Research Article: Analysis of SNPs of MC4R, GNB3 and FTO gene polymorphism in obese Saudi subjects

Date Published: December , 2017

Publisher: Makerere Medical School

Author(s): Said Salama Moselhy, Yasmeen A Alhetari, Archana Iyer, Etimad A Huwait, Maryam A AL-Ghamdi, Shareefa AL-Ghamdi, Khadijah Saeed Balamash, Ashraf A Basuni, Mohamed N Alama, Taha A Kumosani, Soonham Sami Yaghmoor.


The goal of this study was to analyze the association between the FTO rs17817449 (G>T), G protein beta3 subunit (GNB3) C825T and Melanocortin 4 receptor (MC4R) A822G single nucleotide polymorphism (SNP) with obesity in Saudi subjects.

The subjects were divided into 2 groups according to BMI: Obese (BMI> 29.9) and non- obese control (BMI<24.9). Genotyping of the target genes were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis (RFLP). We demonstrated the association of the FTO genotype TT with increased weight, BMI and leptin levels in both males and females. However, there was no association of genotype TT with fasting blood glucose, triglycerides and cholesterol levels. Regarding GNB3 rs5443 polymorphism, the likelihood of obesity was linked to the TT genotype which was also associated with increased leptin levels. On the other hand, the SNP of MC4R A822G did not exhibit any significant association with obesity among studied subjects and showed only the presence of homozygous AA genotype. The polymorphism of FTO gene rs17817449 and GNB3 gene rs5443 (C825T) may be a genetic determinant of obesity in Saudi population whereas impact of MC4R Asn274Ser change could not be detected.

Partial Text

Increasing prevalence of obesity worldwide prompts many researchers to determine genetic factors underlying this disease. Dina et al.1 identified the link between the fat mass and obesity associated (FTO) genotype and obesity among obese European patients. Moreover, the FTO genotype has been reported to be associated with phenotypic variability of BMI2. In parallel, the heterotrimeric G proteins, which are key components of intracellular signal transduction and play a focal role in adipogenesis, have been proposed as candidate genes for obesity3. C825T polymorphism in the G protein beta3 subunit (GNB3) showed to play an important role in the determination of obesity in the German population4. In addition, Melanocortin 4 receptor (MC4R) deficiency that resulted from disruption of one or both MC4R alleles represents the commonest monogenic form of human obesity to date5. Of note, frequency of MC4R gene mutations was found to be lower in some studies than others, accounting for ∼ 6% of severe obesity cases6–8. However a significance of MC4R mutations in Asian obese populations has not been adequately detected compared with non-obese9–11.

Two hundred and twelve unrelated individuals were included in this study, 107 males and 105 females, with mean age of 30.74+10.76 and 35.64+11.01 respectively. The subjects were divided into 2 groups according to BMI; obese (BMI ≥ 30 kg/m2), included 51 males and 55 females, and non – obese (BMI<24.9), included 56 males and 50 females. The subjects were recruited from November 2010 to Jun 2012 at King Fahd Medical Research Center (KFMRC), Mada'en Al-Fahad Medical Center and Medical administration in King Abdulaziz University. This study was approved by the ethics committee of the King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia (reference No 741-12) for sample collection. Written informed consent was obtained from all participants prior to the study. The p value at <0.05 was considered as significant. Deviation from Hardy-Weinberg equilibrium for FTO genotypes and GNB3 genotypes was calculated by the Chi-square test. Analysis of FTO rs17817449, GNB3 rs5443 (C825T) and MC4R A822G polymorphism are showed in figure 1. In FTO polymorphism, the G allele generated an undigested 198-bP product while the T allele yielded 99-bp fragment after digestion. While in GNB3 C825T polymorphism, alleles T represent the absence of restriction site, giving a 268-bp PCR product, and alleles C indicate the presence of restriction site giving 152-bp and 116-bp fragments. For MC4R gene (A822G) polymorphism, the uncut PCR product of 382 bp represents allele G, while restriction fragments of 45bp and 337bp represent allele A. The present study showed that serum leptin level increases significantly as the BMI increases (table 1). Similar results have been reported by previous studies where leptin concentrations showed to be correlated in healthy individuals with the body fat content and body mass index18 Several factors have been proposed for such increase of leptin levels like; a diminished response in the leptin receptor signalling pathway, poor penetration of the bloodbrain barrier by leptin, the presence of less active molecular forms of leptin or Leptin resistance19. The polymorphism of FTO gene rs17817449 and GNB3 gene rs5443 (C825T) may be a genetic determinant of obesity in Saudi population, whereas impact of MC4R Asn274Ser change could not be detected in our sample.   Source:


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