Association of RBP4 gene variants with adverse lipid profile and obesity
Introduction
Obesity is currently a worldwide public health problem (Kelishadi, 2007). Increasing burden of obesity leads to increased morbidity and mortality due to metabolic syndrome, insulin resistance, type-2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) (Mensah et al., 2004). There is a progressive increase in obesity in both children and adolescent groups in the last decade in Iran (Sarrafzadegan et al., 2010).
The underlying mechanism of obesity is very complex, including interactions among behavioral, environmental, and genetic factors. Increasing prevalence of obesity can be attributed to highly calorific food intake and relatively sedentary lifestyle of modern times. Several studies have shown important role of genetic components in the risk of becoming obese (Lyon and Hirschhorn, 2005, Xia and Grant, 2013). Retinol-binding protein4 (RBP4) is a recently discovered adipokine that belongs to the lipocalin family of proteins, which is potentially in association with insulin resistance (Yang et al., 2005). RBP4 is released from the liver as a primary source, and also from the adipose tissue as the alternate source (Tsutsumi et al., 1992). RBP4 acts as a carrier protein for retinol (one of the animal form of vitamin A), and other small hydrophobic molecules (Newcomer and Ong, 2000). Overexpression of RBP4 in visceral adipose tissue would cause elevated level of serum RBP4 and consequently leads to the accumulation of visceral fat and causes insulin resistance (Kloting et al., 2007). Although, the association between RBP4 and level of insulin (Kovacs et al., 2007) and insulin sensitiveness (Craig et al., 2007) was reported in previous researches, further studies couldn't find a significant association (Hu et al., 2008).
Serum RBP4 levels are associated with body mass index (BMI) in diabetic or non-diabetic obese patients (Yang et al., 2005, Graham et al., 2006). There are several RBP4 gene variants that are related to the adiposity level and adipose tissue accumulation (Kotnik et al., 2011). The RBP4 maps to chromosome 10q23–q24 in humans, closely to a region that has been linked with increased risk for type-2 diabetes in other populations (Ping et al., 2012).
Since pivotal role of RBP4 gene in obesity progresses, we therefore aimed to investigate whether genetic variation within the RBP4 gene correlates with the obesity in participants of Isfahan Healthy Heart Program (IHHP). We screened the RBP4 gene for 2 specific sequence variants rs3758539 and rs10882273 that have been previously linked with the development of T2DM and obesity in humans (Craig et al., 2007, Kovacs et al., 2007) and hypothesized that variations of these SNPs are associated with Iranian obese subjects.
Section snippets
Patients and setting
This project was conducted as a sub-study of the Isfahan Healthy Heart Program (IHHP), which is a comprehensive action-oriented integrated community-based intervention program for the prevention and control of non-communicable diseases (NCDs), which was implemented in central Iran. For the current study, we randomly selected 321 samples from participants of IHHP with the age range of 19 to 60 years. The participants were divided in 2 subgroups according to the body mass index (BMI) including 129
Results
In the present study, the relationship among rs3758539 and rs10882280 SNPs and level of various factors of investigated subjects were performed. Demographic characteristic of all participants is demonstrated in Table 2. The summary of SNP description with minor allele frequency is shown in Table 3. Table 4 provided the allele frequencies and also genotype profile of studied population. As demonstrated in Table 4, there was a significant association between G allele and A allele in rs3758539
Discussion
Many studies have reported the impact of genetic variations of RBP4 gene on BMI and obesity. The results of the present study have shown the association between variants in RBP4 gene and BMI level in our population. Although in rs3758539 we found the significant direct proportions of BMI mean level with minor allele frequency in the case group, in the control group minor allele had reverse effect on BMI mean level.
In the current study in agreement with the previous investigation, it has been
Conflicts of interest statement
The authors have declared no conflicts of interest.
References (43)
- et al.
Circulating Nampt and RBP4 levels in patients with carotid stenosis undergoing carotid endarterectomy (CEA)
Clin. Chim. Acta
(2011) - et al.
Serum adipocyte fatty acid-binding protein, retinol-binding protein 4, and adiponectin concentrations in relation to the development of the metabolic syndrome in Korean boys: a 3-y prospective cohort study
Am. J. Clin. Nutr.
(2011) - et al.
Retinol binding protein 4 as a candidate gene for type 2 diabetes and prediabetic intermediate traits
Mol. Genet. Metab.
(2007) - et al.
Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass
Cell Metab.
(2007) - et al.
Genetics of common forms of obesity: a brief overview
Am. J. Clin. Nutr.
(2005) - et al.
Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and their cardiovascular implications
Cardiol. Clin.
(2004) - et al.
Plasma retinol binding protein: structure and function of the prototypic lipocalin
Biochim. Biophys. Acta
(2000) - et al.
Effects of variation in retinol binding protein 4 gene and adipose specific expression of gestational diabetes in Beijing, China
Diabetes Res. Clin. Pract.
(2012) Regulation of lipid and lipoprotein metabolism by retinoids
J. Am. Acad. Dermatol.
(2001)- et al.
Retinoids and retinoid-binding protein expression in rat adipocytes
J. Biol. Chem.
(1992)
Association between serum retinol-binding protein 4 and small dense low-density lipoprotein cholesterol levels in young adult women
Clin. Chim. Acta
RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglyceridemia risk in Chinese Hans
J. Lipid Res.
Vitamin A (retinol) status of first nation adults with non-insulin-dependent diabetes mellitus
J. Am. Coll. Nutr.
Association of retinol-binding protein-4 (RBP4) with lipid parameters in obese women
Obes. Surg.
Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes
Diabetes Care
Retinol-binding protein 4 and insulin resistance
N. Engl. J. Med.
Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes
J. Clin. Endocrinol. Metab.
Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects
N. Engl. J. Med.
Central adiposity rather than total adiposity measurements are specifically involved in the inflammatory status from healthy young adults
Inflammation
Effect of RBP4 gene variants on circulating RBP4 concentration and type 2 diabetes in a Chinese population
Diabet. Med.
Association of serum retinol-binding protein 4 and visceral adiposity in Chinese subjects with and without type 2 diabetes
J. Clin. Endocrinol. Metab.
Cited by (11)
Retinol-binding protein 4 in obesity and metabolic dysfunctions
2021, Molecular and Cellular EndocrinologyCitation Excerpt :Carriers of the risk allele have a ~80% higher T2D risk, suggesting that elevated RBP4 can be an independent risk factor for T2D (van Hoek et al., 2008). RBP4 SNPs and their haplotypes were shown to affect measures of insulin resistance (e.g. fasting plasma insulin and glucose) and obesity-related traits (e.g. BMI, WHR, circulating FFAs), as well as RBP4 mRNA levels in adipose tissue in humans (Kovacs et al., 2007; Shajarian et al., 2015; Munkhtulga et al., 2010; van Hoek et al., 2008). Currently, different studies have identified ten distinct RBP4 gene variants in European, Asian and American populations, which are associated with obesity, insulin resistance, hyperinsulinemia, T2D, gestational diabetes and CVD risk factors (van Hoek et al., 2008; Rychter et al., 2020; Boaghi et al., 2020; Hu et al., 2019; Codoner-Franch et al., 2016; Saucedo et al., 2014; Meisinger et al., 2011; Nair et al., 2010).
Association of MTHFR C677T and ABCA1 G656A polymorphisms with obesity among Egyptian children
2018, Gene ReportsCitation Excerpt :Additionally, in women with polycystic ovarian syndrome, patients with 677CT genotype had higher serum TC and TG than 677CC carriers (Jain et al., 2012). The network link between obesity and dyslipidemia has been well-documented and genetic influences on lipid profile have been reported by various studies (Yin et al., 2012; Shajarian et al., 2015; Shabana and Hasnain, 2015). Many variants disrupting the normal ABCA1 protein function result in altered circulating HDL (Marchesini et al., 2002; Yao et al., 2016; Alharbi et al., 2013).
Association of circulating adipokines with metabolic dyslipidemia in obese versus non-obese individuals
2016, Diabetes and Metabolic Syndrome: Clinical Research and ReviewsCitation Excerpt :We observed that high levels of RBP4 can increase risk of MD in the obese people, however, could not find a significant association between RBP4 levels with MD components. It seems that genetic variation in RBP4 plays an important role in observing these inconsistent results in different populations [30]. As it was mentioned before, previous studies have demonstrated that RBP4 levels increase in obese individuals with higher fat percentage [19].
Association of Leptin and Retinol Binding Protein 4 with the Risk of Gestational Diabetes: A Systematic Review and Meta‑Analysis of Observational Studies
2023, Indian Journal of Endocrinology and Metabolism