© 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.
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Piśmiennictwo
1. Kopelman PG: Obesity as a medical problem. Nature 2000; 404: 635-643.
2. Kaila B, Raman M: Obesity: a review of pathogenesis and management strategies. Can J Gastroenterol 2008; 22: 61-68.
3. Obesity and overweight. Fact Sheet No 311. Geneva (Switzerland): World Health Organization; March 2011. Avaliable: www.who.int/mediacentre/factsheets/fs311/en/print.html. Accessed 5 October 2012.
4. De Luca HF: Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 2004; 80: 1689S-1696S.
5. Holick MF: Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004; 80: 1678S-1688S.
6. Lin R, White JH: The pleiotropic actions of vitamin D. Bioessays 2004 Jan; 26(1): 21-28.
7. Nagpal S, Na S, Rathnachalam R: Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 2005; 26: 662-687.
8. Norman AW: Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology 2006; 147: 5542-5548.
9. Van Belle TL, Gysemans C, Mathieu C: Vitamin D in autoimmune, infectious and allergic diseases: A vital player? Best Pract Res Clin Endocrinol Metab 2011; 25: 617-632.
10. Kopij M, Rapak A: The role of nuclear receptors in cell death. Postepy Hig Med Dosw 2008 (online); 17: 571-581.
11. Pełczyńska K, Jaroszewicz I, Switalska M, Opolski A: Biological activity of calcitriol and its new analogues – potential therapeutic applications. Postepy Hig Med Dosw 2005 (online); 59: 129-139.
12. Adams JS, Hewison M: Update in vitamin D. J Clin Endocrinol Metab 2010; 95: 471-478.
13. Bikle D: Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009; 94: 26-34.
14. Bouillon R, Carmeliet G, Verlinden L et al.: Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 2008; 29: 726-776.
15. Holick MF: Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004; 79: 362-371.
16. Holick MF: Vitamin D deficiency. N Engl J Med 2007; 357: 266-281.
17. Arai H, Miyamoto K, Taketani Y et al.: A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 1997; 12: 915-921.
18. Bogaczewicz J, Kaleta B, Sysa-Jędrzejowska A et al.: Vitamin D receptor gene polymorphism FokI in Polish population does not contribute to the risk of systemic lupus erythematosus. Lupus 2013; 22: 750-751.
19. Crofts LA, Morrison NA, Dudman N, Eisman JA: Differential expression of VDR gene alleles. J Bone Miner Res 1996; 11: S208 (abstract S473).
20. Jurutka PW, Remus LS, Whitfield GK et al.: The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 2000; 14: 401-420.
21. Uitterlinden AG, Fang Y, Van Meurs JB et al.: Genetics and biology of vitamin D receptor polymorphisms. Gene 2004; 338: 143-156.
22. Valdivieso JM, Fernandez E: Vitamin D polymorphisms and diseases. Clin Chim Acta 2006; 371: 1-12.
23. Awad AB, Alappat L, Valerio M: Vitamin d and metabolic syndrome risk factors: evidence and mechanisms. Crit Rev Food Sci Nutr 2012; 52: 103-112.
24. Bao BY, Yao J, Lee YF: 1 alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis 2006; 27: 1883-1893.
25. Ye WZ, Reis AF, Dubois-Laforgue D et al.: Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol 2001; 145: 181-186.
26. Blumberg JM, Tzameli I, Astapova I et al.: Complex role of the vitamin D receptor and its ligand in adipogenesis in 3T3-L1 cells. J Biol Chem 2006; 281: 11205-11213.
27. Kong J, Li YC: Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. Am J Physiol Endocrinol Metab 2006; 290: E916-E924.
28. Wood RJ: Vitamin D and adipogenesis: new molecular insights. Nutr Rev 2008; 66: 40-46.
29. Zeitz U, Weber K, Soegiarto DW et al.: Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J 2003; 17: 509-511.
30. Baker JF, Mehta NN, Baker DG et al.: Vitamin D, metabolic dyslipidemia, and metabolic syndrome in rheumatoid arthritis. Am J Med 2012; 125: 1036.e9-1036.e15.
31. Zittermann A, Gummert JF, Börgermann J: The role of vitamin D in dyslipidemia and cardiovascular disease. Curr Pharm Des 2011; 17: 933-942.
32. Gupta GK, Agrawal T, DelCore MG et al.: Vitamin D deficiency induces cardiac hypertrophy and inflammation in epicardial adipose tissue in hypercholesterolemic swine. Exp Mol Pathol 2012; 93: 82-90.
33. Greenberg AS, Obin MS: Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006; 83: 461S-465S.
34. Binh TQ, Nakahori Y, Hien VT et al.: Correlations between genetic variance and adiposity in postmenopausal Vietnamese women. J Genet 2011; 90: 1-9.
35. Filus A, Trzmiel A, Kuliczkowska-Płaksej J et al.: Relationship between vitamin D receptor BsmI and FokI polymorphisms and anthropometric and biochemical parameters describing metabolic syndrome. Aging Male 2008; 11: 134-139.
36. Schuch NJ, Garcia VC, Vívolo SR, Martini LA: Relationship between Vitamin D Receptor gene polymorphisms and the components of metabolic syndrome. Nutr J 2013; 15: 96.
37. Ochs-Balcom HM, Chennamaneni R, Millen AE et al.: Vitamin D receptor gene polymorphisms are associated with adiposity phenotypes. Am J Clin Nutr 2011; 93: 5-10.
38. Grundberg E, Brändström H, Ribom EL et al.: Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women. Eur J Endocrinol 2004; 150: 323-328.
