Sequence analysis of tumor necrosis factor-α (TNF-α) promoter, 5'UTR and exon1 and association of rs361525 (-238 G>A) with BMI

Abstract

Obesity is among the most common complex diseases with a high rate of morbidity and mortality globally and locally in Kuwait. Tumor Necrosis Factor-α(TNF-α) is a pro-inflammatory cytokine that is primarily secreted by monocytes/macrophage. Increased expression of TNF-α has been observed in the adipodse tissue of obese subjects that could disrupt lipid metabolism and lead to and lead to sustained obese state and obesity-related diseases. The human TNF-α promoter exhibits a high number of genetic variants, mainly single nucleotide polymorphisms (SNPs) that have been shown to influence the level of transcription in association with diseases. The human TNF-α genetic variants have never been fully reported in Arabs, therefore, we aimed to identify these variants by sequencing the TNF-α promoter, 5' UTR, and exon 1 in 290 Kuwaiti Arabs. As a result, we identified 14 genetic variants, including one novel SNP. Two promoter SNPs; rs1800750 (- 376G>A) and rs361525 (-238G>A) were found to be in strong linkage disequilibrium (r2 = 0.73) and (D′ = 1, LOD = 32). To investigate the association of rs361525 (-238G>A) with obesity, we genotyped an additional 573 samples of the general Kuwaiti population by Real-time PCR (total n=863). Linear and logistic regression analysis have not shown any significant association in carriers of the A allele of rs361525 with continuous and categorical BMI, respectively. This is the first study in the Middle East and Kuwait that has sequenced and identified the common, rare and novel genetic variants of TNF-α promoter, 5'UTR and exon 1 in Arabs.