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
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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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