Association of fat mass and obesity-associated (FTO) gene polymorphisms with non-communicable diseases (NCDs) in the Iranian population: A systematic review of observational studies

Abstract

Background

Single nucleotide polymorphisms have been implicated in various diseases, most notably non-communicable diseases (NCDs). The aim of this study was to review available evidence regarding associations between FTO polymorphisms and NCDs in the Iranian population.

Methods

A comprehensive search was conducted through PubMed/Medline and Scopus databases up to December 2021, as well as reference lists of pertinent articles and key journals. All observational studies that examined the association between FTO gene polymorphisms and NCDs in the Iranian population were included. There was no limitation on the publication year. The Newcastle–Ottawa Scale (NOS) was used to assess the study's quality.

Results

The initial search yielded 95 studies, of which 30 studies were included in the current systematic review. The underlying disorders were obesity, type 2 diabetes, breast and colorectal cancers, depression, and metabolic syndrome. These studies found an association between FTO gene polymorphisms and obesity in the Iranian population, but the relationship with other NCDs was debatable. Even though, other diseases such as diabetes and metabolic syndrome, which are closely related to obesity, may also be associated with FTO gene polymorphisms.

Conclusion

FTO gene polymorphism appears to play a role in the occurrence of NCDs. Some of the study results may be misleading due to ethnic differences and the effect of other genetic factors on disease onset, which needs to be investigated further. Finally, FTO gene polymorphisms can be studied as a preventive or therapeutic target.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40200-022-01139-4.

Introduction

Non-communicable diseases (NCDs) are mostly non-infectious chronic diseases that progress slowly and keep the patient occupied for an extended period [1]. Chronic diseases account for 71% of all deaths each year, according to the World Health Organization (WHO) [2]. These diseases are caused by various factors, including genetic, physiological, behavioral, and environmental factors [1]. The study of molecular mechanisms of NCDs is important in disease etiology. So far, several biological mechanisms have been proposed, including physiological and metabolic pathways. Furthermore, genetic risk factors have been proposed as potential contributors to these diseases in biological mechanisms [3]. Single Nucleotide Polymorphisms (SNPs) are differences found in a single nucleotide in relation to another nucleotide in the same DNA sequence. SNPs are the most common type of change and variation of natural sequences found in high density in genomes. SNPs are thought to be a major genetic source of phenotypic variation within a species, as well as an important genetic marker [4]. Several genome-wide association studies (GWAS) have examined the relationship between different polymorphisms and obesity or increased BMI, with several loci reported to be associated with obesity [5–7]. Polymorphisms in the fat mass and obesity-associated (FTO) gene located on chromosome 16q12.2 are strong predictors of obesity in humans [7]. Variations in the FTO gene are frequently linked to obesity, but new research suggests that SNPs and changes in FTO gene expression may be involved in processes related to inflammatory immune responses, metabolic syndrome, diabetes, cardiovascular disease, cancer, and polycystic ovary syndrome [8–13]. There appears to be a link between disease genetic mechanisms and the various races around the world [14]. Based on this principle, many studies on FTO polymorphisms have been conducted [15–23].

As a result, investigating the evidence of the association between diseases and FTO polymorphism as a genetic factor in Iran can provide a wealth of information about population genetics. This study approach was to review available evidence about FTO polymorphisms and their association with NCDs.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to report this study [24].

Search strategy and eligibility criteria

To conduct this systematic review, the PubMed and Scopus databases were searched for entire studies on fat mass and obesity-associated (FTO) gene polymorphisms, as well as reference lists of pertinent articles and key journals, with no restrictions other than publication in Iran, up to December 2021. Fat mass and obesity-associated gene, FTO, and Iran were used as search terms, along with [title/abstract], [MeSH], and [address] tags. This study included all studies that meet the following criteria: A) Observational studies were used to develop the design (case–control, cross-sectional, cohort). B) The disease of interest was known. Animal and intervention studies, letters, comments, review articles, ecological studies, and studies with insufficient data all were excluded. Initially, the results of the two databases' searches were combined, and duplicates were removed. Two separate investigators performed an initial exclusion of irrelevant studies based on article titles and abstracts. Between multiple reports from the same research, only the report with the most comprehensive data were selected.

Data extraction

The full texts of potentially relevant studies were reviewed by two independent authors. The following information will be extracted from articles: type of study, author, year, type of polymorphism, type of disease, other related factors, clinical manifestations, sample size, age, sex, and overall study outcome (Table 1). The data was extracted by two independent investigators and summarized in a pre-designed data extraction table. Disagreements were settled by consulting with the principal investigator.

Table 1.

The characteristics of the studies investigating relationships between fat mass and obesity-associated (FTO) gene polymorphisms with non-communicable diseases (NCDs)

	First author	Year	Type of study	FTO SNPs	Disease	Other associated factors	Clinical manifestation	Polymorphism detection method	Sample size	Age	Female%	Significant outcomes
1	Mahboobeh Mojaver et al. [25]	2015	Case–control	rs1477196 rs9939609	Breast cancer			TaqMan allelic discrimination assay	199	50	100%	There is no association between rs9939609 and rs1477196 polymorphisms in FTO gene and increase in risk of breast cancer
2	Mohsen Mofarrah et al. [26]	2016	Case–control	rs9939609	Type 2 diabetes with coronary artery disease	KALRN rs9289231 ADIPOQ rs2241766		High- resolution melting (HRM)	224	58	49	KALRN, ADIPOQ, and FTO gene polymorphism were associated with in coronary artery disease in type 2 diabetic patients
3	Firoozeh Hosseini-Esfahani et al. [27]	2017	Case–control	rs1421085 rs1121980 rs17817449 rs8050136 rs9939973 rs3751812	Obesity	MDP		ARMS-PCR Sequencing	1254	34.5	50	Individuals with minor allele carriers of rs9939973, rs8050136, rs1781749, and rs3751812 had lower risk of obesity when they had higher Mediterranean dietary score, compared to wild-type homozygote genotype carriers
4	Maryam Abbasi Majdi et al. [28]	2017	Case–control	rs9939609	Obesity Type 2 Diabetes	Resistin Serum Level Anthropometric indices FBS HbA1c Lipid profile		Sequencing of PCR amplicons	78	53	100	There was no significant association between rs9939609 and resistin serum level in type 2 obese diabetic women insulin and HOMA levels were high in AA genotype in rs9939609 SNP FBS and HbA1c were higher in AA and AT genotypes
5	Ramin Saravani et al. [29]	2018	Case–control	rs3751812	Obesity Type 2 diabetes mellitus	perilipin rs1052700		ARMS-PCR	357	51.5	73	Perilipin rs1052700 polymorphism was associated with T2D FTO rs3751812 polymorphism was associated with obesity
6	Farzaneh Ghafarian-Alipour et al. [30]	2018	Case–control	rs763967273 rs759031579 rs141115189 rs9926289, rs76804286 rs9939609	Obesity Type 2 diabetes mellitus	Serum apelin Androgenic hormones	Inflammation	Sequencing of PCR amplicons	197	50	100	FTO variants were associated with T2DM rs9926289 variants had a strong association with apelin and androgenic hormones profile Apelin and androgenic hormones were correlated with T2DM
7	Niloufar Javanrouh et al. [31]	2018	Case–control		Obesity	986 variations located at 16q12.2; build 38hg. Kernel machine regression and single SNP		Genotyping	6928	55.91	59	FTO, AIKTIP and MMP2 genes SNP is associated with obesity
8	Naser Kalantari et al. [32]	2018	Cross‑sectional	rs9930506 rs9930501 rs9932754	Obesity	Anthropometric indices BF% BM%		DNA Sequencing	237	14.1	0	A haplotype in the first intron of the FTO gene had a strong association with obesity indices
9	Mehdi Niknam Moghanloo et al. [33]	2018	Case–control	rs9939609	Obesity Type 2 Diabetes	Leptin		Sequencing of PCR amplicons	76		100	Odds ratio of rs9939609 was higher in diabetic women in comparison with non-diabetic women Leptin level in diabetic women was lower than non-diabetic women
10	Parisa Naseri et al. [34]	2018	Cross-sectional	rs1558902 rs7202116	Metabolic syndrome	HDL-C CETP rs1864163		ARMS-PCR	1776 From 277 families	37.79	48	The conditional logistic model with covariates showed that the linkage results between HDL_C and three marker, rs1558902, rs7202116 and rs1864163 were significant
11	Firoozeh Hosseini-Esfahani et al. [35]	2019	Cohort	rs1421085 rs1121980 rs17817449 rs8050136 rs9939973 rs3751812	Obesity	GRS WDP BMI WC		Genotyping	4292	41.5	56.8	Risk alleles rs1121980, rs1421085, rs8050136, rs1781799 and rs3751812 was associated with BMI related to WDP
12	Amirhosein Khoshi et al. [36]	2019	Case–control	rs9939609	Type 2 diabetes	Omentin rs2274907 FBS Insulin Insulin resistance	Insulin resistance	ARMS-PCR	168	50.72	64.25	polymorphisms of omentin Val109Asp and FTO rs9939609 (T/A) are significantly related to insulin resistance and familial history of diabetes
13	Mina Mozafarizadeh et al.[37]	2019	Cross-sectional	rs9939609	Obesity	MC4R rs17782313 polymorphism BMI		ARMS-PCR	213	> 20	?	rs9939609 polymorphism of FTO gene was associated with BMI
14	Mina Mozafarizadeh et al. [38]	2019	Case–control	rs9939609	Breast Cancer	MC4R rs17782313	BMI	ARMS-PCR	147	over 40 years	100%	No significant associations between any variants and breast cancer risk were seen in obese subjects
15	Farhad Abolnezhadian et al. [39]	2020	Cross-sectional	rs9939609	Obesity	CMI AIP LAP Anthropometric indices Dietary intake	Metabolic health	PCR‑RFLP	165	52.97	?	Obesity-risk allele AA of FTO gene was higher in obesity pheno- types than metabolic phenotypes
16	Meysam Alipour et al.[10]	2020	Cross‑sectional	rs9939609	Obesity Type 2 diabetes mellitus	Anthropometric indices Hypertension Lipid and glycemic profile Inflammatory markers Dietary intake	Cardiovascular risk factors	PCR‑RFLP	155	53	50	The obesity-risk genotype AA of FTO gene was associated with an increased risk for inflammatory obesity in T2DM patients
17	Omid Gharooi Ahangar et al. [40]	2020	Cohort	rs1121980	Obesity	rs569356 rs3790433 rs1514175 rs560887 rs16858082 rs13107325 rs1799883 rs7903146 rs2237892 rs2237897 rs756534 rs6539019 rs2287019 rs6098242 rs223750	Metabolic healthy	Microarray	766	33.39	71	Expression of some genetic markers including FTO rs1121980 polymorphism were associated with persistence of healthy metabolic status, in female obese individuals
18	Mahsa Mehrdad et al. [41]	2020	Cross‑sectional	rs9939609	Overweight	Macronutrients intake		ARMS-PCR	196	33.33	74	Risk allele rs9939609 is associated with the amounts of dietary calorie, carbohydrate, and fat intake
19	Mahsa Mehrdad et al. [42]	2020	Cross‑sectional	rs9939609	Overweight	Serum glucose Serum leptin Insulin Adiponectin lipid profile Serum hormones Dietary intake		ARMS-PCR	196	33.33	74	rs9939609 risk allele was associated with higher serum leptin and lower HDL levels Adjustments for calorie intake and physical activity disappeared leptin association
20	Mahsa Mehrdad et al. [43]	2020	Cross‑sectional	rs9939609	Obesity	BMI Anthropometric indices		ARMS-PCR	198	33.33	75	Risk allele of the FTO rs9939609 polymorphism was associated with greater general and central obesity
21	Mahsa Mehrdad et al. [44]	2020	Cross‑sectional	rs9939609	Overweight	INQ vitamin D Manganese		ARMS-PCR	197	33.33	75	Manganese and Vitamin D have role in incidence of overweight in cases with FTO rs9939609 polymorphism
22	Bahareh Sedaghati-khayat et al. [45]	2020	Case–control	rs6499640 rs1421085 rs1558902 rs1121980 rs8050136 rs7202116	Obesity and Overweight	CETP rs3764261, rs1800775, rs1864163 BMI Metabolic health Lipid profile markers	Metabolic healthy	ARMS-PCR	954	43	52.1	rs1421085, rs1121980, rs1558902 and rs8050136 FTO markers are associated only with unhealthy metabolic obesity
23	Kazem Vatankhah Yazdi et al. [23]	2020	Cross‑sectional	rs8050136	Type 2 diabetes mellitus	SLC30A8 rs13266634 CDKAL1 rs10946398 TCF7L2 rs7903146 KCNQ1 rs2237892 IGF2BP2 rs1470579 MTNR1B rs10830963		ARMS-PCR	268	Case: 65		No significant association with rs8050136
24	Saeid Doaei et al. [46]	2021	Case–control	rs9939609	Breast cancer	Anthropometric indices	Diet Alcohol consumption Smoking	ARMS-PCR	180\360	66	100 %	The FTO gene polymorphism was associated with the risk of breast cancer in overweight individuals, But this association was influenced by environmental factors and lifestyle including diet, alcohol consumption and smoking
25	Maryam Gholamalizadeh et al. [13]	2021	Cross-sectional	rs9939609	Breast cancer	vitamin D	Stage, Pregnancy Marriage Family history Menopause Abortion BMI Smoking Alcohol physical activity Dietary intake Calorie	ARMS-PCR	180	58.52	100%	no significant association between the rs9939609 FTO gene and the risk of breast cancer in Iranian women FTO gene polymorphism may counteract the beneficial effects of vitamin D in preventing breast cancer
26	Golnoosh Goodarzi et al. [47]	2021	Cohort	rs1121980 rs14211085 rs8050136	Obesity	Dietary diversity score GRS BMI VAI Physical activity WC		Microarray	4480	40.25	54.45	Minor allele carriers of rs1121980 had lower body mass index changes and visceral adiposity index when they had higher dietary diversity score Carriers of the minor allele of rs8050136 had significant visceral adiposity index change across dietary diversity score
27	Maryam Gholamalizadeh et al. [48]	2021	Case–control	rs9939609	Colorectal Cancer			ARMS-PCR	375	45.49	????	FTO rs9939609 polymorphism is associated with Colorectal Cancer
28	Mehrdad, Mahsa et al. [49]	2021	Cross-sectional	rs9939609	Depression	Serum vitamin D level	Overweight	ARMS-PCR	197	33.34	74.61%	Depression might be positively associated with FTO rs9939609 polymorphism risk allele Serum vitamin D might be negatively associated with FTO rs9939609 polymorphism risk allele A-allele of FTO rs9939609 polymorphism might be associated with depression independent of serum vitamin D level
29	Mahsa Mehrdad et al. [50]	2021	Cross‑sectional	rs9939609	Overweight	Serum vitamin D Mental health Eating behaviors		ARMS-PCR	197	33.43	74.6	The risk allele of the FTO rs9939609 polymorphism was significantly associated with a higher risk of eating behavior and mental health disorders maybe related to insufficient vitamin D intake
30	Mahsa Mehrdad et al. [51]	2021	Case–control	rs9939609	Overweight	High dietary inflammatory index		ARMS-PCR	197	33.43	74.6	Dietary induced inflammation significantly is related to odds of overweight in adults with rs9939609 polymorphism of the FTO gene

AIP: Atherogenic Index of Plasma, BF%: Body Fat Percentage, BM%: Body Muscle Percentage, BMI: Body Mass Index, GRS: Genetic Risk Score, CMI: Cardiometabolic Index, FBS: Fasting Blood Glucose, HbA1c: HemoglobinA1c, HDL-C: High-Density Lipoprotein Cholesterol, INQ: Index of Nutritional Quality, LAP: Lipid Accumulation Product, VAI: Visceral Adiposity Index, WC: Waist Circumference, WDP: Western Dietary Pattern

Quality assessment

Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of the studies, with each study receiving a score ranging from 1 to 9 (Supplementary Table 1) [52]. In each study, two independent investigators performed quality assessments, and any disagreements were resolved by reaching a consensus on the findings of the studies.

Result

The initial search yielded 95 articles from the databases mentioned above. Articles with no relevant outcomes were excluded after the primary screening. 62 articles were kept for further review of their full text. Following the screening of the full texts. 32 articles were excluded for being in review design (n = 16), FTO gene expression presentation (n = 9), duplicate publication (n = 5), interventional and infection disease association (n = 2). Finally, this systematic review included 30 articles [10, 13, 23, 25–51]. Characteristics of the included studies are summarized in (Table 1). Obesity, type 2 diabetes (T2D), breast and colorectal cancers, depression, and metabolic syndrome were the underlying disorders. Seven studies were conducted solely on women [10, 13, 25, 28, 33, 38, 46], while one study only recruited men [32], one study did not mention the gender of the participants [23] and others were conducted on both genders [10, 26, 27, 29, 31, 34–37, 39–45, 47–51]. There were 14 case–control studies [25–31, 33, 36, 38, 45, 46, 48, 51], 13 cross-sectional studies [10, 13, 23, 32, 34, 37, 39, 41–44, 49, 50] and three cohorts [35, 40, 47]. The sample sizes varied between 76 and 4480 people. Amplification refractory mutation system polymerase chain reaction (ARMS-PCR) was the most commonly used method in Iran for obtaining FTO gene polymorphisms.

FTO

The association between FTO polymorphisms and obesity/overweight was investigated in 15 studies [27, 30–32, 35, 37, 39, 41–45, 47, 50, 51]. Eight studies assessed the link between FTO polymorphisms and T2D [10, 23, 26, 28–30, 33, 36]. Four studies investigated the association of FTO polymorphisms with breast cancer [13, 25, 38, 46], and one study evaluated the link between FTO polymorphisms and depression [49], one study colorectal cancer [48] and one study metabolic syndrome [34]. These articles focus on the rs9939609 polymorphism of the FTO gene, which is followed by rs8050136, rs1121980, rs3751812, and rs1421085, with the other loci being less common.

Obesity

FTO polymorphisms were studied in 15 studies involving obese and overweight subjects [27, 30–32, 35, 37, 39, 41–45, 47, 50, 51]. The most closely related polymorphism to obesity is the rs9939609 FTO polymorphism [37, 39, 41–44, 50, 51]. Also rs1421085 SNP [27, 35, 45, 47], rs1121980 SNP [27, 35, 40, 45, 47], rs17817449 SNP [27, 35], rs8050136 SNP [27, 35, 45, 47], rs9939973, rs3751812 SNPs [27, 35], rs9930506, rs9930501, rs9932754 SNPs [32] and rs6499640, rs1558902, rs7202116 SNPs [45] were presented associated with obesity in included articles. Several studies on vitamin D [44, 50, 53], manganese [44] and dietary diversity/pattern [27, 35, 41], demonstrated the role of dietary intake in obesity control in association with FTO polymorphisms. Mehrdad et al. demonstrated in their study that the FTO rs9939609 risk allele was significantly associated with a higher risk of eating behavior and mental health disorders in overweight adults, possibly due to insufficient vitamin D intake [50]. Sedaghati-khayat et al. discovered that unhealthy metabolic obesity was linked to FTO polymorphisms rs1421085, rs1121980, rs1558902, and rs8050136 [45]. However, in the Gharooi Ahangar et al. study, rs1121980 was associated with a healthy metabolic status [40]. In the study by Abolnezhadian et al., rs9939609 was associated with obesity phenotypes rather than metabolic phenotypes [39]. So, the FTO gene polymorphisms association with obesity is almost proven.

Diabetes

Due to the association between T2D and obesity, five articles examined the relationship between obesity/T2D and the FTO polymorphism [10, 28–30, 33], and three articles have examined the association between type 2 diabetes and polymorphisms in the FTO gene [23, 26, 36].

The rs3751812 SNP was associated with obesity but not diabetes in a study conducted by Saravani et al. [29]. In the studies by Vatankhah Yazdi et al. there was no significant association between T2D and rs8050136 [23]. Ghafarian-Alipour et al. discovered that the SNPs rs763967273, rs759031579, rs141115189, rs9926289, rs76804286, and rs9939609 are linked to T2D. [30]. Niknam Moghanloo et al. found that the odds ratio of rs9939609 SNP was higher in diabetic women in comparison with non-diabetic women [33] and also rs9939609 SNP was significantly related to insulin resistance and familial history of diabetes in Khoshi et al. study [36]. Alipour et al. discovered that rs9939609 is linked to an increased risk of inflammatory obesity and cardiovascular disease in diabetic patients [10]. Mofarrah et al. also mentioned the rs9939609 link to coronary artery disease in type 2 diabetes patients [26]. In Abbasi Majdi et al. study rs9939609 SNP was not associated with obesity but probably has more frequency in T2D women [28]. The above-mentioned studies show that more investigations are needed to better understand of the association between diabetes and FTO gene polymorphisms.

Breast cancer

Four studies examined the FTO gene polymorphism rs9939609 and its association with breast cancer [13, 25, 38, 46]. Mojaver et al. also examined the FTO gene polymorphism rs1477196 and its association with breast cancer [25]. Except for the Doaei et al. study, which concluded that this association is influenced by environmental factors, most studies found no correlation between FTO polymorphisms and breast cancer [46].

Other disease and health-related factors

In terms of the other NCDs, Mehrdad et al. found that the A-allele of the FTO rs9939609 polymorphism was positively associated with depression and negatively associated with serum vitamin D. The depression link is unrelated to serum vitamin D levels [49]. Naseri et al. demonstrated the metabolic syndrome and rs1558902 and rs7202116 FTO gene polymorphisms might be positively associated with each other [34]. In Gholamalizadeh et al. study FTO rs9939609 polymorphisms were associated with Colorectal cancer [48]. Finally, in the case of these disorders, the limited number of studies cannot be enough for a definitive conclusion.

Discussion

Our systematic review revealed that the FTO gene polymorphisms are associated with obesity phenotype in the Iranian population, but its relationship with other NCDs is not fully clear. Around the world, FTO gene polymorphism is regarded as the most important polygenic risk factor for obesity. Numerous GWAS studies have been conducted to identify FTO variants and their association with the obesity phenotype [6, 54]. This relationship has also been validated in systematic reviews and meta-analyses. Furthermore, research indicates that the FTO gene polymorphism may be linked to other diseases such as diabetes and metabolic syndrome. As a result, it can be regarded as a genetic risk factor not only for obesity but also for other related NCDs. Because of the genetic diversity among races and ethnicities, research on FTO gene polymorphisms in various geographical regions is crucial. A systematic review was performed in Iran to address this issue. FTO polymorphism was linked to obesity in Asians in a study by Mohammadi et al., and the rs9939609 and rs8050136 variants had a significant effect on that risk factor [55], which were also the most common found SNPs in our study. FTO polymorphism and post-bariatric weight loss are linked, as shown in the Gupta et al. study by researchers [56]. FTO polymorphisms 9930506, 9939609, 6499640, 713144, 8050136 and 1558902 have been linked to obesity in children/adolescents/adults of various ethnicities [57–60]. FTO gene polymorphisms are widely accepted to be linked to obesity and dietary intake. This has also been confirmed in Iranian studies. Due to the increasing prevalence of obesity and overweight in the Iranian population [61], this relationship is of great importance. After the GWAS identified the FTO gene as positively associated with obesity, researches are in train to find the FTO roles and regulatory mechanisms of action in obesity and metabolic disease [62]. Now GWAS studies discuss about the debates in association between FTO polymorphisms and obesity as well as other diseases like metabolic syndrome, diabetes and psoriasis [6, 63, 64].

Type 2 diabetes has been studied in obese subjects in Iranian FTO polymorphisms studies, confirming the link between diabetes and obesity. As a result of our research, there is a link between type 2 diabetes and the FTO polymorphism, like the Li et al. study, which was conducted on the East and South Asian populations. However, in their study by adjusting obesity, the significance level decreases [65]. This link has been confirmed in several studies conducted in other parts of the world, including South Asia, India, China, and Scandinavia, all of which focused on the FTO gene polymorphism rs9939609, followed by rs8050136 [66–73]. However, some studies have not confirmed the FTO gene polymorphism relationship with diabetes [74, 75], and Vatankhah Yazdi et al. found no significant association between the rs8050136 SNP and diabetes [23]. As a result, further research into the association between type 2 diabetes and FTO gene polymorphisms are required in Iran. Furthermore, in FTO polymorphisms studies, gestational diabetes (70–72) and diabetic nephropathy [22, 76, 77] are important complications that were not considered in the Iranian studies.

In contrast to the systematic review conducted in 2021 [78], in Gholamalizadeh et al. case–control study in Iran, there was an association between rs9939609 SNP and colorectal cancer, so, it need more further evaluation [48].Our findings suggest that there is no link between FTO rs9939609 polymorphism and breast cancer in Iran, which is supported by the Jafari Nedooshan et al. study [79]. But the evidence that approved obesity as a risk factor in the increasing the incidence of 13 different types of cancers [7], cannot be neglected in the study of polymorphism’s relationship with cancers.

The results of GWAS studies can predict the relationship between FTO and metabolic syndrome [6]. The Naseri et al. study results suggest that the rs1558902 and rs7202116 polymorphisms of the FTO gene are linked to the risk of metabolic syndrome in Iranian population [34]. Moreover, in the study by Sedaghati-khayat et al., unhealthy metabolic obesity was linked to FTO polymorphisms rs1421085, rs1121980, rs1558902, and rs8050136 [45]. In comparison, Nagrani et al. found significant associations between rs8050136, rs1121980, rs1558902, rs9939609, and rs1421085 FTO variants and metabolic syndrome risk in their meta-analysis [80], and Wang et al. found the rs9939609 association with metabolic syndrome risk [12].

Mehrdad et al., in the results of their study, presented that FTO rs9939609 polymorphisms are probably associated with depression [49]. Consistent with this result, Rivera et al. study refers to the association between FTO, depression and BMI [81]. But in a systematic review conducted by Zarza-Rebollo et al. in 2021, no significant association with depression was found [3]. Yao et al. in their study mentioned that lack of association between rs9939609 SNP and major depressive disorder in the Asian population can be due to potential genetic heterogeneity in the susceptibility of MDD on this locus[82]. So, this matter needs more investigations too. Also, other remarkable NCDs like polycystic ovary syndrome (PCOS), cardiovascular disease, sarcopenia and cancers have been observed in literature reviews, but not in Iran studies [8, 9, 83–90].

Surprisingly, in addition to NCDs, Naderi et al. discovered a link between the FTO rs9939609 SNP and the risk of pulmonary tuberculosis as an infectious disease [91]. Similarly, this result was observed in Feng et al. study on the Chinese population [92]. According to these findings, it is critical to investigate the underlying mechanisms of FTO protein function in disease occurrence. For example, The alteration of immune response based on FTO genetic variants, could be tested. Furthermore, FTO gene expression in the hypothalamus and adipocytes plays an important role in peripheral energy homeostasis, mitochondrial coupling, and substrate cycling. In this regard, studies in Iran are looking into its impact on disease onset, particularly obesity, as well as the role of interventions on FTO gene expression [53, 93–97]. FTO expression, under the influence of drugs and micronutrients, can regulate metabolic homeostasis [62]. Numerous other gene polymorphisms and their associations with NCDs have also been studied in the Iranian population.

This study provides a good understanding of the relationship between FTO gene polymorphism and NCDs in Iran, which can be very valuable due to the role of ethnicities in genetic factors, and it can be used as a guide for personalized medicine studies. This study also has some limitations. The use of high throughput methods to study polymorphisms can provide a more complete vision for comparison, which was not available in Iranian studies. The heterogeneity of the data precluded meta-analysis, and the role of gender and other variables was not assessed in this study.

Conclusion

Finally, the role of FTO gene polymorphism in the occurrence of NCDs, appears to have been established. Iranian studies show that this role is related to nutritional status and environmental factors. Furthermore, some of the results of the studies may be misleading due to ethnic differences and the effect of other genetic factors on the onset of diseases, which need to be investigated more thoroughly. In addition, given the importance of epigenetics in understanding the underlying causes of diseases, the study of gene regulation and metabolic pathway networks should be considered. Finally, identifying FTO gene polymorphisms can help in NCDs prevention, and these SNPs can also be studied as a therapeutic target.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

ZHT: Investigation, conceptualization, designing, writing – original draft. SMM: Investigation, designing, writing – review & editing. BM and FB: Investigation, writing – review & editing. SHR: Conceptualization, designing, project administration, supervision, writing – review & editing. HSE, KK, SG and BL: Conceptualization, writing – review & editing. All authors reviewed and approved the final manuscript.

Funding

This study was funded by the Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran (Number: 1400–02-105–1164).

Data availability

All data generated in this study are supported by the published articles in PubMed/Medline and Scopus databases, and all data generated are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interests

The authors declare that they have no conflict of interests.