Noi Efecte Ale Vit. D

8/12/2019 Noi Efecte Ale Vit. D

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REVISTAROMNDEPEDIATRIE VOLUMULLX, NR. 4, AN2011310

Adresa de coresponden:Prof. Dr. Sorin Buzinschi, Spitalul Clinic de Copii Braov, Str. Nicopole Nr. 45, Braove-mail: [email protected]

NOI REPERE N STUDIUL EFECTELORBIOLOGICE ALE VITAMINEI D

Prof. Dr. Sorin BuzinschiFacultatea de MedicinBraov, Universitatea Transilvania Braov,

Spitalul Clinic de Copii, Braov

REZUMAT

Dozarea recenta vitaminei D pentru utilizarea clinica schimbat complet nelegerea patologiei sale. S-aconstatat cinsuficiena/deficitul de vitamina D este larg ntlnit n populaia rilor dezvoltate i, surprinztor,

n populaia care triete n climatul cald. Numai o parte a nivelului sanguin al vitaminei D poate filegat desezon, latitudine sau aportul oral. Factorii genetici sunt implicai n toate etapele metabolismului su. Genele

care influeneaznivelul vitaminei D sunt DHCR7, CYP27A1, CYP2R1, gena VDR, CYP24A1 i gena Gc.Sunt prezentate etapele metabolismului vitaminei D, ca i intervenia diferitelor gene implicate. Este discutatfuncia autocrina vitaminei D, care faciliteazexpresia pleiotropica unor gene legate de funcionarea ce-lular. Sunt trecute n revisti unele dintre tulburrile legate de nivelul sczut al vitaminei D, n afarde rahitism.

Cuvinte cheie: vitamina D, nivel sczut, rahitism, boli cronice

REFERATE GENERALE

1

Vitamina D [25(OH)D] a fost descoperit nanul 1920, iar structura sa chimic n 1932, nsrahitismul, boal a crei careno exprim, are oistorie cu mult mai veche. Expunerea la soare i

tratamentul cu vitamina D au fost considerai multvreme factori eficieni profilactici i terapeutici aiunei probleme rezolvate. Cu toate acestea, reapariiadeficitului de vitamina D i a rahitismului n ultimiiani, raportate n USA, Canada, Germania, Anglia,dar i Spania, Grecia, Arabia Saudit, Turcia, Egipt,India (1-8) au fcut ca deficiena vitaminei D sfieconsideratastzi o problemepidemicn ntreagalume (1,5,8), prin afectarea n diferite grade igrupe de vrsta peste 50% din populaia globului(9). Un factor decisiv n reevaluarea statusului vita-

minei D l-a constituit posibilitatea dozrii 25(OH)D n laboratoarele clinice, odatce metoda a prsitcadrul restrns al laboratoarelor de cercetare. ntrefactorii care determin starea vitaminei D, men-ionm: expunerea solar limitat la latitudinilenordice ntre noiembrie i martie, utilizarea din cen ce mai larga cremelor fotoprotectoare n vedereaevitrii neoplasmelor cutanate i variabilitatea ge-netic. Vitamina D s-a dovedit n ultimii ani centrulunui sistem complex de reglare autocrin de tip

hormonal care regleazproliferarea i difereniereacelular. Vitamina D controleazdirect sau indirectpeste 3.000 de gene care regleazmetabolismul Cai cel osos, moduleazimunitatea nnscut, regleaz

producia de insulini renin, induce apoptoza iinhibangiogeneza (5). Pe aceastcale, 25(OH)Dparticip la funcionarea sistemului imunitar, car-diovascular, neuroendocrin (1,9-11). Carena i va-riaiile genetice n metabolismul vitaminei D carepot explica apariia unor semne de rahitism la copiiicu profilaxie corect, pot fiimplicate n adolesceni n viaa adultn apariia a numeroase afeciunicronice ca: infecii micobacteriene (TBC), boli car-diovasculare, diabet, neoplasme, boli autoimmune(sclerozmultipl, lupus eritematos sistemic, pso-

riazis) (9,11). n baza acestor considerente, vitaminaD a devenit acum un cmp foarte activ de cercetare,numai n primele 9 luni ale anului 2010 fiindpublicate peste 2.300 de articole cu acest subiect(10).

SUMAR DE FIZIOLOGIE AL VITAMINEI D

Vitamina D se gsete sub 2 forme: vitamina D2

sau ergocalciferol (calciferol) produs prin iradierea


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REVISTAROMNDEPEDIATRIE VOLUMULLX, NR. 4, AN2011 311

drojdiei de bere, sau din unele plante, i vitaminaD

3(colecalciferol), care se produce prin fotoconversia

7-hidrocolesterolului (7-DHC) cutanat dupexpu-nere la radiaia solarsau la RUV artificial. Can-titatea de vitamina D din alimente este foarte redu-s. Industrial, 25(OH)D se produce pornind de la

lanolin. Pornind de la 7-DHC, vitamina D3 par-curge o serie de transformri pn la metabolitulactiv, 1,25(OH)

2D

3care apoi este degradat n com-

pui inactivi (Figura 1).

Figura 1.Etapele metabolismului vitaminei D

Vitamina D are 2 tipuri de aciuni principale: Endocrine, care regleazmetabolismul Ca,

vitamina D3 fiind produs n urma sintezeiintrarenale;

Autocrine, n care hidroxilarea colecalcife-rolului se produce n esuturi, rezultnd calci-triol cu aciune intracelular, nedetectabil caprodus circulant, avnd caracteristic faci-litarea genelor sau traficul de metabolii in-tracelulari.

Figura 2. Formarea sistemici locala vitaminei D iefectele specifice

Asimilarea vitaminei D ca hormon, de multvreme anticipat(de Luca, cit. 12), se bazeazpeurmtoarele argumente:

Este produsde un organ (rinichi) Circulla esuturi int Interacioneazcu receptori specifici celulari Declaneaz rspunsuri specifice (absorbia

Ca)

METABOLISMUL VITAMINEI D IDETERMINISMUL SU GENETIC

O echipde cercettori din cadrul SUNLIGHTConsortium (Study of Underlyng Genetic Deter-minants of Vitamin D and Highly Related Traits) auanalizat concentraiile 25(OH)D la 33.996 subieciaduli descendeni europeni, n cadrul a 15 cohorte,i au artat cprezena unor alele poate dubla risculde insuficienal vitaminei D (13). Genele n dis-cuie (DHCR7(NADSYN1), CYP2R1 i GC) sunt

implicate n sinteza colesterolului, hidroxilarea itransportul vitaminei D. Concentraiile 25(OH)D,biomarkerul acceptat al vitaminei D sunt mai ri-dicate vara i sczute n sezonul rece. Numai 25%dintre variaiile interindividuale ale acesteia pot filegate de sezon, latitudine sau aportul exogen devitamina D (8). Rezultate ale studiilor pe gemeni ifamilii sugereaz c factorii genetici contribuiesubstanial la aceast variabilitate, care se poateridica la peste 53% (14,48). Aceste date pot explicade ce unii copii r

spund favorabil la aportul de

vitamina D i alii nu, aa cum observm n practicacotidian.

Formarea colecalciferolului

n cursul expunerii la soare, RUV este absorbitde ctre 7-dehidrocolesterol (7-DHC), care se g-sete n membranele keratinocitelor i ale fibrobla-tilor; n urma unui proces de fotoconversie, se for-meazprovitamina D

3sau colecalciferolul, care este

ejectat n spaiul extracelular i transportat la ficat de

o protein transportoare (9,15). Dei sinteza vita-minei D din 7-DHC este un proces fizico-chimic,sinteza colesterolului pornind de la 7-DHC este denaturbiochimic, mediatde o enzim7-DHC re-ductaz, determinat de gena identificat ca DHRC7 (NAD SYN). Polimorfisme ale acestei gene caredeterminscderea produciei de colesterol, pot cretenivelurile sanguine ale vitaminei D. Creterea coles-terolului se nsoete de scderea valorilor 25(OH)Dplasmatice, probabil din motive extragenetice.

Formarea hidroxicolecalciferolului (calciferol sau

calcidiol), 25(OH)D

n ficat, colecalciferolul este hidroxilat n poziia25 pentru a forma 25(OH)D; reacia este catalizat

Metabolismul vitaminei D


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de 25-hidroxilaze, enzime ale citocromului P450avnd sediu microzomal (CYP2R1) i mitocondrial(CYP27A1) n hepatocite. Calcidiolul reprezintmetabolitul principal al vitaminei D; dei nu areactivitate intrinsec, el este utilizat pentru stabilireanivelului sanguin al vitaminei, avnd n vedere

timpul de njumtire de aproximativ 15 zile ifaptul cvaloarea sa crete proporional cu aportulexogen de vitamina D (10,15). La bolnavi cu nivelurisczute ale 25(OH)D au fost identificate mutaii alegenei 2R, fiind evideniat genetic cenzima CYP2R1 este enzima cheie a 25-hidroxilazei (16).

Proteina transportoare de vitamina D (DBPsau Gc)

Asigur vehicularea plasmatic a 25(OH)D;variante genetice comune pot diferenia rspunsulplasmatic la aportul exogen de vitamina D (13).Lauridsen i col. (17) au identificat fenotipurileimplicate n variaiile sanguine ale vitaminei D la595 de persoane adulte; din datele studiului rezultcconcentraia Gc este un predictor independent al1,25(OH)

2D, pe cnd fenotipul Gc este un indicator

semnificativ al concentraiei 25(OH)D. ntr-un stu-diu care a cuprins 4.501 de persoane adulte de origineeuropean, n USA, Ahn i col. (18) au identificatntre cauzele pentru un rspuns inadecvat la vita-mina D, polimorfismul pentru un singur nucleotid(SNP) al genei care codeaz Gc pe cromozomul4q12-13 i SNP DHCR7. Polimorfismul pentru Gcar putea avea cel mai mare impact asupra concen-traiei sanguine a vitaminei D (8)

Formarea 1,25-dihidroxicolecalciferolului

[1,25(OH)2D], calcitriolul

Etapa principal n apariia formei active avitaminei D, calcitriolul, se desfoarcu precderen rinichi, ns numeroase alte esuturi i organeposedcelule capabile sproduc1,25(OH)

2D pe

plan local (plmn, colon, prostat, celulele pan-creatice, monocite, celule paratiroidiene) (9-11,15).n rinichi, reacia de formare a 1,25(OH)

2D este

catalizatde 1hidroxilaz, enzima citocromuluiP450 (CYP27B1), localizat n celulele tubuluiproximal renal. Producia de calcitriol este strnsreglatde activitatea 1hidroxilazei, care la rndulei este stimulatde hipocalcemie, creterea PTH iscderea nivelului plasmatic al precursorului su,calcidiolul. (9,15)

Interaciunea 1,25(OH)2D cu receptorul pentru

vitamina D (VDR)

O parte important a aciunilor calcitrioluluisunt mediate de un factor nuclear de transcripie,

VDR. Acesta, mpreuncu vitamina D, se leagdeRXR (x-receptorul cu acid retinoic) i de elementelede rspuns la vitamina D pentru a iniia reglareaunor gene specifice (10).

Figura 3. Reprezentare schematica rolului VDR nnucleul celular

VDR a polarizat atenia a numeroi cercettorifiind considerat un punct cheie n variaiile derspuns fade 24(OH)D. Existdiferite variantealelice (polimorfisme) ale genei VDR pe cromozo-mul 12, care apar natural n populaie i care au fost

corelate cu rahitismul, rezistena la vitamina D,hiperparatiroidismul, dar i cu susceptibilitatea lainfecii, boli autoimune i cancer (15,19-21). Cutoate cse acceptn nutrigenomicfaptul canu-mite polimorfisme fac gazda purttoare mai sen-sibilla anumite boli, chiar n prezena nutrimentu-lui respectiv, n ceea ce privete aportul de vitaminaD i Ca, condiionarea nu este clar(22).

n diferite studii asupra unor copii cu rahitism ndiferite arii geografice, a fost studiat genotipul

VDR (FoK1, Taq1, Apa1) sau diferite alte varianten ncercarea de a se defini configuraia de risc.Observaiile n care rahitismul sau niveluri sc-

zute ale vitaminei D apar n situaii n care era deateptat la niveluri normale datoritexpunerii marila radiaia solar, a produs o mare surprizpentrucercettori i medicii practicieni. Studiile efectuaten rile unde existo patologie semnificativprinrahitism nu au reuit ns s traneze clar dacexisto susceptibilitate ereditara copiilor pentruaceastafeciune. O metaanalizasupra datelor din

literatur privind legtura dintre polimorfismelepentru un singur nucleotid (SNP) i concentraiileserice ale 25(OH)D au identificat implicarea Gc,VDR i a CYP27B1, sugernd carhitectura gene-tic individualpoate determina nivelul vitaminei


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Figura 4. Structura genomica VDR i poziia polimorfismelor cunoscute. DupFang, 2005

Tabelul1.Polimorfismul VDR la copiii cu rahitism

Autori Modificri genetice VDR Semnificaie

Bora, Orzan, col., 2008

(22)

Polimorfismul genelor FokI, TaqI, Apal la

bolnavi; alelele Apal frecv. ridicat; frecv. Tt iAa incidenredus

Polimorfismele VDR factor important n

rahitismul carenial n Turcia

Baroncelli, Bereket, col.,2008 (23)

Alelele F incidencrescut; genotipul BBasociat cu niveluri sczute ale 25(OH)D

Incidencrescuta alelei F, predispoziie larahitism n Turcia, Egipt

Ismail, Erfan, col., 2011

(24)

Alelele f (Fokl) incidencrescut; combinaiilegenotipurilor VDR pentru Fokl, Apal,Taql

diferite fade control

Relaie pozitivntre polimorfismul genei VDRi susceptibilitatea la rahitism n Egipt

Arabi, Zahed, col., 2009

(25)

Polimorfisme Bsml i Taql Polimor fismul VDR influeneazapoziiascheleticla adolescente sntoase n Liban

Fischer, Thacher, col.,

2000 (26)

Alelele f (Fokl) incidensczut, genotipul FFrelativ crescut

Diferite frecvene ale alelelor, combinaii degenotipuri nu au fost diferite fade grupulmartor n Nigeria

Lu, Li, col. 2003 (27) Alelele Fokl i genotipul FF, incidencrescut Asociere ntre polimorfismul genei VDR irahitismul prin deficit de vitamina D n China

Gong, Li, col., 2010 (28) Alelele F(Fokl) i genotipul FF incidencrescut, corelate cu niveluri sczute ale25(OH)D

Polimorfismul genei VDR joacun rolimportant n apariia rahitismului prin deficit devitamina D, n China

Xi, Yang, col., 2005 (29) Frdiferene semnificative n distribuiagenotipului VDR i a alelelor

Polimorfismul genei VDR poate snu fieimportant n susceptibilitatea individualladeficitul de vitamina D

Kanedo,Urnaa, col.,

2007 (30)

Polimorfismul VDR prin alelele Bsml, Apali Taql, frdiferene seminificative fadegrupul control

Polimorfismul genei VDR nu joacun rolimportant n apariia rahitismului n Mongolia

D (31). Unele date indic faptul canumite poli-morfisme ale VDR pot fi determinante pentru

osteoporoz, facilitatea fracturilor i tonusul mus-cular n patologia adultului (Bsml, Fokl) (Barr-bibl), ceea ce configureaz existena unui profilgenetic particular al unui grup/subgrup de persoane.Este posibil ca acesta sfie o rezultantde sumaie,

deoarece att Cheng (15), ct i Uitterlinden i col.(32) considercalelele Bsm1, Apal, Taq1 nu au

efect asupra nivelului de expresie, nici a activitiiproteinei VDR formate. De menionat c unelelaboratoare din ara noastr pot determina poli-morfismele Fokl, B/b pentru a identifica genotipulasociat cu densitatea osoas sczut i riscul de


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fracturi pentru grupele de risc. Odat ce aciunileclasice, de tip hormonal ale vitaminei D sunt binecunoscute, iar implicarea organelor int(intestin,schelet, rinichi, paratiroide) este pe larg descrisntratatele de fiziologie, vom aborda mai pe largefectele autocrine/paracrine ale 25(OH)D.

ACIUNILE TISULAR SPECIFICE ALEVITAMINEI D

Cu 30 ani n urms-a descoperit cmajoritateaesuturilor i celulelor organismului posedrecep-torul nuclear pentru vitamina D (VDR). Astfel, ce-lulele din creier, muchii scheletici, cord, muscu-latura neted, piele, celulele pancreatice, celulelesistemului imun (macrofage, celule dendritice, lim-focite B i T) dein VDR . S-a constatat, de asemenea,

prezena extrarenala 1-hidroxilazei (CYP27B1)n unele esuturi (colon, prostat, celule dendritice,piele etc.), reprezentnd aparatul necesar pentruformarea i utilizarea locala vitaminei D (10,11,15). Utilizarea 25(OH)D n reglarea unor procesebiologice fundamentale a fost relevatpentru: su-presia creterii celulare, reglarea apoptozei, modu-larea rspunsului imun, controlul diferenierii ifunciei cutanate, controlul sistemului renin-an-giotensin, controlul secreiei de insulin, controlulfunc

iei musculare

i al unor func

ii neuronale.

Toate aceste funcii ale vitaminei D au potenialeaplicaii clinice. ntr-o estimare global, tulburrileproduse sau agravate de nivelurile sczute ale vita-minei D sunt prezentate n tabelul 2.

Tabel 2.Tulburri produse sau agravate de lipsa vitamineiD, dupHeaney, 2008 (11)

AfeciuneNivelul de

eviden

Osteoporoz ++++

Fracturi ++++Diabet zaharat tip 1 ++

Cancer ++++

Boli autoimune ++

HTA +++

Boli ale periodontului ++++

Sclerozmultipl ++

Susceptibilitate/rspuns slab la infecii ++++

Osteoartrit ++

Not: ++++ semnificevidena puternicprin unul sau maimulte trialuri randomizate; +++ date epidemiologice puternice

i consistente, nsfrevidena unor trialuri randomizate;

++ evidene mai putin puternice nssugestive.

Vitamina D i sistemul imun

Modularea funcionrii sistemului imun prin vi-tamina D este dovedit prin prezena VDR n

imunocitele umane activate, prin capacitatea acestorcelule de a produce calcitriol i prin rolul acestuia ninhibiia proliferrii celulelor T (10). S-a demon-strat o relaie cauzalntre funcionarea celularacomplexului 1,25(OH)

2D-VDR i imunitatea nns-

cut i adaptativ fa de infecii. n rahitismul

florid, infeciile respiratorii sunt grevate de o maregravitate i mortalitate; de asemenea, infeciile re-curente reprezinto component a evoluiei rahi-tismului carenial. Modificri ale funcionrii VDRprin expresia unor alele pot influena suscepti-bilitatea la infecii micobacteriene sau virale (15).Numeroase studii au evideniat diferite moduri deimplicare a vitaminei D n procesele infecioase.Astfel, Camargo i col. (33) au constatat o relaieinversntre nivelul vitaminei D n cordonul om-bilical i incidena infeciilor respiratorii la vrsta

de 3 luni, 15 luni, 3 i 5 ani. Un studiu randomizat,dublu-orb, controlat placebo, efectuat n Japonia deUrashima i col. n 2010 (34) a artat csuplimen-tarea copiilor colari cu 1.200 UI/zi vitamina D nsezonul rece a sczut incidena infeciei cu virusgripal A de la 18,6% la 10,8% n grupul tratat. Se-creia de cathelicidin, antibiotic natural din grupulpeptidelor antimicrobiene, este dependent de in-ducia CYP 27B1 i activarea VDR (35,36), fiinddemonstrat aciunea acesteia asupra patogenilorintracelulari ca Mycobacterium tuberculosis (10).

Aceasta poate explica efectul favorabil al expuneriisolare la bolnavii cu TBC, vindecarea mai rapidprin suplimentarea cu vitamina D n cursul trata-mentului antibiotic i susceptibilitatea geneticva-riabilla infecia TB prin polimorfismul genetic alVDR (genotipul Fokl ff la subieci asiatici) (37).Efectul global al 25(OH)D asupra imunitii adap-tative este de tip inhibitor prin scderea producieide anticorpi, limitarea diferenierii limfocitelor Bn plasmocite, promovarea funciilor limfocitelorTh2 i inhibiia rspunsurilor Th1 (15). n psoriazis,capacitatea antiproliferativ a vitaminei D a fostdoveditprin efectul asupra leziunilor cutanate attprin expunere solar, ct i prin tratamentul topiccu vitamina D (9,10,15). Studii experimentale auartat c1,25 (OH)

2D are capacitatea de a inhiba

dezvoltarea encefalomielitei immune, a tiroiditei,DZ tip 1, a bolii inflamatorii intestinale, ca i a altorafeciuni autoimune. Translaia acestor date npractica medicalumannu este un proces liniar inecesitcercetri n continuare.

Vitamina D i diabetul zaharat (DZ)

Rolul vitaminei D ca reglator autocrin al secreieide insulin atestat de activitatea CYP27B1(1-hidroxilaz) n celulele pancreatice, ca i cel de


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regulator al apoptozei (15) conferacesteia valenen prevenirea DZ tip1(38). DZ tip 1 cunoate o pu-ternicsezonalitate diagnostic, debutul fiind maifrecvent n lunile de toamni iarni un gradientgeografic nord-sud, sugernd o corelaie inversntre apariia bolii i expunerea solar(39). Dozri

ale vitaminei D au artat scderi semnificative ale25(OH)D i ale 1,25(OH)2D la momentul diagnos-

ticului comparativ cu cazurile control (39,40). Stu-dii efectuate de Hipponen i col. (38) n provinciilenordice ale Finlandei pe o cohortde 10.366 copiinscui n 1966 au artat cpnn anul 1997, 81dintre acetia au fost diagnosticai cu DZ 1. Supli-mentarea cu vitamina D, 2.000 UI/zi pnla 1 an, adus la scderea incidenei DZ1 cu 80% comparativcu grupul netratat/tratat sporadic cu vitamina D nurmtorii 11 ani (38). Influena unor variante gene-

tice asupra apariiei DZ1 a fost sugerat deOgunkolade i col. (41), care au artat cpolimor-fismele VDR influeneazcapacitatea secretorie apancreasului pentru insulin, i de Bailey i col.(39) care au evideniat polimorfismul pentru genaCY P27B1 ca surspentru susceptibilitatea la DZ1.Creterea aportului de vitamina D este consideratuna dintre cele mai promitoare ci de prevenire aDZ1, considerndu-se cdiminuarea statusului vi-taminei D n ultimele decade a contribuit la recen-tele tendine de cretere a incidenei bolii (42). Pe

de altparte, Bid i col (43) au studiat relaia dintrepolimorfismele VDR (Fokl, Bsml, Taql) i riscul deDZ tip 2, distribuia genotipului i frecvena alelelorfiind comparate ntre bolnavi i grupul control.Autorii constat c acestea nu difer semnificativntre cele dou grupuri n studiu, vrsta medie iparametrii somatici fiind mai ndeaproape asociai,markerii genetici ai afeciunii fiind n continuareobiect de cercetare.

Vitamina D n afeciunile cardiovasculare

Este cunoscut cfactorii de risc pentru afeciunilecardiovasculare ale adultului i au originea n

copilrie (44). Repleia cu vitamina D n copilriei adolescenare potenialul de a ameliora profilulde risc cardiovascular n decada 50 i dup(45). Unstudiu asupra 3.577 de adolesceni n USA, ntre-prins ntre anii 2001-2004 n cadrul programuluiNational Health and Nutrition Examination Survey

(45) a pus n evidencvalorile sczute ale 25(OH)D s-au corelat cu excesul ponderal, obezitateaabdominal, hiperglicemia i HTA. Calcitriolul areefecte antiinflamatorii manifestate prin inhibiiaproduciei de proteinC reactiv(CRP) i a altormarkeri proinflamatori. n insuficiena cardiac, unstudiu pe 93 de bolnavi aduli a artat csuplimen-tarea cu vitamina D a sczut nivelul citochinelorproinflamatorii i a crescut producia celor anti-inflamatorii, fr ns a influena rata de supra-

vieuire pe durata studiului (46). Controlul vitamineiD asupra sistemului renin-angiotensin iniialdemonstrat experimental (15), a fost validat prinunele date clinice. Astfel, ntr-un studiu prospectivpe 4 ani asupra asistentelor medicale din USA(Nurses Health Study), s-a artat criscul de HTAeste de 3,18 ori mai mare la persoanele cu valori ale25(OH)D sub 15 ng/ml fade cele cu valori maimari de 30 ng/ml (47).

CONCLUZII

Majoritatea populaiei nu posed un nivelcorespunztor de vitamina D.

Existvariaii individuale i etnice ale genelorcare codeazmetabolismul vitaminei D.

Polimorfisme genetice care afecteazobinuitun singur nucleotid al genelor metabolismuluivitaminei D determinvariaii semnificativeale riscului pentru numeroase boli.

Variabilitatea geneticpoate explica apariiamodificrilor rahitice la sugari i copii trataicu vitamina D i lipsa acestor manifestri laalii care nu au primit deloc vitamina D.


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New benchmarks in the study of biological effects of vitamin D

Sorin Buzinschi, MD, PhDMedicine Faculty, Transilvania University, Children Clinical Hospital, Brasov

ABSTRACTRecent dosage of vitamin D for clinical usage had changed completely the understanding of pathology

including its deficit. It was seen that insufficient/deficit of vitamin D are encountered in the population of

developed countries and surprisingly in population that live in warm climate. Only a level of the blood levels

of vitamin D may be linked to seasonality, latitude or oral intake. The genetic factors may manifest in all its

metabolism process. The genes that influence the vitamin D level are DHCR7, CYP27A1, CYP2R1 and VDR,

CYP24A1 and Gc gene. There are presented the steps of vitamin D metabolism as well as the intervention

of different genes in the individual network. Through its autocrine function vitamin D facilitates the expression

of genes in cell function its action being pleitropic. There are also listed some of the other disorders apart of

rickets that are inluenced by the low level of vitamin D.

Key words: vitamin D, genes, low level, rickets, chronic disease

Vitamin D [25(OH) D] was discovered in 1920,and its chemical structure in 1932, but rickets, adisease whose deficiency expresses, has a mucholder history. Sun exposure and vitamin D treat-ment were long considered effective, prophylacticand therapeutic factors of a solved problem. How-ever, the reappearance of vitamin D deficiency andrickets in recent years, reported in USA, Canada,Germany, England, but also Spain, Greece, SaudiArabia, Turkey, Egypt, India (1-8) have made vita-

min D deficiency to be considered today a world-wide epidemic problem (1,5,8), by affecting in dif-ferent degrees and different age groups, over 50%of worlds population (9). A decisive factor in re-evaluating the status of vitamin D was the possibil-ity of dosage 25(OH)D in clinical laboratories, oncethe method left the restricted frameworks of re-search laboratories. Among the factors which de-termine the status of vitamin D we mention: sunexposure limited to northern latitudes between No-vember and March, increased use of sunscreen toavoid skin neoplasms, and genetic variability. Vita-min D has in recent years proved to be the center ofa complex hormonal system of autocrine adjust-ment which regulates proliferation and cellular dif-ferentiation. Vitamin D, directly or indirectly, con-trols more than 3,000 genes which regulate themetabolism. As skeletal system, it modulates innateimmunity, adjusts insulin and renin production, in-duces apoptosis and inhibits angiogenesis (5). Thisway 25(OH)D participates in the functioning of im-

mune, cardiovascular and neuroendocrine systems(1,9-11). The deficiency and genetic variations invitamins D metabolism that may explain the ap-pearance of rickets signs in children with correctprophylaxis may be involved in adolescence and

adulthood in the appearance of numerous chronicdiseases such as: mycobacterial infections (tuber-culosis), cardiovascular diseases, diabetes, neo-plasms, autoimmune diseases (multiple sclerosis,systemic lupus erythema, psoriasis) (9,11). Basedon these considerations, vitamin D has now becomea very active research field. Only in the first 9months of 2010 over 2,300 articles on this subjecthave been published (10).

SUMMARY OF VITAMIN D PHYSIOLOGY

Vitamin D is found in two forms: vitamin D2or

ergocalciferol (calciferol) produced by irradiationof yeast or by some herbals and vitamin D

3(chole-

calciferol) produced by photoconversion of cutane-ous hidrocolesterol 7 (7-DHC) after RUV or artifi-cial solar radiation exposure. The amount of vitaminD in food is very low. Industrial 25(OH)D is pro-duced starting from lanolin. From 7-DHC vitaminD

3passes through a series of changes until it be-

comes the active metabolite 1,25 (OH)2D3which isafterwards degraded in inactive composites.

Figure 1.Vitamins D metabolism stages


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Vitamin D has two main types of actions: Endocrine, which regulates Ca metabolism,

vitamin D3 being produced from intrarenal

synthesis Autocrine, in which the hydroxylation of

cholecalciferol is produced in tissues, result-

ing in calcitriol with intracellular action, un-detectable as circulating product, having as acharacteristic genes facilitation or intracel-lular metabolites traffic.

Figure 2.Systemic and local formation of vitamin D and

specific effects

The assimilation of vitamin D as a hormone,long anticipated (by Luke, cit12), is based on fol-

lowing arguments: It is produced by an organ (kidneys) Circulates to target tissues Interacts with specific cellular receptors Triggers specific responses (Ca absorption)

VITAMINS D METABOLISM AND ITS GENETIC

DETERMINISM

A team of researchers from the SUNLIGHT

Consortium (Study of Underlying Genetic Deter-minants of Vitamin D and Highly Related Traits)have analyzed the concentrations of 25(OH)D in33,996 adult subjects of European descendents in15 cohorts and showed that the presence of somealleles can double the risk of vitamin D (13) insuf-ficiency. The genes in question (DHCR7 (NA-DSYN1), CYP2R1 and GC) are involved in choles-terol synthesis, hydroxylation and transport ofvitamin D. The concentrations 25(OH)D, the ac-cepted biomarker of vitamin D is higher in summer

and lower in winter. Only 25% of its inter individu-al variations may be related to season, latitude, orexogenous intake of vitamin D (8). Results of stud-ies conducted on twins and on families suggest thatgenetic factors contribute substantially to this vari-

ability, which may amount to over 53% (14)(48).These data may explain why some children respondpositively to vitamin D intake and others not, as wesee in everyday practice.

The formation of colecalciferol

During sun exposure, RUV is absorbed by 7 de-hydrocholesterol (7-DHC) found in the membranesof keratinocytes and fibroblasts; after a process ofphotoconversion provitamin D

3is formed or cole-

calciferol which is ejected in the extracellular spaceand transported to the liver by a carrier protein (9)(15). Although vitamin D synthesis from 7-DHC isa physical-chemical process, cholesterol synthesisstarting from 7-DHC has a biochemical nature, me-diated by an enzyme 7-DHC reductase, determinedby the gene identified as DHRC7 (NADSYN).Polymorphisms of this gene which determine re-duction of cholesterol production, may increase vi-tamins D blood levels. Increased cholesterol is ac-companied by a decrease in plasmatic 25(OH)Dvalues probably out of extra genetic reasons.

The formation of Hydroxycholecalciferol (calciferol

or calcidiol), 25(OH)D

In liver the colecalciferol is hydroxylated in 25thposition to form 25(OH)D; the reaction is catalyzed

by 25-hydroxylase, enzymes of cytochrome P450having microsomal localization (CYP2R1) and mi-tochondrial (CYP27A1) in hepatocytes. The Cal-cidiol is the major vitamin D metabolite; althoughit has no intrinsic activity it is used to determineblood levels of vitamin having into account thehalving time up to approximately 15 days and thefact that its value increases proportionally with theexogenous intake of vitamin D (10)(15). In patientswith low levels of 25(OH)D were identified 2Rgene mutations, being genetic evidence that the en-

zyme CYP2R1 is the key enzyme of 25-hydroxy-lase (16).

Vitamin D carrier protein (DBP or Gc)

It ensures plasma circulation of 25(OH)D, com-mon genetic variants can differentiate plasma re-sponse to exogenous intake of vitamin D (13). Lau-ridsen and col (17) have identified phenotypesinvolved in blood variations of vitamin D in 595adults. The survey data showed that Gc concentra-

tion is an independent predictor of 1,25 (OH)2D,while the Gc phenotype is a significant indicator of25(OH)D concentration. In a study that included4,501 adults of European origin, the USA, Ahn andcol (18) identified among the causes of an inade-


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quate response to vitamin D, a single nucleotidepolymorphism (SNP) of the gene that codes Gc onthe chromosome 4q12-13 and SNP DHCR7. Thepolymorphism for Gc may have the greatest impacton blood levels of vitamin D (8).

The formation of 1,25-dihydroxycholecalciferol[1,25 (OH) 2 D], calcitriol

The main stage of the active form of vitamin D,calcitriol, takes place mainly in kidneys, but nu-merous other tissues and organs have capable cellsto produce 1,25 (OH)

2D (lung, colon, prostate, pan-

creatic cells, monocytes, parathyroid cells) (9)(10)(11)(15). In kidneys the reaction of formationof 1,25 (OH)

2D is catalyzed by 1hydroxylase an

enzyme of cytochrome P450 (CYP27B1), locatedin the proximal renal tube cells. The production ofcalcitriol is close regulated by 1hydroxylase ac-tivity, which in turn is stimulated by hypocalcemia,the increase of PTH and decrease of plasma levelsof its precursor, the calcidiol (9) (15).

The interaction of 1,25 (OH)2D with vitamin D

receptor (VDR)

An important part of calcitriol actions are medi-ated by a nuclear transcription factor, VDR. This,together with vitamin D binds to RXR (retinoic

acid X receptor) and to vitamins D response ele-ments to initiate regulation of specific genes (10)(Figure 3).

Figure 3. Schematic representation of VDRs role in cell

nucleus

VDR has attracted many researchers attention,being considered a key point in response variationstowards 24(OH)D. There are different allelic vari-ants (polymorphisms) of the VDR gene on the chro-mosome 12 which occur naturally in the populationand which have been linked to rickets, vitamin D re-sistance, hyperparathyroidism but also with suscep-tibility to infections, autoimmune diseases and can-cer (15)(19)(20)(21). Although in nutrigenomic it isaccepted that certain polymorphisms bear host more

sensitive to certain diseases even in the presence ofthat nutrient, in terms of vitamin D and Ca intake,the conditioning is not clear (22).

Figure 4.Genomic structure of VDR and the position of the polymorphisms known after Fang, 2005


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Table 1.VDR polymorphism in children with rickets

Authors Genetic VDR transformations Signification

Bora, Orzan, col, 2008

(22)

Polymorphism of FokI, TaqI, Apal genes in

ill patients, high frequency of Apal alleles,

frequent Tt and reduced Aa incidence

VDR polymorhisms important factor in

deficiency rickets in Turkey

Baroncelli, Bereket, col,

2008 (23)

F alleles increased incidence, BB genotype

associated with low levels of 25 (OH) D

Increased incidence of F allele predisposition

to rockets in Turkey, Egypt

Ismail, Erfan, col, 2011

(24)

F alleles (Fokl) increased incidence, VDR

combination types for Fokl, Apal, Taql different

from control

Positive relationship between VDRs

polymorphism gene and susceptibility to

rickets in Egypt

Arabi, Zahed, col, 2009

(25)

Bsml and Taql polymorphisms VDR polymorphisms influences skeletal

apposition to healthy teenager girls in Lebanon

Fischer, Thacher, col,

2000 (26)

F alleles (Fokl) low incidence, FF genotype

relatively high

Different frequencies of alleles, combinations

of genotypes have not been different from

control group in Nigeria

Lu, Li, col 2003 (27) Fokl alleles and FF genotype, increased

incidence

Association between VDRs polymorphism

gene and rickets by vitamin D deficiency in

China

Gong, Li, col, 2010 (28) F (Fokl) alleles and FF genotype increased

incidence, correlated with low levels of 25(OH) D

VDRs polymorphism gene plays an important

role in the development rickets by vitamin Ddeficiency, in China

Xi, Yang,col, 2005 (29) No significant differences in VDRs and alleles

genotype distribution

VDRs polymorphism gene may not be

important in individual susceptibility to vitamin

D deficiency

Kanedo,Urnaa, col, 2007

(30)

VDR polymorphism by Bsml. Apal and Taq1

alleles Bsml, Apal and Taql no significant

difference from the control group

VDRs polymorphism gene does not play an

important role in the development of rickets in

Mongolia

In various studies on children with rickets in dif-ferent geographic areas the VDR genotype has been

studied (FoK1, Taq1, Apa1) or various other op-tions in trying to define the risk configuration.

The observations, according to which rickets orlow levels of vitamin D occur in expected situa-tions at normal levels due to high solar radiationexposure, came as a big surprise for researchersand practitioners. Studies conducted in countrieswhere there is a significant pathology of ricketsfailed to show clearly whether there is a hereditarysusceptibility of children for this disease. A meta-analysis of literature data on the relationship be-tween polymorphisms for a single nucleotide (SNP)and serum concentrations of 25 ()H)D have identi-fied the involvement of Gc, VDR and CYP27B1,suggesting that the individual genetic architecturecan determine the level of vitamin D (31). Somedata indicate that certain polymorphisms of VDRcan be determinant for osteoporosis, fractures andmuscle tone adult pathology (Bsml, Fokl) (Barr-bibl.), which configures the existence of a particu-lar genetic profile of a group/subgroup of individu-

als. It may be a summative result because both (15)and Uitterlinden and col (32) believe that allelesBsm1, Apal, Taq1 have no effect on the level ofexpression nor on the activity of the formed proteinVDR. To note that, some laboratories in our coun-

try can determine polymorphisms Fokl, B/b toidentify the genotype associated with low bone

density and fracture risk for risk groups.Once the classical actions, hormonal type of vi-

tamin D are well known and the involvement oftarget organs (intestines, skeleton, kidney, parathy-roid) is widely described in the treaties of physiol-ogy, we will approach more fully the effects of au-tocrine/paracrine of 25(OH)D.

TISSUE SPECIFIC ACTIONS OF VITAMIN D

30 years ago it has been revealed that most tis-sues and body cells possess nuclear vitamin D re-ceptor (VDR). Thus, cells in the brain, skeletalmuscles, heart, smooth muscles, skin, pancreatic cells, immune system cells (macrophages, dendriticcells, B and T lymphocytes) have VDR. It has alsobeen noted the extra renal presence of 1-hydroxylase (CYP27B1) in some tissues (colon,prostate, dendritic cells, skin, etc.), representing thenecessary device for formation and local use of vi-tamin D (10)(11)(15). The usage of 25(OH)D in the

regulation of biological processes was relevant for:cell growth suppression, regulation of apoptosis,modulation of immune response, control of skindifferentiation and function, control of renin-angio-tensin system, control of insulin secretion, control


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of muscle function, control of some neuronal func-tions.

All these functions of vitamin D have potentialclinical applications. In a global estimation the pro-duced or worsened disorders by low levels of vita-min D are represented in Table 2.

Table 2.Disorders produced or worsened by lack of

vitamin D, as Heaney, 2008 (11)

Disorder Level of

evidence

Osteoporosis ++++

Fractures ++++

Sugar Diabetes type 1 ++

Cancer ++++

Autoimmune Diseases ++

HTA +++

Periodontal diseases ++++

MS ++

Susceptibility/poor response to infections ++++

Osteoarthritis ++

Note: + + + + means strong evidence through one or more

randomized trials; + + + strong and consistent epidemiological

data but without the evidence of randomized trials, + + less

strong evidences but suggestive.

Vitamin D and immune system

Immune systems functioning modulation by vi-tamin D is proven by the presence of VDR in theactivated human immunocite, through the ability ofthese cells to produce calcitriol and by its role ininhibition, proliferation of T cell (10). A causal re-lationship has been proved between cellular func-tioning of the complex 1,25(OH)

2D-VDR and in-

nate and adaptive immunity against infections. Inflorid rickets respiratory infections are encumberedwith great severity and mortality, recurrent infec-tions are also a component of evolution of Defi-ciency rickets. Changes of VDR functioning by al-

leles expression may infl

uence susceptibility tomycobacterial or viral infections (15). Numerousstudies have shown different ways of involvementof vitamin D in infectious processes. Thus, Cama-rgo and col (33) found an inverse relationship be-tween vitamin D levels in umbilical cord and respi-ratory infections incidence at ages of: 3 months, 15months, 3 to 5 years. A randomized, double-blind,placebo-controlled study conducted in Japan byUrashima and col in 2010 (34) showed that schoolchildrens supplementation with 1200 IU / day vita-

min D in winter has decreased the incidence of Avirus infection from 18.6% to 10.8% in the treatedgroup. Cathelicidin secretion, natural antibioticfrom peptides antimicrobial group is dependent oninduction of CYP27B1 and VDR activation (35)

(36), its action being demonstrated on the intracel-lular pathogens like Mycobacterium tuberculosis(10). This may explain the favorable effect of sunexposure in patients with TB, the more rapid heal-ing with vitamin D supplementation during antibi-otic treatment and variable genetic susceptibility to

TB infection by genetic polymorphism of the VDR(Fokl ff genotype in Asian subjects) (37). The over-all effect of 25(OH)D on adaptive immunity is ofan inhibitor type by decreasing the production ofantibodies, limitation of B lymphocytes differentia-tion into plasma, promoting Th2 cell function andinhibition of Th1 responses (15). In psoriasis anti-proliferative ability of vitamin D was proven by theeffect on skin lesions caused both by sun exposureand by topical vitamin D treatment (9)(10)(15). Ex-perimental studies have shown that 1,25(OH)

2D

has the ability to inhibit the development of im-mune encephalomyelitis, the thyroiditis, type 1 dia-betes, inflammatory bowel disease as well as otherautoimmune diseases. Translation of these data inhuman medical practice is not a linear process andrequires further research.

Vitamin D and diabetes mellitus (DM)

The role of vitamin D as autocrine insulin secre-tion regulator certified by CYP27B1 (1-

hydroxylase) activity in pancreatic cells as well asthe regulator of apoptosis (15) offers to it valencesin preventing Type 1 diabetes (38). Type 1 diabetesexperiences a strong diagnosed seasonality, the de-but being more frequent in autumn and wintermonths and having a north-south geographical gra-dient, suggesting an inverse correlation betweenthe disease and sun exposure (39). Dosage of vita-min D showed significant decreases in 25(OH)Dand in 1,25 (OH)

2D at the moment of compared di-

agnosis to control cases (39)(40). Surveys conduct-

ed by Hipponen and col (38) in the northern prov-inces of Finland on a cohort of 10,366 children bornin 1966 showed that by 1997, 81 of whom werediagnosed with diabetes 1. Supplementation withvitamin D, 2.000 IU/day until 1 year resulted in a80% lower incidence in DM1 compared to the un-treated/sporadically treated group with vitamin Din the next 11 years (38). The influence of somegenetic variants on occurrence of DM1 was sug-gested by Ogunkolade and col (41) which showedthat VDR polymorphisms influence pancreatic in-

sulin secretor capacity, and Bailey and col (39) whichshowed polymorphism for the gene CYP27B1 assource for susceptibility to DM1. Increased intakeof vitamin D is considered one of the most promis-ing ways to prevent DM1, being considered that the


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decrease of vitamins D status in recent decades hascontributed to the recent increasing trends in thisdisease incidence (42). On the other hand Bid andcol (43) studied the relationship between VDRpolymorphisms (Fokl, Bsml, Taql) and risk of type2 diabetes, genotypes distribution and allele fre-

quency were compared between patients and con-trol group. The authors found that they did not dif-fer significantly between the two groups in thestudy, average age and somatic parameters aremore closely associated, genetic markers of the dis-ease being still the subject of research.

Vitamin D in cardiovascular disorders

It is known that the risk factors for cardiovascu-lar disorders in adults have their origins in child-hood (44). Vitamin D repletion in childhood andadolescence has the potential to improve cardiovas-cular risk profile in the 50thdecade and after (45). Astudy undertaken on 3,577 adolescents in the USAbetween 2001-2004 in the National Health and Nu-trition Examination Program Survey (45) has re-vealed that low levels of 25(OH)D were correlatedwith overweight, abdominal obesity, hyperglyce-mia and HTA. The calcitriol has anti-inflammatoryeffects manifested by inhibition of production of C-reactive protein (CRP) and other pro-inflammatory

markers. In heart failure, a study of 93 adult pa-

tients showed that vitamin D supplementation de-creased the proinflammatory cytokines and in-creased the production of inflammatory ones, butwithout influencing survival rate during the study(46). Control of vitamin D on the renin-angiotensinsystem initially experimentally demonstrated (15)

was validated by some clinical data. Thus, a 4-yearprospective study of U.S. nurses (Nurses HealthStudy), showed that the risk of HTA is 3.18 timeshigher in people with values of 25(OH)D below15 ng/ml compared to those with values higher than30 ng/ml (47).

CONCLUSION

The majority of the population does not pos-sess the right level of vitamin D

There are also individual variation as well asethnical variation of the genes that code themetabolism of vitamin D

Genetic polymorphism that affects usuallyone single nucleotide of vitamin D genes de-termines important variations of the risk ofseveral diseases.

Genetic variability may explain the rickets attoddlers and children treated with vitamin Dand the absence of these manifestation at oth-

ers that did not receive at all vitamin D.

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