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© Borgis - Postępy Nauk Medycznych 1/2014, s. 65-69
*Beata Kaleta1, 2, Magdalena Walicka3, Ada Sawicka3, Małgorzata Wrzosek4, Agata Bogołowska-Stieblich3, Grażyna Nowicka4, Andrzej Górski2, Jacek Łukaszkiewicz2, Ewa Marcinowska-Suchowierska3
Polimorfizm genu receptora witaminy D u polskich pacjentów z otyłością olbrzymią
Vitamin D receptor gene polymorphism in Polish patients with morbid obesity**
1Department of Biochemistry and Clinical Chemistry, Medical University of Warsaw
Head of Department: prof. Jacek Łukaszkiewicz, MD, PhD
2Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw
Head of Department: prof. Andrzej Górski, MD, PhD
3Department of Family Medicine, Internal Medicine and Metabolic Bone Diseases, Medical Centre of Postgraduate Education, Prof. W. Orlowski Hospital in Warsaw
Head of Department: Marek Tałałaj, MD, PhD, associate professor
4Department of Pharmacogenomics, Medical University of Warsaw
Head of Department: prof. Grażyna Nowicka, MD, PhD
Streszczenie
Wstęp. Otyłość niesie za sobą poważne konsekwencje medyczne, psychospołeczne i ekonomiczne, przewyższając inne przewlekłe schorzenia. Aktywna forma witaminy D – 1,25(OH)2D, działa za pośrednictwem receptora VDR. Niektóre badania sugerują, iż witamina D i polimorfizm jej receptora mogą uczestniczyć w rozwoju otyłości i jej powikłań metabolicznych.
Cel pracy. Celem niniejszej pracy była wstępna ocena związku polimorfizmu FokI i BsmI genu VDR z indeksem masy ciała (ang. body mass index – BMI), parametrami stanu zapalnego: CRP (białko C-reaktywne, ang. C-reactive protein), OB (odczyn Biernackiego), występowaniem nadciśnienia, dyslipidemii i hiperglikemii u pacjentów z otyłością olbrzymią.
Materiał i metody. W badaniu wzięło udział 152 pacjentów z otyłością olbrzymią (BMI ≥ 40 kg/m2) oraz 100 ochotników z prawidłową masą ciała. DNA zostało wyizolowane z pełnej krwi obwodowej. Genotypowanie wykonano metodą łańcuchowej reakcji polimerazy w czasie rzeczywistym (real-time PCR) z wykorzystaniem testów LightSNiP i sond SimpleProbe. Analiza temperatury topnienia amplikonów umożliwiła identyfikację genotypów FokI i BsmI genu VDR.
Wyniki. Nie wykazano istotnych różnic w częstości występowania genotypów i alleli FokI i BsmI w grupie chorych z otyłością olbrzymią i grupie kontrolnej. W badaniu nie stwierdzono zależności polimorfizmu FokI, BsmI i BMI, CRP, OB oraz częstości występowania nadciśnienia, dyslipidemii i hiperglikemii.
Wnioski. Na podstawie uzyskanych wyników można wnioskować, iż polimorfizm FokI i BsmI genu VDR nie ma związku z indeksem masy ciała, parametrami stanu zapalnego oraz częstością występowania nadciśnienia, dyslipidemii i hiperglikemii u polskich pacjentów z otyłością olbrzymią. Nasze obserwacje należy traktować jako wstępne. Dalsze badania na większych grupach osób są konieczne, aby rzucić więcej światła na potrzebę oznaczania polimorfizmu VDR w przypadku otyłości.
Summary
Introduction. Obesity has important medical, psychosocial and economic consequences which are greater than those of many other chronic disorders. Active form of vitamin D, 1,25(OH)2D exerts its actions through binding to the vitamin D receptor (VDR). Some data suggest a role of vitamin D and VDR polymorphism in obesity and its metabolic complications.
Aim. Our objective was a preliminary evaluation the association of VDR gene FokI and BsmI polymorphism and body mass index (BMI), inflammatory parameters (C-reactive protein – CRP, erythrocyte sedimentation rate – ESR), hypertension, dyslipidemia and hyperglycemia in a morbidly obese Polish patients.
Material and methods. The study involved 152 morbidly obese patients (BMI ≥ 40 kg/m2) and 100 healthy controls. DNA was extracted from peripheral blood. Genotyping was performed by real-time PCR using LightSNiP tests with SimpleProbe probes. Melting curve analysis of PCR amplicons enabled identification FokI and BsmI genotypes.
Results. There were no significant differences between morbidly obese patients and control subjects in the distribution of FokI and BsmI genotypes or alleles. No association between VDR FokI and BsmI polymorphism was observed with the BMI, CRP, ESR, hypertension, dyslipidemia and hyperglycemia.
Conclusions. Based on our results, it can be concluded that FokI and BsmI polymorphism is not associated with the BMI, inflammatory parameters and the frequency of hypertension, dyslipidemia and hyperglycemia in Polish patients with morbid obesity. Our observations should be considered as preliminary. Further studies on larger cohorts of individuals are thus urgently needed to shed more light on the value of assaying the VDR polymorphism in obesity.
Introduction
Obesity is one of the most serious public health problem of the 21st century (1). The World Health Organization defines obesity as a body mass index (BMI) of 30 kg/m2 or more. Morbid obesity is defined as a BMI of 40 kg/m2 (2, 3). Obesity is associated with an increased risk of several diseases (i.e. coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes, cholelithiasis, pulmonary embolism, sleep apnea, psychiatric illness and malignancy: breast, endometrial, prostate and colon) (1, 2).
Vitamin D plays an important role in skeletal metabolism, but has also been shown to be a potential key hormone in immune homeostasis, glucose and lipids metabolism and other non-calcemic actions (4). Active form of vitamin D – calcytriol (1,25(OH)2D) exerts its actions in a variety of cell types through binding to the nuclear vitamin D receptor (VDR) which functions as a ligand-dependent transcriptional factor of many genes (5-11). VDR and 1α-hydroxylase (an enzyme, which catalyses conversion of 25(OH)D to 1,25(OH)2D) is expressed in more than 40 cell types, such as bone, brain, colon, prostate, immune cells, adipocytes, pancreas, and many others (12-16). VDR is a product of VDR gene locus (on chr12q13.1). Several VDR polymorphisms have been found: including FokI, ApaI, BsmI, TaqI, EcoRV, Tru91, Cdx2. The most frequently studied is FokI and BsmI. These are single nucleotide polymorphisms (SNiPs). FokI (rs2228570, T/C) polymorphism is located in the second start codon (ATG) in exon 2. When the C (mutant) allele is present, an alternative start site is used, leading to the expression of a shorter VDR protein (424 aa), which demonstrates a greater transcriptional activity as a consequence of enhanced binding to transcription factor II B. The T (wild-type) allele leads to expression of a longer VDR protein (427 aa). BsmI (rs1544410, G/A) polymorphism is located in intron 8 and affects the level of VDR gene transcription, transcript stability, and posttranscriptional modifications (17-22). VDR gene polymorphism and vitamin D deficiency may cause bone diseases (rickets, osteomalacia, osteoporosis) but also may be a risk factor for other chronic disorders, such as type 2 diabetes, cardiovascular problems, autoimmune diseases (systemic lupus erythematosus, inflammatory bowel disease, scleroderma mellitus, type 1 diabetes, asthma, allergies), psychiatric illness and many others (5, 11, 14, 22-25).
The role of vitamin D and vitamin D receptor in adipocyte metabolism and obesity is not fully explained. VDR is expressed in preadipocytes and may contribute to the action of vitamin D. 1,25(OH)2D via VDR inhibits preadipocytes differentiation in vitro and in animal models (26-28). Moreover vitamin D and VDR is important in the mechanism of insulin release and in the maintenance of glucose tolerance. Vitamin D deficiency and VDR polymorphism may lead to impaired insulin secretion, insulin resistance and may contribute to excessive adipose tissue deposition (29). Moreover vitamin D via its receptor affects hepatic lipid metabolism, promotes intestinal calcium absorption, and calcium may bind to fatty acids to form insoluble complexes that inhibit lipid absorption. Thus, vitamin D deficiency and VDR polymorphism may lead to abnormal processing of lipids due to alterations in calcium availability (30, 31).
Vitamin D via VDR modulates cytokine production, which may have an impact on the inflammatory activity of adipose tissue (32, 33).
Variations at the VDR gene are linked with susceptibility to many disorders. Some literature suggests that vitamin D deficiency and VDR polymorphism may contribute to the development of overweight and obesity (34-37).
Aim
Obesity has became a global epidemic, therefore there is increasing interest in the role of factors that possibly contribute to its development. We conducted this study to investigate the possible association of vitamin D receptor gene FokI and BsmI polymorphism with the body mass index, inflammatory parameters and frequency of hypertension, dyslipidemia, hyperglycemia in a group of morbidly obese Polish patients.
Material and methods
Subjects
Participants provide their written informed consent to participate in this study. The ethics committee of Medical Centre of Postgraduate Education, Warsaw, Poland approved this procedure and the study (agreement No. 49/PW/2011), 02.03.2011.
We studied a group of 152 morbidly obese Polish patients (BMI ≥ 40 kg/m2). All patients (100 women, 52 men) were admitted to the Department of Family Medicine, Internal Medicine and Metabolic Bone Diseases, Prof. W. Orlowski Hospital, Warsaw for medical tests before bariatric surgery. The control group consisted 100 anonymous healthy blood donors with normal weight (BMI 19-24 kg/m2). Measurement of growth was taken by PROSTAND stadiometer Seca 210. Weight was measured with a balance beam scale. ESR and CRP were measured at the prof. W Orlowski Hospital laboratory. The characteristics of the patients and controls is shown in table 1.
Table 1. Characteristics of morbidly obese patients and controls. Data are expressed as minimum – maximum, means ± standard deviation and percentage.
 PatientsControls
Subjects152100
Gender (male/female)100/5263/37
Age (years)18-76 (42.93 ± 11.20)18-61 (40.28 ± 9.20)
BMI (kg/m2)41-75 (45.63 ± 10.0)19-24 (21.25 ± 1.82)
CRP (mg/l)0.5-144 (11.71 ± 17.63)NM
ESR (mm/1h)3-80 (20.86 ± 14.08)NM
Treatment for hypertension [n (%)]129 (85)No
Treatment for dyslipidemia [n (%)]94 (62)No
Treatment for hyperglycemia [n (%)]146 (96)No
BMI – body mass index; CRP – C-reactive protein; ESR – erythrocyte sedimentation rate; NM – not measured
DNA isolation and genotyping
Genomic DNA was extracted from peripheral blood samples by standard procedures using the Blood Mini kit (A&A Biotechnology, Poland). VDR FokI (rs2228570, T/C) and BsmI (rs1544410, G/A) genotyping was performed by LightCycler real-time PCR (Roche, Germany) using commercial LightSNiP (SimpleProbe) assays from TIB-MolBiol (Germany) according to the manufacturer’s recommendations. Melting curve analysis of PCR amplicons enabled identification individual FokI and BsmI genotypes of vitamin D receptor gene. The genotypes were classified as homozygote major allele (TT for FokI, GG for BsmI), heterozygote (TC, GA) and homozygote minor allele (CC for FokI, AA for BsmI).
Statistical analyses
Statistical analyses was performed using Statistica 10.0 (StatSoft Inc). To compare the frequency of genotypes and alleles of VDR FokI and BsmI polymorphisms in patients with morbid obesity and control group the Freeman-Halton extension of Fisher’s exact test for contingency table was used. Correlation analysis of FokI and BsmI genotypes with body mass index, C-reactive protein level, erythrocyte sedimentation rate, treatment for hypertension, dyslipidemia and hyperglycemia was performed using Spearman’s Rank Correlation Test. Hardy-Weinberg equilibrium (HWE) was determined by Pearson’s χ2 goodness-of-fit test. Differences were considered statistically significant at a p value < 0.05.
Results

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otrzymano: 2013-12-02
zaakceptowano do druku: 2013-12-30

Adres do korespondencji:
*Beata Kaleta
Department of Clinical Immunology, Transplantation Institute
Medical University of Warsaw
ul. Nowogrodzka 59, 02-006 Warszawa
tel. +48 600-301-690
fax +48 (22) 502-21-59
kaletabeata1@gmail.com

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