Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/732
Title: Association of Genetic Variants at the TNF-alpha Promoter with Metabolic Diseases in Kuwaiti Arabs
Authors: Sahar A. A. Barhoush 
Supervisor: Dr. Suzanne Al-Bustan
Keywords: TNF-alpha : Kuwaiti Arabs
Issue Date: 2018
Publisher:  Kuwait university - college of graduate studies
Abstract: Chronic inflammation has been associated with an increase in the incidence of many metabolic diseases, such as coronary heart disease (CHD), type 2 diabetes mellitus (T2DM), and Obesity (OB), which are also among the most common complex diseases in the world and especially in Kuwait with a high rate of morbidity and mortality. Tumor Necrosis Factor-alpha (TNF-α) is a pro-inflammatory cytokine involved in the regulation of cell differentiation, proliferation, apoptosis and host defenses. Increased expression of TNF-α has a crucial effect on insulin signalling pathways, lipid metaboism and endothelial function and has been observed to be expressed in the adipodse tissue of obese cases. The human TNF-α gene which is located on chromosome 6 spanning about 3 kb, has been identified as a candidate gene in genetic association studies between inflammation and metabolic diseases. The TNF-α promoter region exhibits a high number of genetic variants, mainly SNPs, that have been associated with changes in the promoter acitivity potentially leading to an increased risk for complex human diseases. These SNPs have been found in linkage disequilibrium in several populations, thus emphasizing the importance of studying them in combination rather than independently. Sequencing of the TNF-α promoter, 5' UTR, and exon 1 regions (1398 bp) in 290 Kuwaiti Arabs samples has identified 14 genetic variants, including one novel synonymous SNP. Two promoter SNPs; rs1800750 (-376G>A) and rs361525 (-238G>A) has been found in strong linkage disequilibrium (r2=0.76) and were significantly deviated from Hardy Weinberg Equilibrium (HWE) (p=0.0001) in OB+ cases (n=79) vs controls (n=211). Further statistical analysis showed a positive association with obesity in carriers of the minor homozygous genotypes -376AA and -238AA (OR=10.63; 95%CI=0.85-126.81; p=0.06), whereas a protective effect was noticed with carriers of the heterozygous genotypes -238GA (OR of 0.28 and significant p-value of 0.04). Moreover, three promoter SNPs; rs1800630 (-863C>A) and rs4248158 (-806C>T) and rs1800629 (-308G>A) revealed a promising association with CHD for carriers of their minor homozygous genotype in CHD+ cases (n=96) vs controls (n=194).This study, the first study in Kuwaiti Arabs to investigate the association of TNF-α genetic variants and metabolic diseases, suggested a strong association of the investigated SNPs with obesity and CHD. Additional studies in a larger cohort is needed to confirm and validate the results presented.
URI: http://hdl.handle.net/123456789/732
Appears in Programs:2050 Molecular Biology

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