Pharmacogenomics ke eng: tataiso e felletseng, liphatsa tsa lefutso, mehlala le liteko

Lilemong tsa morao tjena, meriana e tlohile ho mokhoa o lekanang le o mong ho ea ho oa motho ka mong, 'me pharmacogenomics ke le leng la mabaka. Taeo ena ea ithuta Kamoo mefuta ea rona ea liphatsa tsa lefutso e amang karabelo ea meriana kateng, ka sepheo sa ho fana ka meriana e nepahetseng, ka tekanyo e nepahetseng le ka nako e nepahetseng.

Phetoho ena ea paradigm e re lumella ho tlohela liteko le liphoso ha re fana ka litaelo le ho fokotsa litlamorao tse mpe. Ha se ntho e nyane: Boitšoaro bo bobe ba meriana ke bothata ba bophelo bo botle ba sechaba le sesosa se seholo sa ho kena sepetlele le lefu. Pharmacogenomics e fana ka lisebelisoa tsa ho bolela esale pele katleho le polokeho ea kalafo pele e qala.

Pharmacogenomics ke eng mme ke hobane'ng ha e le bohlokoa?

Pharmacogenomics e kopanya pharmacology (thuto ea lithethefatsi) le the genomics (thuto ea liphatsa tsa lefutso le tšebetso ea tsona) ho utloisisa hore na mefuta e meng ea DNA le polelo ea tsona li fetola karabelo ea kalafo joang. Sena se lumella ho hlophisa hantle meriana le litekanyetso tse thehiloeng ho boemo ba lefutso ea mokuli e mong le e mong.

Ha e le hantle, sena se bolela ho tloha ho "saese e le 'ngoe e lumellanang le bohle" ho ea ho mokhoa o nepahetseng. Meriana e mengata ha e sebetse ka tsela e tšoanang ho bohle. 'me tse ling li ka baka chefo e tebileng ho ba nang le mefuta e fapaneng. Ka boitsebiso ba liphatsa tsa lefutso, lingaka li ka fokotsa likotsi le ho ntlafatsa liphello.

Ho tloha ho moriana o lekanang le o mong ho ea ho oa motho ka mong

Meriana ea kajeno e phehella "sethethefatsi se nepahetseng, ka tekanyo e nepahetseng, ka nako e nepahetseng." Ho finyella sena, re tlameha ho nahana ka phapang e khōlō ea batho ka bomong. Karabelo ea lithethefatsi e itšetlehile ka liphatsa tsa lefutso, epigenetic le maemo a tikoloho, 'me tlatsetso ea e mong le e mong e fapana ho itšetlehile ka sethethefatsi.

Mohlala oa paradigmatic ke warfarin: tekanyo ea eona e nepahetseng e itšetlehile ka liphatsa tsa lefutso.CYP2C9, VKORC1) le ka lintho tseo e seng tsa lefutso tse kang lilemo, bong, boima ba 'mele, ho tsuba, kapa likamano. Ho kopanya li-parameter tsena kaofela E ntlafatsa tlhahiso ea litekanyetso le ho fokotsa liketsahalo tse mpe.

Kajeno re tseba seo Ho feta 90% ea baahi ba na le bonyane mofuta o le mong o ka sebelisoang oa pharmacogenetic, 'me ho na le lithethefatsi tse makholo tse nang le lintlha tsa pharmacogenomic tse amoheloang ke balaoli ba tsamaiso. Sena se matlafatsa ts'ebeliso ea bongaka ea ho kenyelletsa liphatsa tsa lefutso ho fana ka litaelo.

Ha re sheba bokamoso, pharmacogenomics e tla ba senotlolo sa ho iketsetsa mekhoa ea phekolo libakeng tse kang cardiology, oncology, neuroology kapa pulmonology, le ho potlakisa tlhahiso ea meriana e mecha, e sireletsehileng le e sebetsang haholoanyane.

Liphatsa tsa lefutso, li-biomarker le litsela tse khethollang karabo

Phapang ea liphatsa tsa lefutso hangata e lekanngoa ka li-biomarker joalo ka nucleotide polymorphisms e le 'ngoe (SNPs). Mefuta ena e ka fetola li-enzyme, li-receptor kapa lipalangoang, ka hona fetola bokgabane kapa polokeho ea moriana.

Ho metabolism (mohato oa I), lelapa la li-enzyme CYP450 e senya palo e kholo ea lithethefatsi. Nomenclature ea eona e ipapisitse le lelapa, subfamily, le enzyme (mohlala, CYP2E1), 'me mefuta e fapaneng ea allelic e hlalosoa ka mokhoa oa "star" system (*1, *2, *3...). Liphetoho liphatseng tsena tsa lefutso li hlahisa metabolizing phenotypes tse khethollang maemo a plasma le karabelo ea bongaka.

Karolong ea II, glutathione S-transferases, N-acetyltransferase, e hlahella. UGT, sulfotransferase le methyltransferase tse kang TPMT kapa COMT. Mefuta e fapaneng ea li-enzyme tsena e amahanngoa le chefo e itseng. Haeba ho felisoa ho liehisoa ke liphatsa tsa lefutso, moriana o nang le mefuta e fokolang ea phekolo e ka fihla menahanong e kotsi.

Lipheo tsa lithethefatsi le tsona ke tsa bohlokoa: polymorphisms ho liphatsa tsa lefutso tse khoutu ea baamoheli fetola ts'ebetso ea bona kapa polelo le ho fetola kutlo kapa kotsi ea litlamorao tse mpe. Ka mokhoa o ts'oanang, Bapalami ba ABC joalo ka P-gp (ABCB1 / MDR1) fetola ho monya, ho aba le ho felisa, ho ama ho pepeseha ha lisele le karabelo.

Ka bokhutšoanyane, karabelo ea lithethefatsi e hlalosoa ke tšebelisano pakeng tsa pharmacokinetics (ADME) y pharmacodynamics, ka bobeli li fetotsoe ke liphatsa tsa lefutso tsa mokuli, 'me ka linako tse ling, ke tumor genome ka boeona ho oncology.

Metabolism phenotypes: ho tloha ka potlako ho ea ho butle

Ho latela ts'ebetso ea enzyme e kopaneng, motho a ka aroloa e le metabolizer e potlakileng haholo, e potlakileng, e tloaelehileng, e bohareng kapa e liehangLetšoao lena ha le "ntle kapa le lebe" ka bonngoe: bohlokoa ba lona bo itšetlehile ka sethethefatsi le hore na se sebetsa kapa se sebetsa. sehlahisoa.

Haeba motho e le metabolizer e liehang ea tsela e etsang hore moriana o se ke oa sebetsa, o ka bokella maemo a phahameng mme a hlahisa. chefo. Ho fapana le hoo, haeba tsela eona eo e kenya tšebetsong prodrug, metabolizer e liehang e tla ba le motsoako o sa sebetseng haholo. ho hloleha ho phekola. Ke kahoo litataiso tsa kliniki li fetolang likhothaletso tse ipapisitseng le lithethefatsi le phenotype.

• Ka potlako: ho fetola kapa ho felisa lithethefatsi ka potlako haholo; e ka hloka litekanyetso tse phahameng kapa tse ling haeba ho na le tahlehelo ea matla.
• Mahareng/e butle: ho pepeseha ho eketsehileng ho lithethefatsi tse sebetsang; kotsi ea liketsahalo tse mpe le tlhoko ea ho fokotsa litekanyetso kapa ho qoba sethethefatsi.
• Normal: ts'ebetso ea enzyme e lebelletsoeng; litekanyetso tse tloaelehileng li atisa ho lateloa, ho beha leihlo lintlha tse seng tsa lefutso.

Ho phaella ho DNA, karabo ea ho qetela e fetotsoe ke lilemo, thobalano, boima ba 'mele, lijo, li-comorbidities le polypharmacy, e ka susumetsang kapa ea thibela mekhoa ea metabolic le ho fetola khatello ea lithethefatsi.

Re etsa lipatlisiso joang: liphatsa tsa lefutso, GWAS, le liphanele

Ho na le mekhoa e 'meli ea khale ea ho sibolla likamano tsa liphatsa tsa lefutso. Ea pele ke ea lithuto tsa liphatsa tsa lefutso tsa mokhethoa, e tsepamisitse maikutlo ho metabolism, lipalangoang kapa liphatsa tsa lefutso tse lebisitsoeng, ho feta moruo le ho toba ho tiisa likamano tsa genotype-phenotype.

Ea bobeli, e GWASE (lithuto tsa genome-wide association) bapisa litlaleho tsa lefutso pakeng tsa lihlopha (nyeoe le litsamaiso) le ho khetholla mefuta e fapaneng e amanang le karabelo, katleho, kapa chefo. Ka ho theoha ha litšenyehelo tsa tatellano, Liphuputso tsena li na le liphetho tse entsoeng libakeng tse ngata tsa phekolo.

Ka laboratoring ea bongaka, tatellano ea liphatsa tsa lefutso (WGS) ke eona e loketseng tekheniki, empa ka lebaka la litšenyehelo hajoale e sebelisoa haholo-holo. exome (WES) le liphanele tse lebisitsoeng. Phanele e nepahetseng e kenyelletsa matšoao a pharmacokinetic le pharmacodynamic, mefuta e fapaneng e nang le bopaki bo sebetsang le makhetlo a mangata a sebetsang bakeng sa lithethefatsi tse sebelisoang hangata.

Ho tiisa tloaelo, ho na le litataiso le metheo ea tsebo e bokellang bopaki ba kliniki le likhothaletso tsa litekanyetso kapa khetho ea mefuta e meng e thehiloeng ho mofuta oa genotype. Litataiso tsena li etsa hore ho be bonolo ho fetolela liphetho tsa liteko hore e be liqeto tse sebetsang tsa kalafo.

Mehlala ea bongaka moo liphatsa tsa lefutso li etsang phapang

Maemo a mang a tiisitsoe ka thata. Ka mohlala, the clopidogrel Ke prodrug eo bioactivation e itšetlehileng ka CYP2C19. Mefuta ea tahlehelo ea ts'ebetso e amahanngoa le tlhahiso e tlase ea metabolite e sebetsang le ho hlōleha ho feta ho phekola; maemong ana, ho kgothaletswa ho fetohela ho moemeli e mong oa antiplatelet.

ea fluoropyrimidines (5-FU, capecitabine) li angoa ke mefuta e fapaneng ho DPYD: Ts'ebetso e fokotsehileng ea enzyme e eketsa kotsi ea chefo e matla, ke ka lebaka leo melaoana e mengata e sisinyang liphetoho tsa lethal dose kapa mefuta e meng ho bajari ba alleles ea kotsi.

Ka li-opioids, ho fapana ha litsela tsa CYP ho ka fetola tlhahiso ea metabolite e sebetsang le ho eketsa kotsi ea ho tepella maikutlong Haeba metabolism e phahame ka tsela e sa tloaelehang kapa e le tlase ho latela moriana. Sena se bontša kamoo phenotype ea metabolizing e fetolang tekanyo ea kotsi ea melemo.

Taba e 'ngoe ke myopathy le simvastatinMefuta e fapaneng ea lipalangoang tsa sebete (mohlala, SLCO1B1) e fokotsa ho amoheloa le ho eketsa khatello ea eona ea plasma, e amanang le eona. ho senyeha ha mesifa mme e hloka tlhokomeliso khethong kapa tekanyetsong.

Likamano lipakeng tsa HLA tse itseng le maikutlo a matla a letlalo joalo ka lefu la Stevens-Johnson kapa chefo epidermal necrolysis, le semelo sa ho hyperthermia e kotsi ka li-anesthetics maemong a itseng a lefutso.

Tlhahlobo ea Pharmacogenomic: seo e se sekasekang le hore na e etsoa joang

Teko e ka etsoa ka mathe, molomong kapa maling. Laeborari e ntša DNA le ho sekaseka mefuta e fapaneng e amang litlhare tse kenyellelitsoeng ho tataiso ea bongaka. Liphetho ha li fetohe bophelong bohle (genotype ea hau e sala), leha litlhaloso li ntlafatsoa ha bopaki bo ntse bo fetoha.

Ts'ebetsong ea bongaka, litlaleho li bontša liphatsa tsa lefutso, genotypes, phenotypes (mohlala, metabolizer ea mahareng) le likhothaletso: fetola lethal dose, khetha mokhoa o mong, kapa tsoelapele ho sebelisa lithethefatsi ka ho beha leihlo. Ke habohlokoa hore kamehla ho etsoe liphetoho tsa phekolo setsebi sa bophelo bo botle.

Lilaboratori tse ling li fana ka liphanele tse felletseng bakeng sa bakuli ba nang le polypharmacy. Mokhoa ona oa thibelo o lumella qoba litaelo tse kotsi ho tloha qalong ea phekolo, ho e-na le ho itšoara ka mor'a ketsahalo e mpe.

Mefokolo le mathata ao re ntseng re hloka ho a hlola

Litšitiso li ntse li tsoela pele: khaello ea lilaboratori tse bolokang chelete e ngata, litekanyetso tsa boleng Litataiso le litiisetso tse hlalositsoeng hantle tsa molao / tsa boitšoaro, hammoho le lekhalo ho litsebi tse koetliselitsoeng ho hlalosa sephetho.

Moeli o mong o tloaelehileng ke nako ea ho arabela: haeba liteko li etsoa ka mor'a ketsahalo e mpe, li lahleheloa ke boleng ba tsona ba thibelo. Kahoo ho sutumelletsa ho mehlala ea pele (thibelo ea genotyping) e kenyelelitsoe historing ea bongaka le mekhoa ea tšehetso ea liqeto.

Bophahamo ba data le bona ke phephetso: ho kopanya, ho toloka le ho boloka litaba tsa genomic ka mokhoa o sireletsehileng le ka theko e tlase e hloka matsete ho tsamaiso ea litšebeletso tsa motheo le data.

Qetellong, ho hlokahala ho eketsehileng koetliso ea bongaka le lisebelisoa tseo ho leng bonolo ho li sebelisa. Bopaki bo bokellana ka potlako, empa ho bo fetola liqeto tse hlakileng tsa kliniki ke mohato oa bohlokoa oa ho etsa tloaelo ea pharmacogenomics.

Pharmacogenomics vs. pharmacogenetics: ha li ntho e le 'ngoe.

La pharmacogenetics e bua ka hore na mefuta e fapaneng ea liphatsa tsa lefutso e ama metabolism joang le karabelo ea sethethefatsi. pharmacogenomics E atolosa ho tsepamisa maikutlo ho genome eohle, 'me, ntle le liphetoho ho DNA, e kenyelletsa likarolo tsa polelo ea lefutso e tsamaisang karabelo ea pharmacological.

Lingoliloeng, mantsoe ana ka bobeli a ne a sebelisoa ka mokhoa o fapaneng ka lilemo, empa ho phahama ha genomics ho kopantse karohano e nepahetseng haholoanyane: Pharmacogenetics ke karolo ea pharmacogenomics, eseng mantsoe a tšoanang.

Nako ea ho kopa tlhahlobo ea pharmacogenomic

Ho bohlokoa haholo pele o qala lithethefatsi ka kotsi e kholo ea chefo e amahanngoa le mefuta e meng e tsebahalang (mohlala, thiopurines le TPMT/NUDT15; fluoropyrimidines le DPYD; carbamazepine le HLA), ho ho hloleha ho phekola e sa hlalosoang kapa ha ho reriloe polypharmacy.

Hoa utloahala hape ho bakuli bao ho lebelloang ho pepesehela lithethefatsi tse ngata ho bona ha nako e ntse e ea: Sephetho sa liphatsa tsa lefutso se sebetsa bakeng sa bophelo bohle 'me se ka botsoa nako le nako ha lengolo la ngaka le etsoa..

Ho eketsa boleng ba bona, liphetho li tlameha ho kopanngoa ho rekoto ea bongaka ea elektroniki ka litemoso le melao ea liqeto, le ho tsamaea le koetliso bakeng sa sehlopha sa tlhokomelo ea bophelo.

Pharmacogenomics, e sebelisitsoeng hantle, e sebetsa e le karolo e eketsehileng ea tšireletso e eketsang kahlolo ea kliniki, classical pharmacology le likhetho tsa mokuli ho tataisa khetho e ntle ka ho fetisisa ea phekolo.

Bopaki le theknoloji li ntse li tsoela pele ka potlako, 'me ka tsona ho na le monyetla oa hore motho ka mong a fumane phekolo e lumellanang le baeloji ea bona. Ka lihlopha tse koetlisitsoeng, litataiso tse hlakileng, le lintlha tse kopaneng, taelo e nepahetseng ha e sa tla hlola e e-ba mokhelo ho fetoha tloaelo e tloaelehileng.