VDR TaqI is associated with obesity in the Greek population
Highlights
► VDR and FTO polymorphisms were studied in Greek obese and control subjects. ► VDR Taq1 was associated with obesity. ► VDR Taq1 contributes to an elevated BMI of 3 kg/m2 per risk allele. ► VDR as a target for therapeutic intervention in obese individuals
Introduction
Obesity is a complex disease manifested by both genetic and environmental factors. The latter has been the dominant perception for the last hundred years, while the former has been introduced in the early 1990s, mainly by twin and adoption studies, showing that genetic factors play a significant role in body weight regulation and estimated to account for 40–90% of the population variation (Bouchard et al., 1990, Walley et al., 2009). Obesity, defined as body mass index (BMI) > 30, is associated with premature death due to increased risk of many chronic diseases, such as Type 2 Diabetes Mellitus (T2DM), cardiovascular disease and cancer (Cornelis and Hu, 2012, Ritchie and Connell, 2007). Over the last thirty years the prevalence of obesity has increased tragically, with the World Health Organization (WHO) calling it the ‘Epidemic of the 21st century’, estimating that by 2015 almost 1–1.5 billion people will be obese worldwide, thus making it a major public health threat and socio-economical burden (Kaidar-Person et al., 2011). In Greece the latest findings show that approximately 25% of the adult population is obese, while around 35% is overweight, suggesting that there is a trend towards further increase in its prevalence (Kapantais et al., 2006). It is therefore hoped that the identification of the genetic factors underlying the heritable risk of obesity will contribute critically to our basic knowledge of the biology of energy balance and might even highlight molecules and pathways that can be targeted for therapeutic intervention in humans.
The fat mass and obesity-associated (FTO) gene is the one that has attracted major research efforts to elucidate its role in obesity, with association signals mapped to a clearly defined region of the gene (Frayling et al., 2007). However until today there is still considerable doubt, whether FTO is the cause of the obesity phenotype or its rather a nearby gene, such as RPGRIP11 (Frayling et al., 2007), something that is further supported by contradictive results from studies on mice and FTO loss-of-function mutation analysis (Boissel et al., 2009, Fischer et al., 2009). Another good candidate for involvement in obesity pathogenesis is vitamin D, where several studies have suggested that vitamin D levels influence obesity development (Pérusse and Bouchard, 2000). Its action is mediated through the vitamin D receptor (VDR), a nuclear transcription-regulating factor that signals the synthesis of proteins involved in bone mineral homeostasis and cell-cycle regulation, while also interacts with other cell-signaling pathways that influence the development of obesity (Awad et al., 2012). The most important evidence for its role in obesity development derives from studies in transgenic mice over-expressing human VDR in adipocytes resulting in decrease in energy expenditure and induction of obesity (Wong et al., 2011). Genetic variations may phenotypically appear as inter-individual variations in limiting rates of vitamin D synthesis in the skin, hydroxylation in the liver and in the kidney, transport metabolism and degradation that would ultimately influence individual vitamin D status (Uitterlinden et al., 2004). The VDR gene contains several polymorphisms, including three single nucleotide polymorphisms (SNPs) near the 3′ un-translated region (3′ UTR) (Taq1, Bsm1, and Apa1), identified by their restriction endonuclease sites (Uitterlinden et al., 2004). Although not functional these SNPs are strongly linked with a poly(A) microsatellite repeat in the 3′ UTR, which could influence VDR mRNA stability (Ingles et al., 1997). Several studies have also demonstrated a link between VDR gene polymorphisms and T2DM, however the findings differ from one population to another (Hitman et al., 1998, Oh and Barrett-Connor, 2002). Gene–gene and gene–environment interactions may explain in part the inconsistencies in the association between VDR SNPs and obesity and/or T2DM across studies.
The aim of the present report was to study two known VDR and FTO SNPs and their involvement in the genetic predisposition to obesity and/or T2DM in the Greek population.
Section snippets
Patients
The study population consisted of 184 individuals (82 with obesity and 102 controls), from Northern and Central Greece, assessed and collected at the Outpatient Clinic of the Diabetes Center of AHEPA University Hospital in Thessaloniki. All subjects were evaluated for the presence of obesity based on BMI (ΒΜΙ ≥ 30) and obese and controls were grouped accordingly, in order to be age and gender matched. Individuals were also assessed for the presence of T2DM according to standard procedures. Other
Results
The major anthropometric and biochemical characteristics of obesity subjects and controls are summarized in Table 1. Waist and hip circumference and serum triglycerides were significantly elevated in subjects with obesity compared with controls (P < 0.001). Prevalence of T2DM was increased in obesity subjects compared with controls (P = 0.007), confirming the underlying role of obesity in T2DM development. Results of all association analysis with obesity status are shown in Table 2. Both SNPs
Discussion
During the last three decades the dramatic increase in obesity prevalence in western countries, including Greece where the Mediterranean diet did not prove to be a major obstacle (Kapantais et al., 2006), has triggered further increase in lethal diseases such as cardiovascular disease with devastating complications for human health and substantial increase in drug expenditure, allowing WHO to name it the ‘Epidemic of the 21st century’ (Kaidar-Person et al., 2011). Therefore it is widely hoped
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
We are very grateful to all the participants of the study. This work was supported by the postgraduate programs “Biotechnology-Quality Assessment in Nutrition and the Environment” and “Molecular Biology and Genetics Applications — Diagnostic Markers” of the Department of Biochemistry and Biotechnology, University of Thessaly, Greece.
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