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  • 1
    Language: English
    In: Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2014, Vol.369(1645), pp.20130428
    Description: Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.
    Keywords: Mendelian Predisposition ; Complex Genetic Predisposition ; Genetic Variant ; Latent Tuberculosis Infection ; Primary Tuberculosis ; Pulmonary Tuberculosis ; Genetic Variation ; Phenotype ; Genetic Predisposition to Disease -- Genetics ; Tuberculosis -- Epidemiology
    ISSN: 09628436
    E-ISSN: 1471-2970
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  • 2
    Language: English
    In: The American Journal of Human Genetics, 07 March 2013, Vol.92(3), pp.407-414
    Description: Only a small fraction of individuals infected with develop clinical tuberculosis (TB) in their lifetime. Genetic epidemiological evidence suggests a genetic determinism of pulmonary TB (PTB), but the molecular basis of genetic predisposition to PTB remains largely unknown. We used a positional-cloning approach to carry out ultrafine linkage-disequilibrium mapping of a previously identified susceptibility locus in chromosomal region 8q12–13 by genotyping 3,216 SNPs in a family-based Moroccan sample including 286 offspring with PTB. We observed 44 PTB-associated SNPs (p 〈 0.01), which were genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of two correlated SNPs close to , rs1568952 and rs2726600 (combined p = 1.1 × 10 and 9.2 × 10 , respectively), was replicated. Stronger evidence of association was found in individuals who developed PTB before the age of 25 years (combined p for rs1568952 = 4.4 × 10 ; odds ratio of PTB for AA versus AG/GG = 3.09 [1.99–4.78]). The association with rs2726600 (p = 0.04) was subsequently replicated in PTB-affected subjects under 25 years in a study of 243 nuclear families from Madagascar. Stronger evidence of replication in Madagascar was obtained for additional SNPs in strong linkage disequilibrium with the two initial SNPs (p = 0.003 for rs2726597), further confirming the signal. We thus identified around rs1568952 and rs2726600 a cluster of SNPs strongly associated with early-onset PTB in Morocco and Madagascar. SNP rs2726600 is located in a transcription-factor binding site in the 3′ region of , and further functional explorations will focus on CD4 T lymphocytes.
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, June 14, 2016, Vol.113(24), p.6713
    Description: Principal component analysis (PCA), homozygosity rate estimations, and linkage studies in humans are classically conducted through genome-wide single-nucleotide variant arrays (GWSA). We compared whole-exome sequencing (WES) and GWSA for this purpose. We analyzed 110 subjects originating from different regions of the world, including North Africa and the Middle East, which are poorly covered by public databases and have high consanguinity rates. We tested and applied a number of quality control (QC) filters. Compared with GWSA, we found that WES provided an accurate prediction of population substructure using variants with a minor allele frequency 〉 2% (correlation = 0.89 with the PCA coordinates obtained by GWSA). WES also yielded highly reliable estimates of homozygosity rates using runs of homozygosity with a 1,000-kb window (correlation = 0.94 with the estimates provided by GWSA). Finally, homozygosity mapping analyses in 15 families including a single offspring with high homozygosity rates showed that WES provided 51% less genome-wide linkage information than GWSA overall but 97% more information for the coding regions. At the genome-wide scale, 76.3% of linked regions were found by both GWSA and WES, 17.7% were found by GWSA only, and 6.0% were found by WES only. For coding regions, the corresponding percentages were 83.5%, 7.4%, and 9.1%, respectively. With appropriate QC filters, WES can be used for PCA and adjustment for population substructure, estimating homozygosity rates in individuals, and powerful linkage analyses, particularly in coding regions. exome sequencing | genotyping array | population structure | homozygosity mapping | linkage analysis
    Keywords: DNA Sequencing – Methods ; Principal Components Analysis – Usage ; Genetic Variation – Observations
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 4
    Language: English
    In: Science (New York, N.Y.), 01 April 2011, Vol.332(6025), pp.65-8
    Description: Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine interleukin-17F (IL-17F). IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.
    Keywords: Candidiasis, Chronic Mucocutaneous -- Genetics ; Interleukin-17 -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 5
    Language: English
    In: PLoS ONE, 2011, Vol.6(4), p.e18524
    Description: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. ; We searched for mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. ; This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.
    Keywords: Research Article ; Medicine ; Immunology ; Public Health And Epidemiology ; Infectious Diseases
    E-ISSN: 1932-6203
    Source: PLoS
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  • 6
    Language: English
    In: Journal of Infectious Diseases, August 15, 2014, Vol.210(4), p.611(618)
    Description: BACKGROUND: Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity.METHODS: We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population.RESULTS: Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013-.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset 〈25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06-2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression.CONCLUSIONS: Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression.
    Keywords: Pulmonary Tuberculosis -- Genetic Aspects ; Pulmonary Tuberculosis -- Research ; Pulmonary Tuberculosis -- Development And Progression ; Pulmonary Tuberculosis -- Patient Outcomes ; Interleukin-12 -- Research ; Genetic Polymorphisms -- Research
    ISSN: 0022-1899
    E-ISSN: 15376613
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  • 7
    Language: English
    In: The Journal of Allergy and Clinical Immunology, July 2017, Vol.140(1), pp.232-241
    Description: Germline heterozygous mutations in human signal transducer and activator of transcription 1 can cause loss of function (LOF), as in patients with Mendelian susceptibility to mycobacterial diseases, or gain of function (GOF), as in patients with chronic mucocutaneous candidiasis. LOF and GOF mutations are equally rare and can affect the same domains of STAT1, especially the coiled-coil domain (CCD) and DNA-binding domain (DBD). Moreover, 6% of patients with chronic mucocutaneous candidiasis with a GOF mutation have mycobacterial disease, obscuring the functional significance of the identified mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants. We estimated variations in the CCD/DBD of STAT1. We mutagenized 342 individual wild-type amino acids in the CCD/DBD (45.6% of full-length STAT1) to alanine and tested the mutants for STAT1 transcriptional activity. Of these 342 mutants, 201 were neutral, 30 were LOF, and 111 were GOF mutations in a luciferase assay. This assay system correctly estimated all previously reported LOF mutations (100%) and slightly fewer GOF mutations (78.1%) in the CCD/DBD of STAT1. We found that GOF alanine mutants occurred at the interface of the antiparallel STAT1 dimer, suggesting that they destabilize this dimer. This assay also precisely predicted the effect of 2 hypomorphic and dominant negative mutations, E157K and G250E, in the CCD of STAT1 that we found in 2 unrelated patients with Mendelian susceptibility to mycobacterial diseases. The systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and the effect of heterozygous missense mutations in identified in patients with severe infectious diseases, including mycobacterial and fungal diseases.
    Keywords: Signal Transduction and Activator of Transcription 1 ; Alanine Scanning ; Chronic Mucocutaneous Candidiasis ; Mendelian Susceptibility to Mycobacterial Disease ; Reference Database ; Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 8
    Language: English
    In: PLoS ONE, 01 April 2011, Vol.6(4), p.e18524
    Description: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    In: Journal of Clinical Microbiology, 2004, Vol. 42(1), p.461
    Description: Although lower-resource countries have by far the highest burden of tuberculosis, knowledge of Mycobacterium tuberculosis population structure and genetic diversity in these regions remains almost nonexistent. In this paper, 150 Moroccan M. tuberculosis isolates circulating in Casablanca were genotyped by random amplified polymorphic DNA analysis using 10 different primers and by mycobacterial interspersed repetitive units-variable number of tandem repeats typing at 12 loci. The population genetic tests revealed a basically clonal structure for this population, without excluding rare genetic exchanges. Genetic analysis also showed a notable genetic polymorphism for the species M. tuberculosis, a weak cluster individualization, and an unexpected genetic diversity for a population in such a high-incidence community. Phylogenetic analyses of this Moroccan sample also supported that these isolates are genetically heterogeneous.
    Keywords: Mycobacterium Tuberculosis ; Morocco ; Gene Polymorphism ; Tuberculosis ; Genetic Diversity ; Phylogeny ; Genotyping ; Random Amplified Polymorphic DNA ; Population Structure ; Ear, Nose and Respiratory Tract ; Genetics and Evolution;
    ISSN: 0095-1137
    ISSN: 00951137
    E-ISSN: 1098660X
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  • 10
    Language: English
    In: The Journal of Allergy and Clinical Immunology, October 2015, Vol.136(4), pp.993-1006.e1
    Description: Follicular helper T (T ) cells underpin T cell–dependent humoral immunity and the success of most vaccines. T cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. We sought to determine the signaling pathways and cellular interactions required for the development and function of T cells in human subjects. Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cT ) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in , , , , , , , , , , , or . Loss-of-function (LOF) mutations in , , , , , or reduced cT cell frequencies. and LOF and gain-of-function mutations skewed cT cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cT cell function and , as corroborated by hypergammaglobulinemia in patients with , , and LOF mutations. Specific mutations affect the quantity and quality of cT cells, highlighting the need to assess T cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions to restrain T cell–induced B-cell differentiation. These findings shed new light on T cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
    Keywords: Follicular Helper T Cells ; Humoral Immunity ; Primary Immunodeficiencies ; Cytokine Signaling ; Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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