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

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.

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

[IAssociation between Kaposi´s sarcoma and multiple myeloma: is it caused by HHV-8?] / Sarcome de kaposi et myélome multiple: s´agit-il d´une association causée par le HHV-8?

Kaposi´s sarcoma is a tumor characterized by purple or brownish lesions affecting the skin. It is most commonly associated with human herpes virus type 8 (HHV-8) infection and may be secondary to malignant hemopathy, including lymphomas. We here report a new case of a very rare combination: Kaposi´s disease-multiple myeloma. The study involved Mr. aged 67 years, treated for Kaposi´s disease in the Department of Dermatology. Serological test for HHV-8 was positive; it was associated with stage I multiple myeloma IgG Lambda with a poor prognosis. We here report this 21st case of Kaposi-Kahler in order to highlight Kaposi-human herpes 8 virus variant involved in the pathophysiology of multiple myeloma. More studies are needed in order to establish this exceptional link.

[Erythrophagocytosis by blast cells and de novo T cell LAL without cytogenetic abnormalities in a Moroccan patient]. / Un cas marocain d'érythrophagocytose blastique et LAL T de novo sans anomalie cytogénétique.

Erythrophagocytosis by blast cells is due to hyperactivation of blast cells. Erythrophagocytosis is associated with T cell myeloid hemopathies (8;16). This study shows an exceptional case of erythrophagocytosis by blast cells in a patient with acute T-lymphoblastic leukemia without cytogenetic abnormalities. We here report the case of A.Z, aged 19 years presenting with febrile syndrome with dizziness and phosphenes, tumor syndrome with amygdala and gingival hypertrophy. Blood count revealed hyperleukocytosis (399.5 G/L), with aregenerative anemia (Hb: 9.3 g/dl) and thrombocytopenia (platelet count: 40 g/L). Myelogram showed 90% of blast cells (MPO-negative) with erythrophagocytosis by blast cells images. Immunophenotyping confirmed T-cell LAL. Cytogenetic analysis was normal. Erythrophagocytosis by blast cells in patients with T-cell LAL appears to be a separate entity, hence the importance of images on diagnosis, prognosis and treatment of T-cell LAL.