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Susceptibility to Tuberculosis. CONTENT INTRODUCTION GENOME SCAN CANDIDATE GENES CONCLUSION Prepared by, Nadia Hassan Walaa Abdalla. INTRODUCTION

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Presentation Transcript
slide1

Susceptibility to

Tuberculosis

slide2

CONTENT

  • INTRODUCTION
  • GENOME SCAN
  • CANDIDATE GENES
  • CONCLUSION
  • Prepared by,
  • Nadia Hassan
  • WalaaAbdalla
slide3

INTRODUCTION

Tuberculosis, primarily caused by Mycobacterium tuberculosis, continues to be an important public health problem despite the existence of national and international tuberculosis control programs. Recent data from the World Health Organization show that about 8-10 million new cases arise annually and eventually 2-3 million die of the disease every year..

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Tuberculosis is one of the major infections that cause disease and death worldwide. It is estimated that one-third of the World's population is infected with M. tuberculosis, but that only one in ten (10%) of those infected ever develop clinical disease

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RISK FACTORS

Include;

  • PATIENTS WITH DIABETES MELLITUS ARE AT INCREASED RISK.
  • TWIN STUDIES SHOWED THAT SUSCEPTIBILITY TO TUBERCULOSIS WAS INHERITED .
  • PATIENTS WITH VITAMIN D DEFICIENCY.

HOWEVER, TRANSMISSION IS BY INHALING INFECTED DROPLETS FROM TB PATIENTS WHEN THEY COUGH , SNEEZE, SPEAK OR SPIT.

tuberculosis in sudan
TUBERCULOSIS IN SUDAN
  • TB is a significant health problem in Sudan.
  • No study concerning genetic control of human susceptibility to TB is done in Sudan .
  • Study concerning epidemiology & drug resistance patterns of Mycobacterium Tuberculosis isolates was done in eastern Sudan (Kassalla & Gadaref state).

Prof.MaowiaMukhtar, project coordinator.

  • National centre for prevention of Tuberculosis works on the development of this health problem.
genome wide scan linkage analysis
Genome wide scan (linkage analysis)
  • Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. Two-stage genome-wide linkage study was conducted to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance.
  • In the first round of the screen, 299 highly informative genetic markers, sibpairs from Gambia and South Africa. 7 chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified.
  • Second round/ 22 markers from these regions were genotyped in a second set of sibpairs from the same countries.
  • Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping (CAM). (Richard Bellamy, et al. 2000)
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Multipoint maximum lod score analysis for chromosomes 15 and X for combined screen 1 and 2 data, calculated by using mapmaker/sibs. (Proc Natl Acad Sci U S A. 2000 July 5; 97(14): 8005–8009)

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A full microsatellite genome scan was conducted by studying three different phenotypes in Kampala and Uganda (Catherine M. 2008)

  • Manyother chromosomal regions were found to be linked with TB e. g 2q35, 8q12-q13, 11q12.3, 17q11-q21. (Celia MT, et al 2000), (Baghdadi, et al 2006), (Miller, et al 2004) (Jamieson, et al 2004)
candidate genes
Candidate genes

Many candidate genes have been identified from the different chromosomal regions and most of them are related to regulation of the cells and products of the immune system.

hla system 6p21

HLA system (6p21)

Genetic susceptibility to pulmonary tuberculosis (PTb) has been associated with the HLA (Antigens of the Human Leukocytes) system of the MHC (Major Histocompatibility Complex), mainly with HLA-DR and-DQ antigens.

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(SLC11A1 gene)natural-resistance-associated macrophage protein 1 (NRAMP1) (2q35)NRAMP spans 12kb and has15 exons encoding a 550 amino acid protein showing 85% identity (92% similarity) with Nramp. It regulates early innate responses to intracellular pathogens.SLC11A1 influences tuberculosis susceptibility by regulation of interleukin-10.

interferon ifngamma and ifngamma receptor

Interferon-γ(IFNgamma) and IFNgamma receptor

Cytokine gene polymorphisms may alter Th1/Th2 balance with major implications in tuberculosis.

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InterleukinsILs participate in the inflammatory response required for the immunological control of a broad spectrum of infectious agents.
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toll-like receptor variantsTLRs have been reported to recognize mycobacterial antigens and initiate an immune response.
mcp 1 promoter variants 17q11 2
MCP-1 promoter variants (17q11.2)

monocyte chemoattractant protein-1 (MCP-1) cytokine plays a role in recruitment of monocytes to the site of infection.

c type lectin dc sign cd209
C-type lectin DC-SIGN (CD209)/

Function/ Dendritic-cell-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing non-integrin (DC-SIGN) (CD209) is an important pathogen recognition receptor of the innate immune system. Recent studies showed that DC-SIGN is the major receptor of Mycobacterium tuberculosis on human dendritic cells and that polymorphisms in the DC-SIGN promoter region are associated with susceptibility to tuberculosis.

Studies/1- Neither promoter variants nor length variation in the neck region were associated with susceptibility to tuberculosis in Tunisian patients. (Ben-Ali M, Barreiro LB, Chabbou A et al.2007)

2- -336 G/G genotype associated with susceptibility to TB among south Indians with p=0.003. (Selvaraj P, et al. 2009)

PTPN22 R620W polymorphism/

Function/ The PTPN22 gene encodes the lymphoid tyrosine phosphatase that has an important regulatory effect on T- and B-cell activation in immune response.

Studies/ - PTPN22 polymorphisms may have rule in susceptibility to TB in Spain (P=0.01) and Moroccan population.(Gomez LM, Anaya JM, Martin J. 2005(Lamsyah H, Rueda B, Baassi L, et al. 2009) .

nonsynonymous polymorphisms in the nod2 gene
nonsynonymous polymorphisms in the NOD2 gene/

Function/ NOD2 is one of the PRRs (Pattern-recognition receptors) that contribute to the immune response to Mycobacterium tuberculosis infection.

Studies/ Three common nonsynonymous SNPs-Pro268Ser, Arg702Trp, and Ala725Gly--demonstrated significant associations with TB disease in African Americans case control study. (Austin CM, Ma X, Graviss EA. 2008) .

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NOS2 is encoded by polymorphic genesNOS2A

At chromosome 17q11.2-q12.

  • Several SNPs and microsatellite polymorphisms have been reported in populations.
discussion
DISCUSSION
  • Four different VDR polymorphisms have been shown

(Taq1, Apa1, Bsm1 & Fok1) at chromosome 12 q12-14 in different ethnic population studies .

  • After this meta-analysis description, the association of

VDR polymorphisms with susceptibility to tuberculosis

Remains unproved .

  • Most studies conducted until now were in ethnically

& geographically different populations, thus, they were

Underpowered to reach any conclusions by examining

The alleles separately.

slide34

Large studies are required to determine association between VDR polymorphism & TB. worldwide.

  • These studies should be with enough power to detect specific polymorphism related to TB. ,since any association will be diluted due to extended linkage disequilibrium with the specific functional allele.