LACK OF ASSOCIATION BETWEEN VARIANTS WITHIN THE AHSG, HCRT AND NPY2R GENES AND ANTHROPOMETRICAL PARAMETERS IN CZECH POST-MONICA STUDY
Jurcikova L*, Adamkova V, Lanska V, Suchanek P, Hubacek JA
*Corresponding Author: Ing. Lucie Jurčíková, Institute for Clinical and Experimental Medicine, DEM, Videnska 1958/9, Prague 4, 14021, Czech Republic; Tel.: +420-261-362-229; Fax: +420-241-721-574; E-mail: jurl@ikem.cz
page: 63

INTRODUCTION

Obesity is a current world problem that has reached pandemic proportions and is considered a complex disorder that is regulated by behavioral, environmental and genetic factors [1-3]. Recent genetic studies focusing on families, twins and adopted children have demonstrated the influence of heritability on body mass index (BMI) that ranged from 50.0 to 90.0% [1]. Among the candidate genes with the potential to influence BMI, there are also genes for a2-Heremans- Schmid glycoprotein (AHSG), Hypocretin (HCRT) and Neuropetide Y2 receptor (NPY2R). The AHSG (also called Fetuin A) is mainly secreted by hepatocytes and is abundant in blood plasma. The AHSG gene is located at chromosome 3q27 whose locus is associated with type 2 diabetes, metabolic syndrome [4] and adipocyte insulin action in humans [5]. Serum AHSG is a natural endogenous inhibitor of the insulin-stimulated insulin receptor tyrosin kinase activity [4-6], insulin receptor autophosporylation, and insulin substrate 1 phosporylation [4]. Rs4917 (Thr248Met) is considered the strongest marker of AHSG plasma levels [7]. In humans, an increased level of AHSG in plasma is associated with insulin resistance and impaired glucose tolerance [8] and plasma cholesterol [6]. However, no relationship between AHSG polymorphisms and coronary atherosclerosis has been found [7]. Mice with knockout AHSG gene were found to be more sensitive to insulin, resistant to weight gain after a fat enriched diet and also to have a decreased body fat content [9]. The HCRT gene for orexin encode prepro-orexine precursor from which orexin A and orexin B neuropep-tides, (also called hypocretins: HCRT1 and HCRT2) that regulate sleep, appetite and energy intake, are derived [10, 11]. The expression of both neuropeptides is highly limited to neurons located in the lateral hypothalamic area [12,11], which is known as the “hunger center” [10,12,13]. Hara et. al. [14] generated transgenic mice with ablated orexin-containing neurons by expression of toxic ataxin-3. The transgenic mice exhibited late-onset obesity despite their lower food intake in comparison with non transgenic litter mates. A negative correlation between orexin A plasma levels and BMI in children [15] and adults [16] has been observed. It is possibly induced by the ability of orexin to regulate the plasma leptin circadian rhythmicity. Patients with narcolepsy accompanied by a low level of HCRT1 also demonstrated lower leptin levels (reduced by 50.0%) without the nocturnal increase that is observed in healthy subjects [17]. Since there exists a premise for a link between orexin levels in the blood and susceptibility to obesity, we focused on an examination of polymorphisms in the regulatory region. Within the 3 kb region upstream of the HCRT start codon we found only the rs760282 (–909 T>C) polymorphism with sufficient rate of occurrence. While the rs760282 SNP is unlikely to be able to influence transcription it is used as an informative one [18]. This SNP was chosen because it is near to the regulatory region of the HCRT gene and it can be a marker of the regulation of the HCRT gene transcription rate. The NPY2R gene encodes the Neuropeptide Y2 receptor which belongs to a heterogeneous family of G-protein-coupled receptors [19]. Four binding subtypes of neuropeptide receptors (Y1-Y4) were described. The Y1 and Y2 receptors bind to peptide YY (PYY) and neuropeptide Y (NPY) [20]. These abdominal hormones are members of the pancreatic polypeptide family together with pancreatic polypeptide (PP). All these polypeptides have been described as strong central regulators of gastric function [1,21]. Neuropeptide Y is an appetite hormone and is widely distributed throughout the central and peripheral nervous systems. The NPY is the most abundant neuropeptide in the brain and is associated with the regulation of blood pressure, appetite, mood and circadian rhythms [19]. Single nucleotide polymorphisms in the NPY2R genes have been found to play a role in obesity, having an additive effect on other genes [22]. In a study performed on French Caucasians, rs1047214 was selected for genotyping from 12 investigated SNPs [21]. In accordance with the French and other studies, we decided to investigate this SNP on our database [23]. In our study, we analyzed the effect of the SNPs within the AHSG (rs4917), HCRT (rs760282) and NPY2R (rs1047214) genes on anthropo-metrical and biochemical parameters in the Czech-Slavonic population.



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