Publications by authors named "Jamila El-Baghdadi"

21 Publications

  • Page 1 of 1

Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria.

Cell 2020 Dec 8;183(7):1826-1847.e31. Epub 2020 Dec 8.

St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY, USA. Electronic address:

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 γδ T lymphocytes, and of Mycobacterium-non reactive classic T1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 αβ T and non-classic CD4 αβ T1 lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 αβ T, and CD4 αβ T1 cells unable to compensate for this deficit.
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http://dx.doi.org/10.1016/j.cell.2020.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770098PMC
December 2020

Prevalence and risk factors for latent tuberculosis infection among healthcare workers in Morocco.

PLoS One 2019 15;14(8):e0221081. Epub 2019 Aug 15.

Genetics Unit, Military Hospital Mohamed V, Rabat, Morocco.

Increased prevalence of latent tuberculosis infection (LTBI) has been observed among high-risk populations such as healthcare workers (HCWs). The results may depend on the method of LTBI assessment, interferon-gamma release assay (IGRA) and/or tuberculin skin test (TST). Here, we investigated the prevalence and risk factors for LTBI assessed by both IGRAs and TST in HCWs living in Morocco, a country with intermediate tuberculosis (TB) endemicity and high BCG vaccination coverage. HCWs were recruited in two Moroccan hospitals, Rabat and Meknes. All the participants underwent testing for LTBI by both IGRA (QuantiFERON-TB Gold In-Tube, QFT-GIT) and TST. Different combinations of IGRA and TST results defined the LTBI status. Risk factors associated with LTBI were investigated using a mixed-effect logistic regression model. The prevalence of LTBI among 631 HCWs (age range 18-60 years) varied from 40.7% (95%CI 36.9-44.5%) with QFT-GIT to 52% (95%CI 48.2-56.0%) with TST using a 10 mm cut-off. The highest agreement between QFT-GIT and TST (κ = 0.50; 95%CI 0.43-0.56) was observed with the 10 mm cut-off for a positive TST. For a definition of LTBI status using a double positive result for both QFT-GIT and TST, significant associations were found with the following risk factors: being male (OR = 2.21; 95%CI 1.40-3.49; p = 0.0007), belonging to age groups 35-44 years (OR = 2.43; 95%CI 1.45-4.06; p = 0.0007) and even more 45-60 years (OR = 4.81; 95%CI 2.72-8.52; p = 7.10-8), having a family history of TB (OR = 6.62; 95%CI 2.59-16.94; p = 8.10-5), and working at a pulmonology unit (OR = 3.64; 95%CI 1.44-9.23; p = 0.006). Smoking was associated with LTBI status when defined by a positive QFT-GIT result (OR = 1.89; 95%CI 1.12-3.21; p = 0.02). A high prevalence of LTBI was observed among HCWs in two Moroccan hospitals. Male gender, increased age, family history of TB, and working at a pulmonology unit were consistent risk factors associated with LTBI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221081PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695119PMC
March 2020

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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http://dx.doi.org/10.1126/sciimmunol.aau8714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341984PMC
December 2018

Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants.

J Allergy Clin Immunol 2017 Jul 20;140(1):232-241. Epub 2016 Dec 20.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.

Background: Germline heterozygous mutations in human signal transducer and activator of transcription 1 (STAT1) 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 STAT1 mutation have mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants.

Objective: We estimated variations in the CCD/DBD of STAT1.

Methods: 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.

Results: 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.

Conclusion: The systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and the effect of heterozygous missense mutations in STAT1 identified in patients with severe infectious diseases, including mycobacterial and fungal diseases.
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http://dx.doi.org/10.1016/j.jaci.2016.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471135PMC
July 2017

Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.

J Exp Med 2016 07 11;213(8):1589-608. Epub 2016 Jul 11.

Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.

Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.
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http://dx.doi.org/10.1084/jem.20151467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986526PMC
July 2016

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage.

Proc Natl Acad Sci U S A 2016 06 31;113(24):6713-8. Epub 2016 May 31.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065;

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.
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http://dx.doi.org/10.1073/pnas.1606460113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914194PMC
June 2016

Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

J Exp Med 2015 Sep 24;212(10):1641-62. Epub 2015 Aug 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
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http://dx.doi.org/10.1084/jem.20140280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577846PMC
September 2015

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

J Allergy Clin Immunol 2015 Oct 7;136(4):993-1006.e1. Epub 2015 Jul 7.

Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia. Electronic address:

Background: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.

Objective: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.

Methods: 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 (cTFH) 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 STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK.

Results: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations.

Conclusion: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH 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.
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http://dx.doi.org/10.1016/j.jaci.2015.05.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042203PMC
October 2015

BRCA genetic screening in Middle Eastern and North African: mutational spectrum and founder BRCA1 mutation (c.798_799delTT) in North African.

Dis Markers 2015 28;2015:194293. Epub 2015 Feb 28.

Département d'Oncogénétique, Centre Jean Perrin, 58 rue Montalembert, 63011 Clermont-Ferrand, France.

Background: The contribution of BRCA1 mutations to both hereditary and sporadic breast and ovarian cancer (HBOC) has not yet been thoroughly investigated in MENA.

Methods: To establish the knowledge about BRCA1 mutations and their correlation with the clinical aspect in diagnosed cases of HBOC in MENA populations. A systematic review of studies examining BRCA1 in BC women in Cyprus, Jordan, Egypt, Lebanon, Morocco, Algeria, and Tunisia was conducted.

Results: Thirteen relevant references were identified, including ten studies which performed DNA sequencing of all BRCA1 exons. For the latter, 31 mutations were detected in 57 of the 547 patients ascertained. Familial history of BC was present in 388 (71%) patients, of whom 50 were mutation carriers. c.798_799delTT was identified in 11 North African families, accounting for 22% of total identified BRCA1 mutations, suggesting a founder allele. A broad spectrum of other mutations including c.68_69delAG, c.181T>G, c.5095C>T, and c.5266dupC, as well as sequence of unclassified variants and polymorphisms, was also detected.

Conclusion: The knowledge of genetic structure of BRCA1 in MENA should contribute to the assessment of the necessity of preventive programs for mutation carriers and clinical management. The high prevalence of BC and the presence of frequent mutations of the BRCA1 gene emphasize the need for improving screening programs and individual testing/counseling.
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http://dx.doi.org/10.1155/2015/194293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359853PMC
December 2015

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

Immunol Rev 2015 Mar;264(1):103-20

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, INSERM-U1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.
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http://dx.doi.org/10.1111/imr.12272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405179PMC
March 2015

Human genetics of tuberculosis: a long and winding road.

Philos Trans R Soc Lond B Biol Sci 2014 12;369(1645):20130428. Epub 2014 May 12.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, , 75015 Paris, France.

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.
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http://dx.doi.org/10.1098/rstb.2013.0428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024222PMC
January 2015

Association study of genes controlling IL-12-dependent IFN-γ immunity: STAT4 alleles increase risk of pulmonary tuberculosis in Morocco.

J Infect Dis 2014 Aug 8;210(4):611-8. Epub 2014 Mar 8.

Genetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.

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.
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http://dx.doi.org/10.1093/infdis/jiu140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111910PMC
August 2014

Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region.

Am J Hum Genet 2013 Mar 14;92(3):407-14. Epub 2013 Feb 14.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U980, Paris, France.

Only a small fraction of individuals infected with Mycobacterium tuberculosis 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 TOX, rs1568952 and rs2726600 (combined p = 1.1 × 10(-5) and 9.2 × 10(-5), 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(-8); 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 TOX, and further functional explorations will focus on CD4 T lymphocytes.
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http://dx.doi.org/10.1016/j.ajhg.2013.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591857PMC
March 2013

Mutation screening of the BRCA1 gene in early onset and familial breast/ovarian cancer in Moroccan population.

Int J Med Sci 2013 10;10(1):60-7. Epub 2012 Dec 10.

Laboratoire de Recherche et de Biosécurité P3, Hôpital Militaire d'Instruction Mohammed V, Rabat, Maroc.

Worldwide variation in the distribution of BRCA mutations is well recognised, and for the Moroccan population no comprehensive studies about BRCA mutation spectra or frequencies have been published. We therefore performed mutation analysis of the BRCA1 gene in 121 Moroccan women diagnosed with breast cancer. All cases completed epidemiology and family history questionnaires and provided a DNA sample for BRCA testing. Mutation analysis was performed by direct DNA sequencing of all coding exons and flanking intron sequences of the BRCA1 gene. 31.6 % (6/19) of familial cases and 1 % (1/102) of early-onset sporadic (< 45 years)were found to be associated with BRCA1 mutations. The pathogenic mutations included two frame-shift mutations (c.798_799delTT, c.1016dupA), one missense mutation (c.5095C>T),and one nonsense mutation (c.4942A>T). The c.798_799delTT mutation was also observed in Algerian and Tunisian BC families, suggesting the first non-Jewish founder mutation to be described in Northern Africa. In addition, ten different unclassified variants were detected in BRCA1, none of which were predicted to affect splicing. Most unclassified variants were placed in Align-GVGD classes suggesting neutrality. c.5117G>C involves a highly conserved amino acid suggestive of interfering with function (Align-GVGD class C55), but has been observed in conjunction with a deleterious mutation in a Tunisian family. These findings reflect the genetic heterogeneity of the Moroccan population and are relevant to genetic counselling and clinical management. The role of BRCA2 in BC is also under study.
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http://dx.doi.org/10.7150/ijms.5014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534878PMC
July 2013

IL-12Rβ1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey.

PLoS One 2011 Apr 13;6(4):e18524. Epub 2011 Apr 13.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United States of America.

Background And Objectives: 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.

Methods And Principal Findings: We searched for IL12RB1 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 IL12RB1 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.

Significance: 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018524PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076373PMC
April 2011

Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.

Science 2011 Apr 24;332(6025):65-8. Epub 2011 Feb 24.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, U980, and University Paris Descartes, Necker Medical School, 75015 Paris, France.

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.
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http://dx.doi.org/10.1126/science.1200439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070042PMC
April 2011

Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries.

Authors:
Ludovic de Beaucoudrey Arina Samarina Jacinta Bustamante Aurélie Cobat Stéphanie Boisson-Dupuis Jacqueline Feinberg Saleh Al-Muhsen Lucile Jannière Yoann Rose Maylis de Suremain Xiao-Fei Kong Orchidée Filipe-Santos Ariane Chapgier Capucine Picard Alain Fischer Figen Dogu Aydan Ikinciogullari Gonul Tanir Sami Al-Hajjar Suliman Al-Jumaah Husn H Frayha Zobaida AlSum Sulaiman Al-Ajaji Abdullah Alangari Abdulaziz Al-Ghonaium Parisa Adimi Davood Mansouri Imen Ben-Mustapha Judith Yancoski Ben-Zion Garty Carlos Rodriguez-Gallego Isabel Caragol Necil Kutukculer Dinakantha S Kumararatne Smita Patel Rainer Doffinger Andrew Exley Olle Jeppsson Janine Reichenbach David Nadal Yaryna Boyko Barbara Pietrucha Suzanne Anderson Michael Levin Liliane Schandené Kinda Schepers André Efira Françoise Mascart Masao Matsuoka Tatsunori Sakai Claire-Anne Siegrist Klara Frecerova Renate Blüetters-Sawatzki Jutta Bernhöft Joachim Freihorst Ulrich Baumann Darko Richter Filomeen Haerynck Frans De Baets Vas Novelli David Lammas Christiane Vermylen David Tuerlinckx Chris Nieuwhof Malgorzata Pac Walther H Haas Ingrid Müller-Fleckenstein Bernhard Fleckenstein Jacob Levy Revathi Raj Aileen Cleary Cohen David B Lewis Steven M Holland Kuender D Yang Xiaochuan Wang Xiaohong Wang Liping Jiang Xiqiang Yang Chaomin Zhu Yuanyuan Xie Pamela Pui Wah Lee Koon Wing Chan Tong-Xin Chen Gabriela Castro Ivelisse Natera Ana Codoceo Alejandra King Liliana Bezrodnik Daniela Di Giovani Maria Isabel Gaillard Dewton de Moraes-Vasconcelos Anete Sevciovic Grumach Alberto Jose da Silva Duarte Ruth Aldana Francisco Javier Espinosa-Rosales Mohammed Bejaoui Ahmed Aziz Bousfiha Jamila El Baghdadi Namik Özbek Guzide Aksu Melike Keser Ayper Somer Nevin Hatipoglu Çigdem Aydogmus Suna Asilsoy Yildiz Camcioglu Saniye Gülle Tuba T Ozgur Meteran Ozen Matias Oleastro Andrea Bernasconi Setareh Mamishi Nima Parvaneh Sergio Rosenzweig Ridha Barbouche Sigifredo Pedraza Yu Lung Lau Mohammad S Ehlayel Claire Fieschi Laurent Abel Ozden Sanal Jean-Laurent Casanova

Medicine (Baltimore) 2010 Nov;89(6):381-402

From Laboratory of Human Genetics of Infectious Diseases U980 (LDB, A. Samarina, J. Bustamante, A. Cobat, SBD, J. Feinberg, L. Jannière, YR, MDS, XFK, OFS, A. Chapgier, CP, LA, JLC) and Laboratory of Normal and Pathologic Development of the Immune System U768 (AF), Institut National de la Santé et de la Recherche Médicale, Paris, France; University Paris Descartes (LDB, A. Samarina, J. Bustamante, A. Cobat, SBD, J. Feinberg, L. Jannière, YR, MDS, XFK, OFS, A. Chapgier, CP, AF, LA, JLC), Necker Medical School, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases (A. Samarina, SBD, XFK, LA, JLC), The Rockefeller University, New York, New York; Prince Naif Center for Immunology Research (SAM, SAH, ZAS, AA, JLC) and Department of Pediatrics (SAM, ZAS, AA), College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Pediatrics (SAM, SAH, SAJ, HHF, AAG), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Study Center of Primary Immunodeficiencies (CP) and Pediatric Hematology-Immunology Unit (AF, JLC), Necker Hospital, AP-HP, Paris, France; Department of Pediatric Allergy and Immunology (FD, AI), Ankara University School of Medicine, Ankara, Turkey; Dr Sami Ulus Children Health and Diseases Training and Research Center (GT), Ankara, Turkey; Department of Pediatrics (SAA), King Abdulaziz Medical City, King Fahad National Guard Hospital, Riyadh, Saudi Arabia; Division of Infectious Diseases and Clinical Immunology (PA, DM), National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Teheran, Iran; Laboratory of Cytoimmunology (IBM, RB), Pasteur Institut of Tunis, Tunis-Belvédère, Tunisia; Department of Immunology (JY, M. Oleastro, AB), Juan-Pedro Garrahan National Hospital of Pediatrics, Buenos Aires, Argentina; Department of Pediatrics (BZG), Schneider Children's Medical Center of Israel, Petah Tiqva, Israel; Department of Immunology (CRG), Gran Canaria Dr Negrin University Hospital, Las Palmas de Gran Canaria, Spain; Laboratory of Immunology (IC), Vall d'Hebron Hospital, Barcelona, Spain; Department of Pediatrics (NK, GA), Ege University Medical School, Izmir, Turkey; Department of Clinical Biochemistry and Immunology (DSK, S. Patel, RD), Addenbrookes Hospital, Cambridge, United Kingdom; Immunology Laboratory and Respiratory Infection, Inflammation and Immunology Unit, Departments of Pathology and Thoracic Medicine (A. Exley), Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom; Astrid Lindgren Childrens Hospital Karolinska University Hospital (OJ), Huddinge, Sweden; Department of Immunology (JR) and Department of Infectious Diseases (DN), University Children's Hospital of Zurich, Zurich, Switzerland; Lviv Regional Specialized Children's Hospital (YB), Lviv, Ukraine; Department of Immunology (BP, MP), Children's Memorial Health Institute, Warsaw, Poland; Department of Pediatrics (S. Anderson, ML), Imperial College School of Medicine, St Mary's Hospital, London, United Kingdom; Immunobiology Clinic (LS, A. Efira, FM) and Immunodeficiency Department (KS), Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Vaccinology and Mucosal Immunity (FM), Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Virus Control (MM), Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine (TS), National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan; Department of Pediatrics (CAS), University of Geneva, Geneva, Switzerland; Department of International Relations (KF), Ministry of Health, Bratislava, Slovak Republic; Department of Pediatric Hematology and Oncology (RBS), Giessen, Germany; Department of Pediatric Pulmonology and Neonatology (J. Bernhöft), Hannover Medical School, Hannover, Germany; Department of Pediatrics (J. Freihorst, UB), University Hospital Center-Rebro, Zagreb, Croatia; Department of Pediatric Pulmonology and Immunology (FH, FDB), University Hospital Ghent, Ghent, Belgium; Infectious Diseases Unit (VN), Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom; MRC Center for Immune Regulation (DL), The Medical School, University of Birmingham, Birmingham, United Kingdom; Department of Pediatric Hematology and Oncology (CV), Cliniques Universitaires Saint Luc et Université Catholique de Louvain, Brussels, Belgium; Department of Pediatrics (DT), Mont-Godinne Clinics, Université Catholique de Louvain, Brussels, Belgium; Department of Internal Medicine/Division of Clinical and Experimental Immunology (CN), Maastricht University Medical Centre, Maastricht, The Netherlands; Unit for Respiratory Infections, Department of Infectious Disease Epidemiology (WHH), Robert Koch Institute, Berlin, Germany; Institut für Klinische und Molekulare Virologie (IMF, BF), Universität Erlangen-Nürnberg, Germany; Pediatric Department (JL), Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; Department of Pediatric Hematology (RR), Apollo Speciality Hospitals, Chennai, India; Department of Pediatrics (ACC, DBL), Stanford University School of Medicine, Stanford, California; Laboratory of Clinical Infectious Diseases (SMH) and Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses (SR), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Department of Pediatric Allergy (KDY), Immunology and Rheumatology and Department of Medical Research, Chang Gung Children's Hospital, and Chang Gung University, Kaohsiung, Taiwan; Department of Clinical Immunology (Xiaochuan Wang), Children's Hospital of Fudan University, Shanghai, China; Clinical Immunology Laboratory (Xiqiang Yang), Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Paediatrics and Adolescent Medicine (PPWL, KWC, YLL), Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; Department of Pediatrics (TXC), Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Immunology (GC), Federal University of Bahia, Brazil; University Hospital of Caracas (IN), Caracas, Venezuela; Luis Calvo Mackenna Hospital (A. Codoceo, AK), Santiago, Chile; Department of Immunology (LB, DDG, MIG), Ricardo Gutiérrez Children Hospital, Buenos Aires, Argentina; Laboratory of Investigation in Dermatology and Immunodeficiencies, Department of Dermatology (DDMV, ASG, AJDSD), University of São Paulo Medical School, São Paulo, Brazil; Department of Pulmonology (RA), Children's Hospital Federico Gomez, Mexico City, Mexico; Department of Immunology (FJER), National Institute of Pediatrics, Mexico City, Mexico; National Center of Bone Marrow Graft (MB), Tunis, Tunisia; Clinical Immunology Unit (AAB), Ibn-Rochd Hospital, Casablanca, Morocco; Laboratory of Immunology (JEB), Military Hospital Mohamed V, Hay Riad Rabat, Morocco; Department of Pediatrics (NÖ), Baskent University School of Medicine, Ankara, Turkey; Department of Pediatric Infectious Diseases and Clinical Immunology (MK, A. Somer), Istanbul University Faculty of Medicine, Istanbul, Turkey; Department of Pediatric Infectious Diseases and Immunology (NH, CA), Bakirkoy Maternity and Children's State Hospital, Istanbul, Turkey; Department of Pediatrics (S. Asilsoy, SG), Dr Behçet Uz Children Research and Training Hospital,Izmir, Turkey; Department of Pediatrics, Infectious Diseases, Clinical Immunology and Allergy Division (YC), Cerrahpaşa Medical School, Istanbul University, Cerrahpaşa, Istanbul, Turkey; Immunology Division (TTO, OS), Hacettepe University Children's Hospital, Ankara, Turkey; Division of Pediatric Infectious Disease (M. Ozen), Faculty of Medicine, Inonu University, Malatya, Turkey; Department of Pediatrics (SM, NP), Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Biochemistry (S. Pedraza), INCMNSZ, Ministry of Health, Mexico City, Mexico; Section of Allergy-Immunology, Department of Pediatrics (MSE), Hamad Medical Corporation, Doha, Qatar; and Adult Immunopathology Unit (CF), Saint-Louis Hospital, AP-HP, Paris, France.

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
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http://dx.doi.org/10.1097/MD.0b013e3181fdd832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129625PMC
November 2010

Primary immunodeficiencies of protective immunity to primary infections.

Clin Immunol 2010 May 16;135(2):204-9. Epub 2010 Mar 16.

Clinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, Morocco.

The vast majority of primary immunodeficiencies (PIDs) predispose affected individuals to recurrent or chronic infectious diseases, because they affect protective immunity to both primary and secondary or latent infections. We discuss here three recently described groups of PIDs that seem to impair immunity to primary infections without compromising immunity to secondary and latent infections. Patients with mutations in IL12B or IL12RB1 typically present mycobacterial disease in childhood with a favorable progression thereafter. Cross-protection between mycobacterial infections has even been observed. Patients with mutations in IRAK4 or MYD88 suffer from pyogenic bacterial diseases, including invasive pneumococcal diseases in particular. These diseases often recur, although not always with the same serotype, but the frequency of these recurrences tails off, with no further infections observed from adolescence onwards. Finally, mutations in UNC93B1 and TLR3 are associated with childhood herpes simplex encephalitis, which strikes only once in most patients, with almost no recorded cases of more than two bouts of this disease. Unlike infections in patients with other PIDs, the clinical course of which typically deteriorates with age even if appropriate treatment is given, the prognosis of patients with these three newly described PIDs tends to improve spontaneously with age, provided, of course, that the initial infection is properly managed. In other words, although life-threatening in early childhood, these new PIDs are associated with a favorable outcome in adulthood. They provide proof-of-principle that infectious diseases of childhood striking only once may result from single-gene inborn errors of immunity.
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http://dx.doi.org/10.1016/j.clim.2010.02.001DOI Listing
May 2010

An autosomal dominant major gene confers predisposition to pulmonary tuberculosis in adults.

J Exp Med 2006 Jul 26;203(7):1679-84. Epub 2006 Jun 26.

Laboratory of Immunology, Military Hospital Mohamed V, Hay Riad Rabat, Morocco.

The molecular basis of genetic predisposition to pulmonary tuberculosis in adults remains largely elusive. Few candidate genes have consistently been implicated in tuberculosis susceptibility, and no conclusive linkage was found in two previous genome-wide screens. We report here a genome-wide linkage study in a total sample of 96 Moroccan multiplex families, including 227 siblings with microbiologically and radiologically proven pulmonary tuberculosis. A genome-wide scan conducted in half the sample (48 families) identified five regions providing suggestive evidence (logarithm of the odds [LOD] score >1.17; P < 0.01) for linkage. These regions were then fine-mapped in the total sample of 96 families. A single region of chromosome 8q12-q13 was significantly linked to tuberculosis (LOD score = 3.49; P = 3 x 10(-5)), indicating the presence of a major tuberculosis susceptibility gene. Linkage was stronger (LOD score = 3.94; P = 10(-5)) in the subsample of 39 families in which one parent was also affected by tuberculosis, whereas it was much lower (LOD score = 0.79) in the 57 remaining families without affected parents, supporting a dominant mode of inheritance of the major susceptibility locus. These results provide direct molecular evidence that human pulmonary tuberculosis has a strong genetic basis, and indicate that the genetic component involves at least one major locus with a dominant susceptibility allele.
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http://dx.doi.org/10.1084/jem.20060269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118352PMC
July 2006

Association of IL12RB1 polymorphisms with pulmonary tuberculosis in adults in Morocco.

J Infect Dis 2004 Aug 6;190(3):580-7. Epub 2004 Jul 6.

Laboratory of Human Genetics of Infectious Diseases, University of Paris Rene Descartes, INSERM U550, Paris, France.

Five disease-causing genes, including the IL12RB1 gene that encodes the beta 1 chain of the receptor for interleukin (IL)-12 (IL-12R beta 1), are known to be associated with the syndrome of Mendelian susceptibility to mycobacterial diseases. Some IL-12R beta 1-deficient patients present with tuberculosis as the only clinical phenotype. A comprehensive genetic study of IL12RB1 was conducted among 101 Moroccan families, including 157 offspring (age, >15 years) who had culture-positive pulmonary tuberculosis (PTB). The promoter, exons, and flanking intron regions of IL12RB1 in 40 randomly selected patients with PTB were entirely sequenced, leading to the detection of 19 variants (including 10 novel mutations). Blood cells obtained from individuals who were homozygous for any of the 13 most common variants responded to IL-12, indicating that these polymorphisms were not loss-of-function mutations. By use of a family-based study, 2 promoter polymorphisms that were in strong linkage disequilibrium were found to be associated with PTB, especially -2C-->T (odds ratio for CT or TT vs. CC, 2.69 [95% confidence interval, 1.19-6.09]). This result suggests that IL12RB1 polymorphisms might influence the risk of development of PTB in adults.
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http://dx.doi.org/10.1086/422534DOI Listing
August 2004

Genetic diversity and population structure of Mycobacterium tuberculosis in Casablanca, a Moroccan city with high incidence of tuberculosis.

J Clin Microbiol 2004 Jan;42(1):461-6

Génétique des Maladies Infectieuses, UMR CNRS-IRD 9926, IRD, 34394 Montpellier Cedex 5, France.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC321657PMC
http://dx.doi.org/10.1128/jcm.42.1.461-466.2004DOI Listing
January 2004