Abstract
Obesity is a growing public health challenge with complex causes involving both environmental and genetic factors. This study explored the contribution of genetic variants in the UCP3 gene (implicated in energy metabolism) to obesity risk in a Pakistani population. Using a case-control design, 400 participants from Karachi (200 cases-individuals with obesity; 200 controls-individuals with normal body mass index or BMI) were assessed for sociodemographic, obesity-related physical signs, comorbidities, anthropometric, metabolic, and lifestyle factors, alongside next-generation sequencing of the UCP3 gene. Individuals with obesity (cases) were more frequently married, had a family history of obesity, and exhibited obesity-related physical signs compared to controls. All anthropometric (except height) and metabolic (except HDL-C) variables were significantly aberrant in cases. Similarly, behavioral patterns such as random eating, a tendency toward fat-dense food, low physical activity, and irregular sleep-wake cycles were more prevalent among cases. Genetic analysis revealed 43 variants after quality filtering, with most located in regulatory regions rather than altering protein structure. Three variants, including rs35517703, rs142107918, and rs928421426, were observed exclusively in the individuals with obesity (cases). Additionally, three novel variants [73712770 (GA > GAA), 73718482 (CTTT > CTT), and 73718482 (CTTT > CTTTT)] were identified that may reflect population-specific genetic diversity. By focusing on UCP3 variants with population relevance, this research provides new insights into the genetic architecture of obesity in Pakistanis or South Asians in general. It supports the value of regional genetics and genomics studies in global health contexts.