A54T polymorphism in fatty acid binding protein 2 gene is associated in Type 2 Diabetes Mellitus in adult subjects

1 Introduction

Diabetes mellitus comprises a group of metabolic disorders which is defined by abnormal glucose levels related to insulin action, insulin secretion, or a combination thereof (Tang et al., 2019). Diabetes is associated with an increased risk for cardiovascular disease as well as for the resulting morbidity and mortality. The global prevalence of diabetes has been progressively increasing for the last 2–3 decades (Allen and Vessey, 2004). Presently, diabetes is the fastest growing, debilitating disease worldwide. According to WHO estimates, globally, 422 million adults have either type 1 diabetes or Type 2 Diabetes Mellitus (T2DM) (Caroline, 2003). T2DM is defined as a group of multiple metabolic disorders with numerous etiologies characterized by insulin resistance at the onset (Tang et al., 2019; Mohsin et al., 2007). T2DM is documented as a metabolic, non-communicable disease associated with the endocrine system (Zhang et al., 2019). Presently, lifestyle modification via physical exercise, dietary changes and limited pharmaceutical intervention is recommended for management of T2DM (Kerrison et al., 2017; Ribeiroet al., 2019). T2DM has also been described as a public health issue caused by inadequate insulin secretion (Karimian et al., 2019). A well-documented risk factor associated with T2DM is obesity, a very common global issue afflicting approximately 312 million people worldwide (Bego et al., 2019). T2DM is also characterized by a high level of interaction with environmental and genetic factors (Zhou et al., 2019). Pakistan, which is a South Asian country with a population of 207.7 million, covers an extended area of 0.8 million km² (Aamir et al., 2019). A majority of the Pakistani population is rural. However, in urban areas, exposure to pollution may lead to diabetes and metabolic disorders (Meo et al., 2016). According to the International Diabetes Federation (IDF), global prevalence of T2DM is expected to rise to 642 million cases by 2040. Additionally, by the end of 2024, the prevalence of diabetes in Pakistan is expected to reach 11.5 million cases. Globally, approximately 200 million diabetic subjects go undiagnosed, raising the possibility of future complications such as diabetic neuropathy, nephropathy, retinopathy, and stroke (Mohammad and Nanji, 2018).

The human data base, which is based on global and national human genome studies, has precisely documented the prevalence of single nucleotide polymorphisms (SNPs) associated with specific diseases. Genetic linkage analysis, case-control and associated studies have proved that SNPs are stably inherited through generations. Genetic polymorphism has become a useful tool for investigating human diseases via genetic research in a variety of fields, such as population, agriculture and human, molecular, and forensic genetics (Reis et al., 2016). Genetic studies have been conducted to evaluate the association between SNPs and the risk for developing T2DM and other diabetic diseases. Specific SNPs are used to study precise combinations of 90% of the coding/non-coding sections of genes as also to elucidate the pathophysiology of human diseases regulated by human DNA via proteins (Khan et al., 2019). Genome-wide association studies (GWAS) have documented multiple genes and SNPs associated with T2DM in the human population. Xue et al. (2018) conducted meta-analyses and GWAS studies in a population of 16 million and confirmed 139 variants of European ancestry. Intestinal FABP2 is one of the genetic markers associated with the T2DM disease pathway (Alharbi et al., 2014). Apart from GWAS, meta-analysis studies have positively confirmed Alanine-54-Threonine (Ala54Thr) polymorphism in FABP2. Amino acid substitution has an effect on lipid metabolism and plays an important role in fatty acid (hydrophobic) transport from the cell membrane to the endoplasmic reticulum (Khattab et al., 2017). Only a limited number of case-control studies on genetic polymorphism have been reported in the Pakistani population. Ala54Thr polymorphism in FABP2 has not been studied in any of the human diseases in Pakistan. Therefore, the current study investigated the genetic basis of Ala54Thr in FABP2 in individuals diagnosed with T2DM in the Pakistani population.

2 Methods

3 Results

4 Discussion

The current study screened T2DM patients exhibiting A54T polymorphism in FABP2 in the Pakistani population. At present, studies documenting A54T polymorphism in T2DM patients in the Pakistani population are lacking. To our knowledge, the current study is the first to demonstrate significant association between A54T polymorphism and T2DM cases when compared with controls. Our results indicate that, within the Pakistani population, A54T polymorphism in FABP2 is genetically associated with variant genotypes (p = 0.0003) and mutant alleles (p = 0.0001) as well as with dominant (p = 0.003) and recessive models (p = 0.0001).

Adipose tissue is loosely connected to adipocyte cells in the skin. Hormone sensitive lipase, which is located on the cell-membrane, is an intercellular lipase capable of hydrolyzing lipids, such as triglycerides. The association between various fatty acids and the risk of inconsistent T2DM is well documented (Lankinen et al., 2015). FABP2, a 15 kDa protein, is secreted via epithelial-cells and binds fatty acids (Goncalves et al., 2015). It is located in the 4q28-31 region of the chromosome and has 4 exons and 3 introns. The rs1799883 polymorphism, considered as a missense mutation present in exon-2, results from adenine-guanine substitution. FABP2 consists of 3382 nucleotides (Exon-700; Intron-2650), and encodes a small-bowel fatty acid which is a member of a protein family that regulates lipid transport and metabolism (Abbas et al., 2017; Han and So, 2019).

Younis et al. (2018) studied 1940 Pakistani subjects diagnosed with diabetic foot ulceration and concluded that peripheral neuropathy was the common causative factor for the development of foot ulcers. This indicates that, in the Pakistani population, any form of diabetes may lead to further complications. Sikhayeva et al. (2017) studied 28 different SNPs associated with T2DM in the Kazakh population and confirmed that FABP2 was genetically associated with numerous SNPs. Our study also substantiates a study by Shabana et al., which found a significant association between Ala54Thr polymorphism and obesity in the Pakistani population (p = 0.002); (Shabana, 2015). Ala54Thr polymorphism studies have been conducted in relation to many human diseases including T2DM, obesity, metabolic syndrome, hypertension, and stroke (Song et al., 2014; Alharbi et al., 2014). However, only a limited number of meta-analyses have been performed to evaluate the association between T2DM and other diseases and other diseases in the global population (Qiu et al., 2014).

Furthermore, 73.8% of T2DM patients had a high school degree (Fall, 2001). The socioeconomic status of diabetes patients had a highly significant effect on disease affliction (P < 0.05). Prevalence of T2DM within populations appears to vary with socioeconomic status (Vijayakumar et al., 2009). Our study also indicated that the prevalence of diabetes increased rapidly among urban and rural areas (Sowers et al., 2001). The lifestyle of an individual may exert an effect on the incidence of diabetes. As 72% of T2DM patients reported as nonsmokers, it was concluded that smoking was not a risk factor for T2DM. A sedentary lifestyle lacking physical activity may lead to obesity which is a possible risk factor for diabetes. Overweight/obesity, family history, hypertension, and age at onset have been declared as possible risk factors for the increased prevalence of T2DM (Koopman et al., 2005). A previous study concluded that diabetes was a function of a positive family history of diabetes, obesity, and hypertension (Vijayakumar et al., 2009). Diabetes is also associated with a positive family history, which, in turn, may be affected by both maternal and paternal pedigrees (Estacio et al., 2000).

The major limitation of this research was its lack of cross-sectionality, as it only measured the A54T variant

5 Conclusion

It has been concluded, the current study found a significant association between Ala54Thr polymorphism in FABP2 and T2DM in the Pakistani population. Interestingly, a similar variant was also found to be associated with obesity in the Pakistani population. This study recommends that genetic studies be implemented to investigate Ala54Thr polymorphism in other metabolic diseases in the Pakistani population to rule out diseases associated with FABP2 genetic polymorphism. However, in order to validate results, further studies should be conducted utilizing large sample sizes.