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Search Results: 1 - 4 of 4 matches for " Edhyana Sahiratmadja "
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Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis
Sonia Davila ,Martin L. Hibberd,Ranjeeta Hari Dass,Hazel E. E. Wong,Edhyana Sahiratmadja,Carine Bonnard,Bachti Alisjahbana,Jeffrey S. Szeszko,Yanina Balabanova,Francis Drobniewski,Reinout van Crevel,Esther van de Vosse,Sergey Nejentsev,Tom H. M. Ottenhoff,Mark Seielstad
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000218
Abstract: Despite high rates of exposure, only 5–10% of people infected with Mycobacterium tuberculosis will develop active tuberculosis (TB) disease, suggesting a significant role for genetic variation in the human immune response to this infection. Here, we studied TB association and expression of 18 genes involved in the Toll-like receptor (TLR) pathways. Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients and 387 controls from Indonesia. We found that four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2–2.7). We genotyped these four TLR8 polymorphisms in an independent collection of 1,837 pulmonary TB patients and 1,779 controls from Russia and again found evidence of association in males (for rs3764880 P = 0.03, OR = 1.2, 95% c.i. = 1.02–1.48). Combined evidence for association is P = 1.2×10?3–6×10?4. In addition, a quantitative PCR analysis indicated that TLR8 transcript levels are significantly up-regulated in patients during the acute phase of disease (P = 9.36×10?5), relative to baseline levels following successful chemotherapy. A marked increase in TLR8 protein expression was also observed directly in differentiated macrophages upon infection with M. bovis bacille Calmette-Guérin (BCG). Taken together, our results provide evidence, for the first time, of a role for the TLR8 gene in susceptibility to pulmonary TB across different populations.
Polymorphisms in Autophagy Genes and Susceptibility to Tuberculosis
Mario Songane, Johanneke Kleinnijenhuis, Bachti Alisjahbana, Edhyana Sahiratmadja, Ida Parwati, Marije Oosting, Theo S. Plantinga, Leo A. B. Joosten, Mihai G. Netea, Tom H. M. Ottenhoff, Esther van de Vosse, Reinout van Crevel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041618
Abstract: Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1β, IL-6, IL-8, IFN-γ and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02) and MTOR (p = 0.02) and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04). All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production.
Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis
Tom H. M. Ottenhoff, Ranjeeta Hari Dass, Ninghan Yang, Mingzi M. Zhang, Hazel E. E. Wong, Edhyana Sahiratmadja, Chiea Chuen Khor, Bachti Alisjahbana, Reinout van Crevel, Sangkot Marzuki, Mark Seielstad, Esther van de Vosse, Martin L. Hibberd
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045839
Abstract: Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (α/β) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (α/β) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient’s blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection.
A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians
Eileen Png, Bachti Alisjahbana, Edhyana Sahiratmadja, Sangkot Marzuki, Ron Nelwan, Yanina Balabanova, Vladyslav Nikolayevskyy, Francis Drobniewski, Sergey Nejentsev, Iskandar Adnan, Esther van de Vosse, Martin L Hibberd, Reinout van Crevel, Tom HM Ottenhoff, Mark Seielstad
BMC Medical Genetics , 2012, DOI: 10.1186/1471-2350-13-5
Abstract: In stage 1, we used the Affymetrix 100 K SNP GeneChip marker set to genotype 259 Indonesian samples. After quality control filtering, 108 cases and 115 controls were analyzed for association of 95,207 SNPs. In stage 2, we attempted validation of 2,453 SNPs with promising associations from the first stage, in 1,189 individuals from the same Indonesian cohort, and finally in stage 3 we selected 251 SNPs from this stage to test TB association in an independent Caucasian cohort (n = 3,760) from Russia.Our study suggests evidence of association (P = 0.0004-0.0067) for 8 independent loci (nominal significance P < 0.05), which are located within or near the following genes involved in immune signaling: JAG1, DYNLRB2, EBF1, TMEFF2, CCL17, HAUS6, PENK and TXNDC4.Mechanisms of immune defense suggested by some of the identified genes exhibit biological plausibility and may suggest novel pathways involved in the host containment of infection with TB.Tuberculosis (TB) remains one of the leading causes of infection-associated mortality, with close to 10 million new cases and 2 million deaths annually [1,2]. Although Mycobacterium tuberculosis has infected around a third of the world's population, only 3-10% of those infected develop active disease during their lifetime [3]. More than 90% of infected individuals remain asymptomatic with a latent infection. This indicates that host immune/defense pathways are often highly effective in controlling this disease. Because the infection causes such a burden of disease in those unable to contain the infection, it is important to discover underlying mechanisms to aid the development of more effective interventions such as better vaccines and novel treatments for latent and active infection. Similarly, it is important to identify predictive biomarkers that might identify individuals who are most susceptible to developing active TB disease.Studies of heritability using twins and other familial designs have convincingly implicated a genetic
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