Susceptibility to Tuberculosis. CONTENT INTRODUCTION GENOME SCAN CANDIDATE GENES CONCLUSION Prepared by, Nadia Hassan Walaa Abdalla. INTRODUCTION
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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..
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
HOWEVER, TRANSMISSION IS BY INHALING INFECTED DROPLETS FROM TB PATIENTS WHEN THEY COUGH , SNEEZE, SPEAK OR SPIT.
Prof.MaowiaMukhtar, project coordinator.
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)
A full microsatellite genome scan was conducted by studying three different phenotypes in Kampala and Uganda (Catherine M. 2008)
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.
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.
(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.
Cytokine gene polymorphisms may alter Th1/Th2 balance with major implications in tuberculosis.
monocyte chemoattractant protein-1 (MCP-1) cytokine plays a role in recruitment of monocytes to the site of infection.
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) .
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) .
At chromosome 17q11.2-q12.
(Taq1, Apa1, Bsm1 & Fok1) at chromosome 12 q12-14 in different ethnic population studies .
VDR polymorphisms with susceptibility to tuberculosis
Remains unproved .
& geographically different populations, thus, they were
Underpowered to reach any conclusions by examining
The alleles separately.
Large studies are required to determine association between VDR polymorphism & TB. worldwide.