This study analyzed the baseline characteristics of 123 Northern Lebanese participants, divided into non-obese (n = 65) and obese (n = 58) groups, to explore the association between UCP2 45-bp I/D polymorphism and obesity. While no significant differences were found in gender and stress levels between the two groups, highlighting their weak contribution with obesity in the context of our study, significant differences emerged in other variables.

As anticipated, the obese group exhibited a significantly higher mean weight (92.0 kg) and BMI (34.0 kg/m2) compared to the non-obese group (65.0 kg and 22.0 kg/m2, respectively, P < 0.001). Surprisingly, significant differences were also observed in two key BMI confounders: age and physical activity. The obese group had a higher median age (33 vs. 21 years, P < 0.001) and engaged in less regular physical exercise compared to the non-obese group (15.8% vs. 41.5%, P = 0.003). Adjusting for these confounders was crucial, as they could substantially influence obesity outcomes independent of the UCP2 polymorphism. Initial attempts to control for these factors using logistic regression analysis were insufficient. This necessitates a refinement of our study design through stratification by age and physical activity.

Current research indicates that the UCP2 45-bp I/D polymorphism exhibits a consistently dominant D allele across different regions. The highest D allele frequency was reported in Indonesia (81.5%) and the lowest in Germany (65.6%). In our study, the D allele frequency is 69.5%, which is closer to Germany’s than to the higher frequencies observed in Italy (76.85%) and Saudi Arabia (76.4%). Conversely, the I allele is most prevalent in Germany (34.4%) and least prevalent in Indonesia (18.5%). The I allele frequency in our study is 30.5%, aligning more closely with Germany and higher than Italy (23.15%) and Saudi Arabia (23.6%) [8, 10, 11, 13].

Genotypic distribution further illustrates regional variations: Indonesians exhibit the highest DD genotype frequency (68%) [10], followed by Italian (59%) [13] and Saudi Arabian (58.3%) populations [14]. German population has a lower DD frequency (52.4%) but a higher ID frequency (39.8%) [8]. In our study, the DD and ID genotypes are equally distributed (46.3%), with a lower frequency of the II genotype (7.4%). The II genotype is generally uncommon, with the lowest frequencies in Indonesia (5%) [10] and Saudi Arabia (5.3%) [14], and slightly higher frequencies, comparable to our study, in Germany (7.8%) [8] and Italy (7%) [13].

These findings underscore the dominant nature of the D allele across regions, while also highlighting significant regional variations in the genotypic distribution of the UCP2 45-bp I/D polymorphism.

Furthermore, our results revealed that there are no notable differences in genotype distribution across gender, age, physical activity, and stress levels, compared to the German study done by Evans et al. [8], which found that the UCP2 polymorphism’s association with obesity was more pronounced in older individuals. Similarly, the Pima Indian study also observed a significant association with BMI in participants over 45 years old, suggesting that age could be a critical factor in the expression of this genetic association [15]. Additionally, research on Spanish children failed to establish a strong link between this polymorphism and obesity [16]. Research among Turkish children found that the I/I genotype and I allele of the UCP2 polymorphism were associated with an increased risk of childhood obesity and related metabolic disorders [17].

The lack of significance in gender differences in our study contrasts with the South Indian study, which found a significant association between the UCP2 insertion allele and increased BMI in women but not in men [18]. Similarly, the Indonesian study also reported gender-specific associations with the UCP2 polymorphism [10].

We subsequently applied logistic regression analysis to account for the confounding effects of BMI-related factors such as age and physical activity. However, these factors could not be fully adjusted, as their adjusted p-values remained significant. To address potential confounding factors, we conducted a stratified analysis based on age and physical activity. This approach allowed for a more accurate assessment of genotype-BMI associations by accounting for these critical variables, thereby minimizing the risk of erroneous conclusions. In our study on the North Lebanese population, we explored the association of the 45-bp I/D polymorphism in the UCP2 gene with obesity across three strata. After logistic regression analyses and adjustments for stress and gender, the odds ratios and p-values for the I/D  genotype remained consistently non-significant. The analysis of the I/I genotype was only possible in S1, with no significant findings. The combined I/D  + I/I genotypes also showed no significant association between the UCP2 45-bp I/D polymorphism and obesity. Differences are also statistically unsignificant in terms of allele distribution between both groups. These results suggest that UCP2 45-bp I/D genotypes are not significantly associated with obesity when accounting for confounders.

Some studies have reported significant associations between the UCP2 45-bp I/D polymorphism and obesity. For example, research among Turkish children found that the I/I genotype and I allele were associated with an increased risk of childhood obesity and metabolic disorders [17]. Similarly, a South Indian study identified a significant association between the insertion allele and increased BMI in women [18]. Additionally, a Malaysian research found a significant association between the I/I genotype and overall adiposity [9]. These findings suggest that the impact of the UCP2 45-bp I/D polymorphism on obesity may vary depending on population, ethnicity, and other demographic factors.

In contrast, several international studies, including those on Pima Indians [15]. Danish Caucasians [12], and German children [8], found no significant link between the UCP2 polymorphism and obesity or BMI. Similarly, a French study found no correlation between this polymorphism and metabolic outcomes in morbidly obese patients [11], and Saudi Arabian research indicated that while the D/D genotype was more prevalent among severely obese individuals, the I/D polymorphism itself was not significantly associated with obesity [14].

Meta-analyses and studies from Italy and Denmark also found no significant association [12, 13]. This lack of significance is further supported by broader analyses, which suggest that the UCP2 45-bp I/D polymorphism does not significantly impact obesity across diverse populations [19, 20].

The discrepancies in the association between the UCP2 45-bp I/D polymorphism and obesity observed across different studies may be attributed to several factors, including genetic diversity, population-specific allele frequencies, and variations in study design, such as sample size and the adjustment for confounding variables. Additionally, environmental and lifestyle factors, such as diet and physical activity, which vary across populations, may also influence the expression of the UCP2 gene and its impact on obesity. These differences underscore the importance of considering ethnic and regional variability in genetic studies and suggest that the role of the UCP2 polymorphism in obesity may be context-dependent rather than universally applicable. Further large-scale studies across diverse populations, with careful consideration of confounding factors, are necessary to clarify the relationship between UCP2 polymorphism and obesity.