Association of Tumor Necrosis Factor-α 308A/G Gene Polymorphism with Obesity among a Population of Southwestern Nigeria

Introduction

Obesity, described as excessive fat in the body is associated with dyslipidemia, high blood pressure and Type

2 diabetes mellitus. It is preventable if interplay of genetics, nutrition and lifestyle is fully understood [1, 2]. An imbalance between energy intake and utilization is often responsible for obesity. This could result from changes to ‘Western’ lifestyle and dietary habits [3]. Obesity linked to cardio- metabolic disorders may result in poor health outcomes and mortality. There were estimated 12 million obese individuals in Nigeria with a female preponderance. A high prevalence of obesity (31%) has been reported among a population of Southwestern Nigerian descent [4]. Activation of the innate immune system in adipose tissue promotes pro-inflammatory status and oxidative stress, triggering a systemic acute-phase response. Inflammation of adipose tissue in obese patients was hypothesized to play a critical role in the pathogenesis of obesity-related complications [5]. Tumor Necrosis Factor-α gene, an adipocyte-derived cytokine, and its 308A allele are up regulated in obesity and is a genetic marker for susceptibility to obesity [6, 7, 8]. Tumor Necrosis Factor- 308 polymorphism has been found on promoter region of TNF- alpha gene with G → A substitution therefore increasing transcriptional activation of the gene [9].

Genetic variation is a non-modifiable factor for interpersonal propensity to develop and regulate obesity [2]. The impact of TNF-α G308A polymorphism on obesity might be limited because of involvement of multiple factor [1, 2]. Despite extensive work done on different populations [3, 7], there are inconsistent reports on association between TNF-α G308A polymorphism and obesity [3, 4, 5, 6, 7, 8, 9]. The present study investigates the frequency of occurrence of TNF-α G308A polymorphism and its association with cardiovascular disease risk among an obese population of Southwestern Nigeria.

Results

The mean ages of obese and non-obese subjects were 38.57±0.90 and 39.22±0.93 years (p>0.05), all female participants have a mean age of 37.54 years while their male counterparts were aged 43.63 years respectively. The mean values of body weight, height, body mass index and waist circumference of the non-obese group were significantly increased compared to that of obese subjects (Table 1).

Table 1: Anthropometric, Phenotypic Parameters and FBS levels among Obese and Non-obese Subjects (mean ±SD). *significant at p<0.05(female obese vs non-obese) #significant at p<0.05 (male obese vs non-obese) WC - Waist Circumference; HC - Hip Circumference; WHR - Waist Hip Ratio; SBP - Systolic Blood Pressure; DBP - Diastolic Blood Pressure; FBS - Fasting Blood Sugar There were no significant differences in the mean age distribution among the female obese (37.55±0.89) and non- obese (37.54±0.94) as well as the male obese (48.89±2.56) and non-obese subjects (48.40±1.75) at p>0.05. The mean BMI, SBP and FBS values were increased among the male obese compared to non-obese subjects (p<0.05) while mean body weight, BMI, WC, HC were significantly increased in obese than non-obese females (Table 2).

Discussion

Worldwide, more than 3 million deaths were related to overweight and obesity [4]. Chronic Inflammation accompanied with high levels of proinflammatory cytokines such as TNF-α, is an important feature of obesity [10]. This case-control study investigated the relationship of TNF-α 308G/A polymorphism, phenotypic and anthropometric parameters with obesity among a population of Southwestern Nigeria. Our findings in this study did not show a significant difference in mean age distribution within the obese and non-obese groups. This is at variance with a report that showed increased obesity in older adults [11]. A possible explanation for the disparity in the results could be due to small sample size. It was previously suggested that increased hormonal changes and inactive lifestyle common with aging increases risk of developing obesity. In addition, muscle mass tends to reduce with age [12] giving rise to decreased body metabolism. Data from this study showed that obesity has a female preponderance with higher mean BMI recorded among obese females compared to males. This finding is in agreement with earlier studies that found an association between TNF-α levels and obesity risk in women [3, 13]. Tumor Necrosis Factor - α has two regions G-308A and G-238A of which 308 is a promoter region for TNF- α and has been linked with increased TNF- α production in adipose tissue which is implicated in pathogenesis of obesity [9]. Waist and hip circumferences are important estimations in predicting cardiovascular disease occurrence in obesity with increased WC and decreased HC associated with increased risk of obesity-related mortality [14, 15]. We recorded a contrasting observation of lower WC among our study participants. This coupled with the non-significant differences of FBS and measured anthropometric parameters in the TNF- α G-308A genotypes suggests that our subjects are at reduced risk of developing cardio-metabolic disorders associated with obesity. We hope to establish this in a further investigation involving a larger sample size.

The G-308A mutation in the promoter region of TNF- α acts as a potent transcriptional activator resulting in higher TNF- α concentrations with consequent reduction in insulin sensitivity [16, 17]. Genotyping of TNF-α 308 loci in this present study showed that the distribution of homozygous genotype AA was higher among obese than non-obese participants while the AG genotype showed a higher frequency in the non-obese. This is similar to results from an investigation that reported an association between AA genotype and increased TNF- α expression with obesity[7] but at variance with another that linked heterozygous TNF-a-308 G>A gene polymorphism to higher risk of developing obesity and associated disorders [18].

Obese carriers of the TNF- α 308 A allele have been shown to be more susceptible to increased effect of dyslipidemia and development of insulin resistance [17]. However, the mean FBS value (4.77±0. 66 mmol/l) of the obese participants of this study was not up to the fasting glucose diagnostic criteria for diabetes mellitus of ≥7.8 mmol/l [19] suggesting that the subjects did not develop insulin resistance nor diabetes mellitus, both metabolic consequences of obesity. Findings from this study also showed a higher occurrence of GG genotype among the non-obese controls than the obese group thereby indicating a weak association of GG with obesity. A similar observation reported that the odd of being obese was lower in individuals with G/G genotype [3] and at variance with another [20].

Results of this study revealed that AA (51%) and AG (43%) genotypes show a trend for association (OR = 0.4071, 8.137, p<0.05) in the obese participants. Another study also reported increased risk of developing obesity among participants with AG and AA genotype. And that TNF- α 308 G/A gene polymorphism reconciles the relationship between dietary fat intake and obesity risk [3] while another reported no associations [21]. Significant changes in TNF- α 308 G/A gene polymorphism observed among our studied population suggests that AG genotype was not independently associated with obesity.

Conclusion

It could be hypothesized from our observations that AA genotype of TNF- α 308 may be a predisposing factor for development of obesity whereas GG genotype did not show a significant association (p>0.05) with obesity in our study population. We suggest a more detailed dietary –genetic interaction based study to establish the contributions of TNF- α 308 G/A gene polymorphism to obesity among a larger cohort in our study population. This is important in predicting susceptibility to obesity for quick intervention.