Genetic Analysis of FTO Polymorphism and BMI in Indians

Introduction

Obesity is a pervasive global health issue, closely tied to increased morbidity and mortality rates, and a significant contributor to the overall disease burden worldwide (Wu et al., 2018). Its association with numerous non-communicable diseases makes it a major obstacle to achieving sustained global health improvements. The World Health Organization's (WHO) goal of reducing global obesity levels by 2025 is threatened by the rising prevalence of overweight and obesity in India, a country housing almost one-sixth of the world's population (Luhar, Mallinson, Clarke, & Kinra, 2018).

Obesity arises from a multifaceted interplay of environmental and genetic factors, coupled with psychological, cultural, and physiological influences. While external factors like sedentary lifestyles and excessive calorie intake have contributed to the recent surge in overweight and obese individuals, genetic factors are estimated to account for 40% to 90% of the population variability in body mass index (BMI) (Fawcett, 2010). Therefore, recognizing the substantial contribution of genetic factors to body weight is imperative (Farooqi & Rahilly, 2006).

Genes play a pivotal role in regulating food intake, metabolism, and the body's response to physical activity, among other functions.

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Minor genetic variations can significantly impact the activity levels of these genes, potentially influencing BMI. Several genes have been identified within the associated regions, falling into two primary categories:

• Genes influencing central nervous system (CNS) function
• Genes with peripheral effects, often mediated through adipose tissue

Many of these genes, located in or near the associated regions, are highly expressed in the CNS, particularly in the hypothalamus. They appear to be involved in appetite regulation, satiety, energy expenditure, and behavior.

This suggests that similar mechanisms could be affected in common forms of obesity as well as in monogenic forms.

Nutrigenomics is an emerging scientific field that employs molecular tools to investigate the relationship between nutrition and genetics. It aims to identify, assess, and understand the various responses individuals and population groups exhibit when subjected to specific dietary interventions (Pavlidis, Patrinos, & Katsila, 2015).

In 2007, the development of high-throughput genotyping techniques and the advent of genome-wide association studies (GWAS) established a clear association between single nucleotide polymorphisms (SNPs) in the FTO gene region and body mass index (BMI) and obesity risk in diverse populations. This breakthrough marked the FTO gene locus as the first unequivocally linked to adiposity. Building on these findings, we hypothesize that FTO variants may play a significant role in predisposing individuals to obesity, overweight conditions, and related non-communicable diseases. This retrospective study aims to provide compelling evidence supporting a holistic approach and personalized solutions for such individuals, integrating genetics, nutrition, and exercise.

Review of Literature

The gene responsible for encoding the fat mass and obesity-associated protein (FTO) is located on chromosome 16 in humans, spanning over 400 kb and comprising 9 exons. Initially discovered in a fused-toe mouse model in 1999, this gene earned the name "Fatso" due to its substantial size. In 2007, the association between the FTO rs9939609 single nucleotide polymorphism (SNP) and obesity was first elucidated through a genome-wide association study (GWAS) conducted by Frayling et al. The same year, two other research groups independently confirmed these findings. Subsequently, numerous GWAS studies have reaffirmed the link between various FTO SNPs and body mass index (BMI) in both children and adults. While these studies have investigated different variants and variables, certain SNPs, such as rs1421085, rs17817449, and rs9939609, are known to exhibit strong linkage disequilibrium (Katus et al., 2020).

FTO plays a critical role in nucleic acid demethylation and is prominently expressed in brain regions governing energy balance and feeding behavior (Fawcett, 2010). The FTO protein belongs to the non-heme dioxygenase family, relying on 2-oxoglutarate as a cofactor, and is predominantly localized in the cell nucleus. Expression studies indicate broad distribution of FTO across many tissues, with its highest expression in the brain, particularly in the hypothalamic arcuate nucleus, a region deeply involved in the regulation of food intake and energy expenditure (Speakman, Rance, & Johnstone, 2008).

Within the first intron of the FTO gene, a cluster of single nucleotide polymorphisms (SNPs) has shown a significant association with type 2 diabetes risk. However, after adjusting for BMI, this association with type 2 diabetes completely disappears, suggesting that the link between FTO and type 2 diabetes is mediated through its influence on BMI (Wu et al., 2018). Consequently, FTO variants are implicated in type 2 diabetes susceptibility, particularly in an obesity-dependent manner. A genome-wide association analysis involving 1,924 type 2 diabetics paired with 2,938 controls replicated the impact of polymorphic variations in the FTO gene across 13 different cohorts, encompassing approximately 39,000 individuals.

This evidence strongly supports the notion that certain common FTO gene variants, specifically the genotypes AA and AT, predispose individuals to obesity in comparison to the wild-type genotype TT (Speakman et al., 2008).

A study by Claussnitzer et al. (2015) shed light on the role of the FTO rs1421085 C-allele in preadipocytes IRX3 and IRX5, showing that increased expression of these genes was associated with reduced browning of white adipocytes, leading to decreased mitochondrial thermogenesis (Katus et al., 2020). Despite the robust evidence linking FTO intronic variants to obesity, the precise biological mechanisms and the developmental stages at which these differences manifest remain unknown.

An FTO rs17817449 SNP has been strongly linked to obesity and obesity-associated traits, such as fasting blood glucose, insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR), and fat mass, under a recessive pattern (Srivastava, Mittal, Prakash, & Srivastava, 2015). A recent study revealed that individuals homozygous for the obesity-predisposing rs9939609 allele exhibit dysregulated circulating ghrelin concentrations, a crucial hormone regulating hunger, leading to reduced post-prandial hunger and ghrelin levels. Subjects carrying specific FTO genotypes also displayed varying neural sensitivity to circulating ghrelin within specific brain regions. These findings offer insights into how FTO alleles associated with obesity risk contribute to increased energy consumption and obesity in humans (Huang et al., 2014). Both children and adults with at least one rs9939609 FTO obesity-risk allele (homozygous= AA and heterozygous= AT) have been shown to have higher average energy intake compared to individuals with two wild-type alleles (TT) (Tanofsky-Kraff et al., 2009).

Several variants of the FTO gene have been linked to elevated BMI in specific ethnic groups, increasing the risk of obesity. These variants and their impact on genotypes are summarized as follows:

While the precise molecular function of the FTO gene remains elusive, epidemiological studies and animal models have demonstrated that FTO SNPs associated with increased BMI are strongly correlated with higher caloric intake, elevated consumption of saturated fat or protein, heightened appetite, reduced satiety, poor dietary choices, and a lack of control over eating behaviors (Wang et al., 2016).

Individuals carrying FTO variants are more prone to overeating due to reduced satiety. Eating behaviors associated with low satiety include:

1. Eating larger quantities (more calories)
2. Preference for high-calorie foods, such as biscuits, cakes, pastries, cheese, and fatty meats
3. Consuming appetizers, desserts, and snacks after a main meal
4. Increased tendency to snack

The SNP rs8050136 is located within the first intron of the FTO gene, which exhibits high conservation across species and lies within the binding site of the putative transcription factor Cutl like 1 (CUTL1). On the other hand, the rs11076023 SNP resides in the 3' untranslated region (3'UTR) of the FTO gene, suggesting a potential impact on mRNA stability and gene expression (Prakash, Mittal, Srivastava, Awasthi, & Srivastava, 2016).

A recent meta-analysis of data from eight Indian studies revealed that the FTO variant rs9939609 increases the risk of obesity by 1.15 times, equivalent to a 0.30 kg/m² increase in BMI per impact allele (Genetic, 2014). Earlier research conducted on the South Indian population (CURES) found that FTO SNPs, specifically rs1588413 and rs8050136, raised the risk of obesity by 1.27 and 2.06 times, corresponding to a 0.33 and 0.54 kg/m² increase in BMI per impact allele, respectively (Shahid, Rehman, & Hasnain, 2020).

India ranks second globally in the number of people with diabetes, with 62.4 million individuals affected, as reported by the Indian Council for Medical Research-India Diabetes (ICMR-INDIAB) study. Asian Indians exhibit unique clinical and biochemical characteristics often referred to as the 'South Asian' or 'Asian Indian Phenotype,' including higher waist circumference, increased levels of total and visceral fat, hyperinsulinemia, insulin resistance, and a heightened predisposition to diabetes. While a strong genetic component contributes to these characteristics, it has also been demonstrated that unhealthy diets and physical inactivity play a significant role in the growing prevalence of metabolic diseases among Asian Indians (Vimaleswaran et al., 2016).

Materials and Methods

This retrospective population-based study was conducted between February 2020 and April 2020 at geneOmbio Technologies Pvt. Ltd. in Pune, Maharashtra, in collaboration with Symbiosis School of Biological Sciences, Pune, Maharashtra. The study involved screening the data from the total-health panel at the geneOmbio laboratory to select participants for inclusion in the study.

The data focused on the following genetic variants:

• Variants - T>A
• TT (Homozygous wild)
• TA (Heterozygous)
• AA (Homozygous variant)

Subsequent screening was carried out based on predefined inclusion and exclusion criteria.

Inclusion Criteria

• Indian participants residing within the Indian subcontinent
• Participants with an existing genetic profile for the FTO gene
• Participants with existing data on physical activity, dietary habits, and anthropometric measurements

The FTO genetic profile was available for 110 Indian participants, comprising 60 males and 50 females. Further analysis of the data from these 110 participants was conducted to fulfill the study's objectives. All 110 participants had available data for BMI, while 105 had data available for physical activity and exercise, 103 for appetite, 62 for body fat percentage, and 40 for waist circumference (WC). The data were further segregated based on gender.

The BMI categories were defined as follows:

• < 18.5 = Underweight
• 18.5-22.9 = Normal
• 23-24.9 = Overweight
• 25-32.9 = Obese class I
• 33-39.9 = Obese class II
• > 40 = Obese class III

High WC was defined as > 90cm in males and > 80cm in females, while a body fat percentage > 27% was considered high in both males and females.

Physical activity was categorized into sedentary, moderate, and high, while exercise was broadly categorized as either exercise or no exercise.

Statistical analysis was performed using Microsoft Excel (version: 16.34 - 20011502).

The frequencies of the observed alleles were tested against the Hardy–Weinberg equilibrium. Statistical significance was defined at p < 0.05.

Results

3.1. Hardy-Weinberg Equilibrium Representation of FTO Polymorphism

The genotype frequency distribution of the total study population for the FTO gene, assessed for BMI, was found to be in Hardy–Weinberg equilibrium (p=0.91). This equilibrium held true for subgroups within the study, including male participants (p=0.93), female participants (p=0.88), obese individuals (p=0.91), and non-obese individuals (p=0.91). Likewise, when assessing body fat percentage, the genotype frequency distribution of the total population (62) was in Hardy–Weinberg equilibrium (p=0.91), as were the genotype frequencies for males (p=0.92) and females (p=0.87). In the case of waist circumference, genotype frequencies for the total population (40) were also in equilibrium (p=0.89), along with those for males (p=0.92) and females (p=0.87).

Abbreviations: BMI - Body mass index, BF% - Body fat percentage, WC - Waist circumference, MAF - Minor allele frequency, HWE - Hardy–Weinberg equilibrium

3.2. Distribution of FTO Gene Polymorphism According to BMI Multiclassification

Table 2 presents the distribution of genotypes and alleles of the FTO gene T/A polymorphism in a sample population of 110 participants, categorized by BMI. The analysis did not reveal a significant association between the FTO polymorphism and overweight or obesity as defined by BMI.

Discussion

The distribution of the FTO gene T/A polymorphism in the study population was analyzed with respect to BMI categories, aiming to explore any potential associations with overweight and obesity. However, the analysis did not reveal a significant link between the FTO polymorphism and BMI-defined overweight or obesity. This finding suggests that, in this specific sample population of 110 Indians, the FTO gene T/A polymorphism may not play a major role in determining BMI variations related to overweight or obesity. It is essential to acknowledge that genetic factors contributing to obesity can be highly complex and may involve interactions with various environmental and lifestyle factors.

Conclusion

In this retrospective population-based study conducted at geneOmbio Technologies Pvt. Ltd. in collaboration with Symbiosis School of Biological Sciences, Pune, Maharashtra, data from 110 Indian participants were examined for associations between the FTO gene T/A polymorphism and BMI-defined overweight and obesity. The analysis did not reveal a significant relationship between the FTO polymorphism and BMI-defined categories of overweight or obesity.

It is important to note that this study has limitations, including its sample size and the potential influence of uncontrolled environmental factors. Future research with larger and more diverse populations, as well as additional genetic markers and comprehensive environmental data, may provide further insights into the genetic and environmental factors contributing to obesity in the Indian population.