Jussi Jokinen, Adrian E. Boström, Lena Chatzittofis, Diana M. Ciuculete, Katarina Görts Öberg, John N. Flanagan, Stefan Arver, Helgi B. Schiöth
DOI: http://dx.doi.org/10.1016/j.psyneuen.2017.03.007
Lintlha-khōlō Tsa
- • Bakuli ba nang le tšoaetso e matlafatsang ba ne ba fokolitse methylation sebakeng sa mofuta oa CRH.
- • Bakuli ba nang le lefu la ho ferekana kelellong ba ne ba e-na le maemo a holimo (TNF) -pi ha ba bapisoa le baithaopi ba phetseng hantle.
inahaneloang
Hypersexual Disorder (HD) e hlalositsoeng e le pherekano ea takatso ea thobalano e se nang paraphilic e nang le likarolo tsa ho qobella, ho ts'oaroa le ts'ebeliso ea boitšoaro, 'me e reriloe e le tlhahlobo ho DSM 5, e arolelana likarolo tse ling tse mabapi le ts'ebeliso ea lithethefatsi ho kenyeletsa le li-system tse tloaelehileng tsa neurotransmitter le dysregured hypothalamic-pituitary -adrenal (HPA) tshebetso ya axis. Thutong ena, e nang le bakuli ba banna ba 67 HD le baithaopi ba phetseng hantle ba banna ba 39, re ikemiselitse ho supa libaka tsa HPA-axis tse kopantsoeng le libaka tsa CpG, moo ho fetoloang boemo ba setšoantšo sa epigenetic bo amanang le hypersexuality.
Sebopeho sa methylation sa genome ka bophara se lekantsoe maling a mangata se sebelisa Illumina Infinium Methylation EPIC BeadChip, e lekanya boemo ba methylation bo fetang libaka tsa 850 K CpG. Pele ho tlhahlobo, sebopeho sa methapo ea methapo ea lefatše sa DNA se ile sa sebetsoa pele ho latela liprotheine tse tloaelehileng le ho fetoloa bakeng sa mofuta o mosoeu oa sele ea mali. Re kenyelelitse libaka tsa CpG tse fumanehang kahara 2000 bp ea setsi sa ho qala sa transaction sa mefuta e latelang ea HPA-axis e kopantsoeng: Corticotropin e lokolla li-hormone (CRH), corticotropin e lokolla protheine e kopanyang lihormone (CRHBP), corticotropin e lokolla li-receptor tsa hormone ea 1 (CRHR1). receptor 2 (CRHR2), FKBP5 le glucocorticoid receptor (NR3C1). Re entse mefuta e mengata ea methapo ea methapo ea methapo ea methapo mokhoeng oa phapang e fapaneng ea khatello ea maikutlo, re lokisa boemo ba khatello ea maikutlo, dexamethasone maemo a sa hatelleheng, Sekolo sa lipotso tsa bana sa Trauma Traumaire se akaretsang le lintlha tsa plasma tsa TNF-alpha le IL-6.
Har'a libaka tse 76 tse lekiloeng tsa CpG, tse 'ne li ne li le bohlokoa ka lebitso (p <0.05), tse amanang le liphatsa tsa lefutso CRH, CRHR2 le NR3C1. Cg23409074 – e fumanehang 48 bp noka ea sebaka sa ho qala sa ho ngola mofuta oa CRH - e ne e le hypomethylated haholo ho bakuli ba nang le khatello ea maikutlo kamora ho khalemeloa liteko tse ngata u sebelisa mokhoa oa FDR. Litekanyetso tsa methapo ea cg23409074 li ne li amana hantle le mofuta oa mofuta oa CRH ho sehlopha se ikemetseng sa lithuto tsa banna tsa 11 tse ikemetseng. Tekanyo ea methylation sebakeng sa CRH se khethiloeng, cg23409074, e ne e amana haholo pakeng tsa mali le likarolo tse 'ne tse fapaneng tsa boko.
CRH ke karolo ea bohlokoa ea likarabo tsa khatello ea maikutlo tsa neuroendocrine bokong, mme karolo ea bohlokoa lits'ebetsong tsa bokhoba. Liphetho tsa rona li bonts'a liphetoho tsa epigenetic ho mofuta oa CRH tse amanang le lefu la hypersexual ho banna.
Puisano
Thutong ena, re fumane hore bakuli ba banna ba nang le hypersexual disorder ba fokotse maemo a methylation sebakeng sa methylation locus (cg23409074) se fumanehang 48 bp setsing sa phepelo ea transaction ea mofuta oa CRH. Ntle le moo, sebaka sena sa methylation se ne se lumellana hantle le mofuta oa mofuta oa CRH ka har'a sehlopha se ikemetseng sa banna ba phetseng hantle. Ho tsebo ea rona, ena ke tlaleho ea pele mabapi le liphetoho tsa epigenetic tse amanang le lefu la hypersexual. Re sebelisitse lisebelisoa tsa mofuta oa methylation ka bophara ba libaka tsa 850K CpG, le ha ho le joalo, ho ipapisitse le liphumano tsa rona tsa pejana mabapi le taolo ea HPA ho banna ba nang le lefu la hypersexual (Chatzittofis et al., 2016), re sebelisitse mokhoa o reretsoeng ho latela mefuta ea moemeli oa HPA.
CRH ke mohokahanyi oa bohlokoa oa likarabo tsa khatello ea kelello bokong, ho itšoara hantle le tsamaiso ea methapo e ikemetseng (Arborelius et al., 1999), hammoho le neuroplasticity (Regev & Baram, 2014). Ha re nahana ka ts'oaetso ea hypersexual molemong oa ho lemalla neurobiology, ho netefalitsoe hore CRH e na le karolo ea bohlokoa ts'ebetsong ea bokhoba ba lithethefatsi (Zorrilla et al., 2014). Mefuteng ea litoeba, sistimi ea CRF e khanna bokhoba ka liketso tse bohareng ba amygdala, e hlahisang boits'oaro bo ts'oanang le matšoenyeho, likhaello tsa meputso, boits'oaro ba lithethefatsi le khatello ea maikutlo e bakoang ke khatello ea maikutlo (Zorrilla et al., 2014). Ntle le moo, ts'ebetso ea li-neuron tsa CRF ka har'a medial preortal cortex e ka kenya letsoho tahlehelong ea taolo e bonoang lihloohong tsa HD. Ho bonts'itsoe hore ts'ebeliso e mpe ea lithethefatsi e lebisa ho axis e matla ea HPA-axis e nang le maemo a eketsehang a ACTH ha CRH e bapala karolo ea mantlha ho arabeleng likarabo tse mpe tsa khatello ea maikutlo nakong ea ho tlohela lithethefatsi (Kakko et al., 2008; Koob et al., 2014). Ka mokhoa o ts'oanang, HPA-axis e matla e nang le maemo a phahameng a ACTH le liphetoho tsa epigenetic ho liphatsa tsa lefutso tsa CRH ho bakuli ba batona ba nang le lefu la hypersexual e ka lebisa ho selikalikoe sa takatso le ho oela hape, ka boemo bo bocha ba maikutlo a mabe, ho boloka boits'oaro ba bosodoma ka boiteko ba lefeela ba ho lefella boemo ba maikutlo bo sithabetsang. Ho pheta-pheta likhopolo-taba tsa thobalano, litakatso kapa boits'oaro bo arabelang maemo a khatello ea maikutlo le / kapa ho arabela liketsahalong tsa khatello ea bophelo ke matšoao a mantlha mokhoeng oa tlhahlobo ea ts'oaetso ea hypersexual (Kafka, 2010). Liphuputso tsa rona tsa hypomethylation ea mofuta oa CRH o amanang le methylation locus banyalani e neng e amana ka polelo ea liphatsa tsa lefutso sebakeng se ikemetseng, e eketsa ho tse fumanoeng tse fetileng tsa Hys axis dysregulation ho bakuli ba banna ba nang le phallo ea hypersexual mokhatlong oa limolek'hule. Boitšoaro ba taolo ea Heroin bo ne bo amana le tšebeliso ea mofuta oa CRH e bonts'ang karolo e laoloang ke liphetoho tsa methylation mohlaleng oa phoofolo (McFalls et al., 2016) le tlhahiso ea tlhahiso ea tlhahiso ea tlhahiso ea tlhahiso ea basebetsi e tlalehiloe e ama sebopeho sa polelo sa CRH (Chen et al., 2012). Leha ho le joalo, phapang e kholo ea methylation ho CRH gene locus (cg23409074) e ne e le tlase haholo (e bolela phapang e ka bang 1.60%), le boleng ba mmele liphetoho tse poteletseng tsa methylation ha li hlakisoe ka botlalo. Ho na le leha ho le joalo, ho na le sehlopha se ntseng se eketseha sa lingoliloeng ho mefuta e ikhethang, e fana ka tlhahiso ea litla-morao tse fapaneng tsa mongolo le phetolelo ea tse poteletseng Liphetoho tsa methylation (1-5%), haholo-holo ka li-syndromes tse rarahaneng tsa multifactorial tse kang khatello ea maikutlo kapa schizophrenia (Leenen et al., 2016).
Thutong ena, re nkile liphapang tse amehang ka ho fetesisa, tse kang khatello ea maikutlo, boemo ba ho se sebetse ha DST, boemo ba kakaretso ba CTQ le boemo ba plasma ba TNF-alpha, ho latela tlhaiso-leseling lipakeng tsa methylation ea liphatsa tsa lefutso tse amanang le HPA-axis le hypersexual disc . Ho khahlisang, bakuli ba nang le lefu la hypersexual disc ba ne ba e-na le maemo a phahameng haholo (TNF) -pi ha a bapisoa le baithaopi ba phetseng hantle (Jokinen et al., 2016). E tlameha lipakeng pakeng tsa li-glucocorticoids le ho ruruha le liphapang tsa sehlopha ho TNF-alpha le litekanyetso tsa IL-6 lipakeng tsa bakuli le taolo e phetseng hantle, re sebelisitse matšoao a tšoaetso e le covariates ho nahana ka ho ferekanya ho ka bang teng ka sehlopha se tlase sa neuroinfigueation. Tekanyetso ea mmele ea boits'oaro ke ea bohlokoa ho pathophysiology e bakang mafu a mangata a kelello a kenyeletsang khatello e kholo ea maikutlo, ho ferekana ha kelello le schizophrenia (Danzer et al., 2008). Neuroinflammation ea maemo a tlase e atisa ho bonoa ho bakuli ba nang le HPA axis dysregulation (Horowitz et al., 2013) mme hypothesis ea methapo e hatella karolo ea litheko tsa psycho-neuroimmunological dysfunctions (Zunszain et al., 2013). Ho ka etsahala hore ho ts'oareha le ho ts'oaroa ha glucocorticoid ho etsahale ka boits'oaro mohahong le lits'ebetsong tse ts'oanang ntle le ho sebelisana ka kotloloho ho fella ka tšenyo e kholo ea tšenyo; ho bakuli bana ba banna ba nang le HD ba neng ba e-na le HD ba ne ba e-na le maemo a phahameng a TNFcy ha a bapisoa le baithaopi ba banna ba phetseng hantle ho sa tsotelehe dysregulation ea HPA-axis (Jokinen et al., 2016). As e tlalehiloeng pejana (Chatzittofis et al., 2016), meriana e loantšang khatello ea maikutlo kapa khatello e matla ea maikutlo e ne e se e amanang haholo le mehato ea ts'ebetso ea HPA ho bongata bona ba lipatlisiso.
Ho ea pele thutong ena, ka lebaka la hore bakuli ba tlalehile mathata a bophelo ba bongoaneng ha ba bapisoa le taolo e phetseng hantle le litlamorao tse tsebahalang tsa ts'itiso ea bongoana ho epigenome, re sebelisitse mathata a bophelo ba pele mefuteng ea khatello ho ela hloko litlamorao tse ka bang teng tsa bongoana ts'oaetso ea methylation. HPA-axis dysregulation e amanang le mathata a bophelo ba bongoaneng e bonts'a ts'oaetso le boiteko ba matšeliso a litlamorao tsa mathata a bongoana (Heim et al. 2008) le mathata a bophelo ba bongoaneng a amana le liphetoho tsa epigenetic tsa liphatsa tsa lefutso tse amanang le HPA (Turecki & Meaney, 2016).
Kameho ea conceptualization ea hypersexual disc e qotsitsoe haholo mme leha tlhahlobo e sa ka ea kenyelletsoa ho DSM-5, lefapha la boithuto le bontšitse tekanyo e phahameng ea ho ts'epahala le ho nepahala bakeng sa litekanyetso tse khethiloeng tsa tlhahlobo ea lefu la hypersexual (Reid et al. , 2012).
Matla a thuto ke bongata ba bakuli ba sa tsotelleng ba nang le tlhahlobo e felletseng ea lefu la khatello ea maikutlo, sehlopha se lekanang sa lilemo tsa baithaopi ba phetseng hantle, ntle le mathata a kelello a nakong e fetileng kapa a nakong e fetileng hammoho le nalane ea malapa ea likotsi tse kholo tsa mafu a kelello le liphihlelo tse mpe tse bohloko. Ho feta moo, ho nahanisisa ka li-confounders tse ka bang joalo ka mathata a bongoana, khatello ea maikutlo, matšoao a neuroinfigueatory le sephetho sa liteko tsa dexamethasone li ka bonoa e le matla.
Mefokolo e meng: boitlhahlobo ba mathata a bophelo ba pele le sebopeho sa thuto, ha li lumelle liqeto mabapi le ho qhekella. Ntle le moo, kaha ona ke tlhahlobo ea pele e etsang lipatlisiso ka li-epigenomics ho banna ba nang le lefu la hypersexual, ho ka ba molemo hore re phetise seo re se fumaneng sehlopheng se ikemetseng sa lithuto tsa HD. Ntle le moo, le ha cg23409074 e bonts'itsoe ho hokahana le polelo ea mofuta oa CRH taolong e phetseng hantle, e ntse e bonts'oa ho isa bohōleng bofe hore sena se ka bonahatsa liphetoho tse etsahalang lithutong tsa HD le tekanyetso ea CRF e kanna ea ba ea bohlokoa bakeng sa thuto. Ho hlokahala lithuto tse ling hape ho etsa lipatlisiso ka mokhoa o ka khethollang CRH ho banna ba nang le HD. An Potso ea bohlokoa ke hore na methapo eohle ea mali ea CRH methylation e bonts'a litlamorao ho bokong. U sebelisa sesebelisoa se tšepahalang ho bapisa methylation lipakeng tsa mali le boko, methapo ea methyl ho sebaka sa CRH se khethiloeng, cg23409074, se ne se amana haholo le mali le tse 'ne tse fapaneng libaka tsa bokong, ka khokahano e matla ka ho fetisisa ea preortal cortex, molaoli oa bohlokoa oa karabelo ea khatello ea maikutlo. Sena se fana ka tšehetso e 'ngoe eo maemo a methylation a khetholloang maling ohle a ka khonang bonts'a liphetoho tse etsahalang libakeng tse itseng tsa boko. Ntle le moo, tlhahlobo ea kopanelo ea methylation le polelo e entsoe sehlopheng se fokolang sa baithaopi ba phetseng hantle 'me e ne e le bohlokoa mefuteng e matla, empa eseng ka ho hokahanya ha Pearson. Sephetho sena se hanyetsanang se ka hlalosoa ka hore mehlala ea methapo e matla e khothalletsoa hore e sebelisoe haeba ho na le sampole e nyane, ho ikarabella bakeng sa ba kantle ho tsohle kapa heteroscedasticity ho data e ka hlahisang litholoana tse mpe (Joubert et al., 2012). Ntle le moo, ka ho etsa tlhahlobo ea maiketsetso e sekaseka kahare ho motho ka mong, re fokotsa haholo menyetla ea ho ferekanya ka lebaka la ho fapana ho ts'oanang, Lintho tse ling tse sa baleheng tse ka ba le tšusumetso le tsona li ka baka liphetoho methapong ea methapo, mohlala, lipehelo tsa lijo kapa linaha tse hloahloa (Rask-Andersen et al., 2016) 'me ha ho joalo ho laola ho tsepamisa mohopolo ea plasma ea dexamethasone nakong ea DST (Menke et al., 2016).
Ha re phethela, re tla fumana epigenetic boemo ho mofuta oa CRH, o hokahanang le lingoliloeng tse amanang le bokhoba ba joala ba lithethefatsi, ho banna ba nang le lefu la hypersexual, li ka kenya letsoho ho hlakiseng mekhoa ea likokoana-hloko ea pathophysiological ea hypersexual disorder.
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