Abstract
Background: Obesity has reached epidemic proportions worldwide resulting in a serious public health problem. In Saudi Arabia, 28.7% of the population is obese due largely to the adoption of western dietary patterns over the last decade. The Fat-mass and obesity associated (FTO) and melanocortin-4 receptor (MC4R) genes are ubiquitously expressed in the brain and pancreatic islets, and are the main link between the central nervous system and energy homeostasis based on food intake and energy expenditure. Genetic variants in the FTO and MC4R gene have been strongly associated with an increased obesity risk. Aim: To identify novel mutations in the MC4R gene and to perform correlation analysis of the known variants rs9939609 and rs1421085 in the FTO gene and rs17782313 near the MC4R gene in an obese Saudi population. Materials and Methods: A total of 136 obese patients and 104 healthy controls from King Fahd Hospital, Al-Khobar, were genotyped for single-nucleotide polymorphisms within or near the FTO and MC4R genes using the TaqMan assay. Leptin levels were determined by enzyme-linked immunosorbent assay. Targeted sequencing of MC4R exon was done by Sanger sequencing method. Results: The study included 58 obese males and 78 obese females with a mean age of 39.7812.77 years and a mean body mass index (BMI) of 42.65 +/- 9.03kg/m(2). A significant increase in the levels of leptin and triglycerides was associated with an increase of BMI. Other factors such as lactate dehydrogenase, gamma-glutamyltransferase, and high-density lipoprotein were also significantly higher in the severely obese cohort. The FTO polymorphisms were associated with a significantly increased risk for obesity and in BMI-stratified cohort, rs9939609 (T/A: odds ratio [OR]=1.73, p=0.007) and rs1421085 (T/C: OR=1.56, p=0.03) showed even stronger association. Genotyping for the near MC4R, polymorphism, rs17782313 revealed an association with moderately obese patients (T/C: OR=1.73, p=0.038). Conclusion: The studied FTO gene polymorphisms were found to be significantly associated with increased BMI and were highly significantly associated with severe obesity. These FTO gene polymorphisms combined with a high-fat diet appear to promote early-onset obesity in the Saudi population. FTO polymorphisms appear to be universally associated with the risk of obesity, and further investigation into this genetic locus may provide clues for potential therapeutic targets.