The association of the common fat mass and obesity associated gene polymorphisms with type 2 diabetes in obese Iraqi population

doi:10.1016/j.dsx.2019.06.024

Diabetes & Metabolic Syndrome: Clinical Research & Reviews

Volume 13, Issue 4, July–August 2019, Pages 2451-2455

https://doi.org/10.1016/j.dsx.2019.06.024 Get rights and content

Highlights

•
The FTO gene polymorphisms (rs9939609) is a potential predictor of type 2 diabetes (T2D).
•
There is a 2-fold increase in the risk of T2D within the TT group (OR = 2.43, P ≤ 0.001) as compared to the AA group.
•
A significantly higher level of the T allele in T2D patients when compared to the control group, (P ≤ 0.001).
•
The FTO (rs918031) genotype did not show similar significance as to the (rs9939609) in Iraqi cohort.

Abstract

Background & objectives

This study investigates the association of two potential Fat mass and obesity associated gene (FTO) gene polymorphisms (rs9939609 and rs918031) as potential predictors of type 2 diabetes (T2D) in obese Iraqi population and their metabolic effects on hyperglycemia and insulin sensitivity.

Materials & methods

The study included 400 participants with obesity & T2D, with a matching 400 obese non-diabetic cohort. Venous blood samples were collected for DNA extraction. Using specific primers and restriction enzymes, genotyping was performed to identify the various alleles for each gene. The genotype and allele frequencies determined by multinomial logistic regression analysis for FTO single nucleotide polymorphisms (rs9939609) among all the study groups.

Results

There is a two-fold increase in the risk of T2D within the homozygous genotype (TT) group (OR = 2.43, CI 95% 3.57–11.2, P ≤ 0.001) as compared to the wild type (TA). In addition, there was a significantly higher level of the minor allele genotype (T) in T2D patients when compared to the control group, (P ≤ 0.001).

Conclusion

We conclude that the FTO rs9939609 genotype significantly affect the development of insulin resistance, therefore the future occurrence of T2D, in obese individuals.

Introduction

Type 2 diabetes (T2D) and obesity have reached epidemic proportions worldwide and the prevalence is still increasing at critical rates, especially in developing countries [1]. Previous studies revealed that obesity is related to both genetic and environmental factors [2]. Fat mass and obesity associated gene (FTO) is a diabetogenic gene which previously showed to affect the degree of obesity, and is strongly linked to “body mass index” (BMI) [2].

FTO was the first gene found to be linked with common forms of obesity in 2007 [3]. FTO gene spans more than 400 Kb on chromosome 16 and has 9 exons. The first intron is most associated with obesity [4]. This association has been confirmed in several countries with different ethnic background and various age groups [4]. It was showed that the FTO single nucleotide polymorphisms (SNPs) possess similar effects on obesity in Asian countries as well as in European & African countries [5]. However, there is no current evidence to show that the FTO SNPs influence the degree of physical activity [4]. Having said that, studies showed that physical activity may reduce the effects of FTO gene on obesity by up to 30% [4].

FTO protein is a 2-oxyglutarate dependent non-heme dioxygenase family member and localizes in nucleus [6]. Studies suggest that FTO is highly expressed not only in the hypothalamic nuclei involved in energy balance but also in the peripheral tissues [7]. The hypothalamic expression of FTO suggests an increased potential in the control of food intake and whole-body metabolism [7]. A number of SNPs in FTO gene have act as risk factor with obesity in all age groups [6].

In this study, we focused on rs918031 and rs9939609. These are two SNPs, which were showed to be associated with obesity and diabetes [[8], [9], [10]]. However, inconsistent data were previously reported about their activities in obesity and diabetes. Therefore, we tested both SNPs individually in this study [[8], [9], [10]].

Section snippets

Study protocol

Four-hundred patients with clinically diagnosed T2D [11], aging between 42 and 70 years (mean 54.77 ± 8.84 years), were included in this study. A matching group of 400 obese participants were included as control subjects [12]. With age ranged between 40 and 70 years with mean 53.9 ± 8.98 [12]. The Diabetes Clinic at Al-Sadar Teaching Hospital in Al-Najaf receive patients from all regions of Iraq, therefore, this study should be representative of the Iraqi population. The current study was

Results

Table 3 shows the characteristics of all participants in this study, Table 3.

The FTO (rs9939609) genotype was digested using ScaI restriction enzyme, giving rise to 1 (182 bp) band for AA wild type; 3 (182, 154, 28 bp) bands for heterozygous (TA) and 2 (154, 28 bp) bands for homozygous (TT) genotypes, Fig. 1.

The FTO (rs918031) genotype was digested by HaeIII restriction enzyme, giving rise to 1 (206 pb) for (CC) wildtype, 2 (196, 10bp) for (TT) homozygous, and 3 (206, 196, 10 bp) bands for (CT)

Discussion

Obesity and its related cardiovascular diseases account for a large-scale of morbidity and mortality all over the world [15], which possess significant health burdens. Obesity is the main risk factor for T2D [12], both of which, currently affecting millions of individuals worldwide [15]. Both of these conditions share common risk factors, which predispose the development of obesity and T2D [1], such as genetic predisposition [16], composition of the bowel microbiota [17], as well as the

Conflicts of interest

There is no conflict of interest associated with this manuscript.

Funding source

Nothing to declare.

Acknowledgments

Authors would like to thank the Department of Clinical Biochemistry, Kufa University for their help in this study.

References (26)

A.N. Kaftan et al.
Association of adiponectin gene polymorphism rs266729 with type two diabetes mellitus in Iraqi population. A pilot study
Gene
(2015)
S. Kurisu et al.
Frontal QRS-T angle and World Health Organization classification for body mass index
Int J Cardiol
(2018)
L.A. Younus et al.
FTO gene polymorphisms (rs9939609 and rs17817449) as predictors of Type 2 Diabetes Mellitus in obese Iraqi population
Gene
(2017)
A. Vecchie et al.
Obesity phenotypes and their paradoxical association with cardiovascular diseases
Eur J Intern Med
(2018)
M.E. Hess et al.
The fat mass and obesity-associated (FTO) gene: obesity and beyond?
Biochim Biophys Acta
(2014)
A. Misra et al.
Diabetes in developing countries
J Diabetes
(2019)
B. Mittal et al.
Is fat mass & obesity-associated (FTO) gene master regulator of obesity ?
Indian J Med Res
(2016)
P. Burton et al.
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
Nature
(2007)
R.J. Loos et al.
The bigger picture of FTO: the first GWAS-identified obesity gene
Nat Rev Endocrinol
(2014)
E. Wheeler et al.
Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity
Nat Genet
(2013)

C. Schroder et al.

Fat mass and obesity-related gene variants rs9939609 and rs7185735 are associated with second-generation antipsychotic-induced weight gain

Pharmacopsychiatry

(2019)

J.R. Speakman

The 'fat mass and obesity related' (FTO) gene: mechanisms of impact on obesity and energy balance

Curr Obesity Rep

(2015)

L.L. Quan et al.

Association of fat-mass and obesity-associated gene FTO rs9939609 polymorphism with the risk of obesity among children and adolescents: a meta-analysis

Eur Rev Med Pharmacol Sci

(2015)

Cited by (8)

A systematic review exploring the mechanisms by which citrus bioflavonoid supplementation benefits blood glucose levels and metabolic complications in type 2 diabetes mellitus
2023, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citrus bioflavonoids are polyphenolic compounds that are derived from citrus fruits and vegetables. Although they are well known for their powerful antioxidant properties, their effects on glycemic control are not well understood. This review aims to highlight the potential benefits of using citrus bioflavonoids in patients with type 2 diabetes mellitus and its metabolic complications, as well as the medicinal effects of known subclasses of naturally occurring citrus bioflavonoids.
In this systematic review, a survey of studies was conducted from January 2012 to February 2023 using various databases (PubMed, Medline, Google Scholar, and Scopus) to determine the effects of citrus bioflavonoid supplementation on reducing oxidative stress, improving lipid profiles, and glycemic index in patients with diabetes mellitus, as well as the proposed mechanisms of action.
The results of the survey indicate that citrus bioflavonoids may have a positive impact on reducing oxidative stress levels in patients with type 2 diabetes mellitus. In addition to reducing oxidative stress, citrus bioflavonoids may also have a positive impact on other markers of diabetes. For example, studies have shown that they can reduce non-enzymatic protein glycation, which is a process that occurs when glucose molecules bind to proteins in the body.
The reduction in oxidative stress that can be achieved using citrus bioflavonoids may help to maintain antioxidant levels in the body, thereby reducing the severity of diabetes and its complications. These findings suggest that citrus bioflavonoids may be a useful complementary therapy for patients with diabetes.
Exosomal non coding RNAs as a novel target for diabetes mellitus and its complications
2023, Non-coding RNA Research
Diabetes mellitus (DM) is a first-line priority among the problems facing medical science and public health in almost all countries of the world. The main problem of DM is the high incidence of damage to the cardiovascular system, which in turn leads to diseases such as myocardial infarction, stroke, gangrene of the lower extremities, blindness and chronic renal failure. As a result, the study of the molecular genetic mechanisms of the pathogenesis of DM is of critical importance for the development of new diagnostic and therapeutic strategies. Molecular genetic aspects of the etiology and pathogenesis of diabetes mellitus are intensively studied in well-known laboratories around the world. One of the strategies in this direction is to study the role of exosomes in the pathogenesis of DM. Exosomes are microscopic extracellular vesicles with a diameter of 30–100 nm, released into the intercellular space by cells of various tissues and organs. The content of exosomes depends on the cell type and includes mRNA, non-coding RNAs, DNA, and so on. Non-coding RNAs, a group of RNAs with limited transcriptional activity, have been discovered to play a significant role in regulating gene expression through epigenetic and posttranscriptional modulation, such as silencing of messenger RNA. One of the problems of usage exosomes in DM is the identification of the cellular origin of exosomes and the standardization of protocols for molecular genetic studies in clinical laboratories. In addition, the question of the target orientation of exosomes and their targeted activity requires additional study. Solving these and other problems will make it possible to use exosomes for the diagnosis and delivery of drugs directly to target cells in DM. This study presents an analysis of literature data on the role of exosomes and ncRNAs in the development and progression of DM, as well as the prospects for the use of exosomes in clinical practice in this disease.
The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases
2021, Genes and Diseases
Citation Excerpt :
Type 2 diabetes (T2D) is characterized by deficient insulin, insulin resistance and hyperglycemia. FTO rs9939609 and rs9940128 variants are closely related to hyperglycemia, insulin resistance and diabetes mellitus in several populations.56–60 Dysfunction of glucose metabolism is one of main characteristics of diabetes mellitus.
N6-methyladenosine (m6A) RNA methylation is an emerging area of epigenetics, which is a reversible and dynamic modification mediating by ‘writers’ (methylase, adding methyl groups, METTL3, METTL14, and WTAP), ‘erasers’ (demethylase, deleting methyl groups, FTO and ALKBH5), and ‘readers’ (YTHDF1-3, YTHDC1 and YTHDC2). Recent studies in human, animal models and cell levels have disclosed a critical role of m6A modification in regulating the homeostasis of metabolic processes and cardiovascular function. Evidence from these studies identify m6A as a candidate of biomarker and therapeutic target for metabolic abnormality and cardiovascular diseases (CVD). Comprehensive understanding of the complexity of m6A regulation in metabolic diseases and CVD will be helpful for us to understand the pathogenesis of CVD. In this review, we discuss the regulatory role of m6A in metabolic abnormality and CVD. We will emphasize the clinical relevance of m6A dysregulation in CVD.
RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy
2024, Signal Transduction and Targeted Therapy
The role of m<sup>6</sup>A and m<sup>6</sup>Am RNA modifications in the pathogenesis of diabetes mellitus
2023, Frontiers in Endocrinology
Assessing the Fat Mass and Obesity Associated Gene Polymorphisms (rs17817449 and rs1588413) in Obesity and Type 2 Diabetes Mellitus
2020, Systematic Reviews in Pharmacy

View all citing articles on Scopus

View full text

Original ArticleThe association of the common fat mass and obesity associated gene polymorphisms with type 2 diabetes in obese Iraqi population

Highlights

Abstract

Background & objectives

Materials & methods

Results

Conclusion

Introduction

Section snippets

Study protocol

Results

Discussion

Conflicts of interest

Funding source

Acknowledgments

Gene

Int J Cardiol

Gene

Eur J Intern Med

Biochim Biophys Acta

Diabetes in developing countries

J Diabetes

Is fat mass & obesity-associated (FTO) gene master regulator of obesity ?

Indian J Med Res

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Nature

The bigger picture of FTO: the first GWAS-identified obesity gene

Nat Rev Endocrinol

Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity

Nat Genet

Fat mass and obesity-related gene variants rs9939609 and rs7185735 are associated with second-generation antipsychotic-induced weight gain

Pharmacopsychiatry

The 'fat mass and obesity related' (FTO) gene: mechanisms of impact on obesity and energy balance

Curr Obesity Rep

Association of fat-mass and obesity-associated gene FTO rs9939609 polymorphism with the risk of obesity among children and adolescents: a meta-analysis

Eur Rev Med Pharmacol Sci

Original Article
The association of the common fat mass and obesity associated gene polymorphisms with type 2 diabetes in obese Iraqi population