlap in the genetic control of Crohn's disease and leprosy.


Subject(s)
Asian People/genetics , Crohn Disease/genetics , Leprosy/genetics , Family , Gene Expression Regulation , Genetic Predisposition to Disease , Genotype , Humans , Leprosy/epidemiology , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/metabolism , Polymorphism, Single Nucleotide , Signal Transduction , Vietnam/epidemiology
13.
J Infect Dis ; 203(9): 1274-81, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21459816

ABSTRACT

Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10⁻9)-rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10⁻7 and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis.


Subject(s)
Genetic Predisposition to Disease , Histocompatibility Antigens Class I/genetics , Leprosy/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Child , Child, Preschool , Gene Frequency , Genotype , Humans , India , Infant , Leprosy/immunology , Middle Aged , Vietnam , Young Adult
14.
Hum Genet ; 127(3): 337-48, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20035344

ABSTRACT

The chromosomal region 10p13 has been linked to paucibacillary leprosy in two independent studies. The MRC1 gene, encoding the human mannose receptor (MR), is located in the 10p13 region and non-synonymous SNPs in exon 7 of the gene have been suggested as leprosy susceptibility factors. We determined that G396S is the only non-synonymous exon 7-encoded polymorphism in 396 unrelated Vietnamese subjects. This SNP was genotyped in 490 simplex and 90 multiplex leprosy families comprising 704 patients (47% paucibacillary; 53% multibacillary). We observed significant under-transmission of the serine allele of the G396S polymorphism with leprosy per se (P = 0.036) and multibacillary leprosy (P = 0.034). In a sample of 384 Brazilian leprosy cases (51% paucibacillary; 49% multibacillary) and 399 healthy controls, we observed significant association of the glycine allele of the G396S polymorphism with leprosy per se (P = 0.016) and multibacillary leprosy (P = 0.023). In addition, we observed a significant association of exon 7 encoded amino acid haplotypes with leprosy per se (P = 0.012) and multibacillary leprosy (P = 0.004). Next, we tested HEK293 cells over-expressing MR constructs (293-MR) with three exon 7 haplotypes of MRC1 for their ability to bind and internalize ovalbumin and zymosan, two classical MR ligands. No difference in uptake was measured between the variants. In addition, 293-MR failed to bind and internalize viable Mycobacterium leprae and BCG. We propose that the MR-M. leprae interaction is modulated by an accessory host molecule of unknown identity.


Subject(s)
Exons , Lectins, C-Type/genetics , Leprosy/genetics , Mannose-Binding Lectins/genetics , Polymorphism, Single Nucleotide , Receptors, Cell Surface/genetics , Case-Control Studies , Cells, Cultured , Cloning, Molecular , Genetic Predisposition to Disease , Humans , Lectins, C-Type/metabolism , Lectins, C-Type/physiology , Linkage Disequilibrium , Mannose Receptor , Mannose-Binding Lectins/metabolism , Mannose-Binding Lectins/physiology , Mutant Proteins/genetics , Mycobacterium bovis/metabolism , Mycobacterium leprae/metabolism , Polymorphism, Single Nucleotide/physiology , Protein Binding , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/physiology , Transfection
15.
s.l; s.n; 2003. 4 p. tab, graf.
Non-conventional in English | Sec. Est. Saúde SP, HANSEN, Hanseníase Leprosy, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1241003

ABSTRACT

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year. Clinically, leprosy can be categorized as paucibacillary or multibacillary disease. These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation. We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P = 5 x 10(-6)). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 x 10(-4) and P = 5.9 x 10(-5), respectively).


Subject(s)
Male , Female , Humans , Alleles , /genetics , /genetics , Lod Score , Leprosy/genetics , Genetic Linkage , Microsatellite Repeats , Vietnam
16.
Nat Genet ; 33(3): 412-5, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12577057

ABSTRACT

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year. Clinically, leprosy can be categorized as paucibacillary or multibacillary disease. These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation. We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P = 5 x 10(-6)). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 x 10(-4) and P = 5.9 x 10(-5), respectively).


Subject(s)
Chromosomes, Human, Pair 6/genetics , Leprosy/genetics , Alleles , Chromosomes, Human, Pair 10/genetics , Female , Genetic Linkage , Humans , Lod Score , Male , Microsatellite Repeats , Vietnam
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