Faʻasagaina o le MicroRNA Faʻaaliga Numera e Fesootai ma le Initaneti Taulaga (2018)

. 2018; 9: 81.

Lomia i luga o le initaneti 2018 Mar 12. Tui:  10.3389 / fpsyt.2018.00081

PMCID: PMC5858605

PMID: 29593587

lē faʻatino

tua

O le fa'aogaina o le Initaneti ma ta'aloga i luga ole laiga o se fa'afitauli fa'ale-mafaufau e ta'ua o le Internet gaming disorder (IGD). O fa'amatalaga fa'amatalaga o le microRNA (miRNA) ua suia i le toto ma le fai'ai o tagata mama'i o lo'o iai ni fa'afitauli o le mafaufau ma ua fa'ailoa mai e fai ma fa'ailoga. Ae ui i lea, e leai ni lipoti i luga ole toto miRNA talaaga ile IGD.

Metotia

Ina ia maua IGD-fesoʻotaʻi miRNAs, matou suʻesuʻeina faʻamatalaga faʻamatalaga miRNA o 51 faʻataʻitaʻiga (25 IGD ma 26 pule) faʻaaoga le TaqMan Low Density miRNA Array. Mo le faʻamaonia, na matou faia le PCR faʻasologa faʻasolosolo faʻatasi ma 36 faʻataʻitaʻiga tutoʻatasi (20 IGD ma 16 pule).

i'uga

E ala i le mauaina ma le faʻamaonia tutoʻatasi, na matou iloa ai ni miRNA se tolu (hsa-miR-200c-3p, hsa-miR-26b-5p, hsa-miR-652-3p) na matua faʻaititia i le vaega IGD. O tagata taʻitoʻatasi ma suiga uma e tolu o le miRNA na sili atu le maualuga o le lamatiaga o le IGD nai lo i latou e leai se suiga [odds ratio (OR) 22, 95% CI 2.29-211.11], ma o le ORs na faʻateleina fua faʻalagolago i le numera o miRNA ua suia. O genes taulaʻi fuafuaina o miRNA e tolu na fesoʻotaʻi ma ala neural. Na matou suʻesuʻeina le faʻamatalaga o le polotini o kenera e tolu i lalo ifo i le itu i sisifo ma faʻamaonia o le faʻaaliga o le GABRB2 ma le DPYSL2 na sili atu le maualuga i le vaega IGD.

iʻuga

Na matou matauina o faʻamatalaga o le hsa-miR-200c-3p, hsa-miR-26b-5p, ma le hsa-miR-652-3p na faʻaititia i le IGD maʻi. O a matou taunuʻuga o le a fesoasoani e malamalama ai i le pathophysiology o le IGD.

uputatala: Le fa'aletonu o taaloga i luga ole Initaneti, microRNA, biomarker, vaisu, western blot

faʻatomuaga

O le faʻaaogaina o le Initaneti ma taʻaloga i luga ole Initaneti e le naʻo se faʻalavelave faʻaagafesootai i totonu o atunuu o loʻo i ai le tele o fesoʻotaʻiga Initaneti, ae o se faʻafitauli o le mafaufau e taʻua o le Internet gaming disorder (IGD) (-). E tusa ai ma lipoti a le epidemiological, o fua faatatau o le IGD i tupulaga talavou e eseese i atunuu, mai le 0.8 i le 26.7% (). Aemaise lava, o suʻesuʻega o loʻo faʻaalia ai le maualuga o le 10% i tupulaga talavou i le tele o atunuu Asia e pei o Korea i Saute, Saina, Taiuani, Hong Kong, ma Sigapoa (). O le IGD e fesoʻotaʻi ma le faʻaleagaina i le mafaufau, mafutaga faʻaagafesootai, ma le olaga i aso uma; mo se fa'ata'ita'iga, fa'aitiitia le fa'atinoga o a'oa'oga po'o galuega (-). O loʻo aofia nei le IGD i le Vaega III (Tulaga mo Suʻesuʻega Faʻaopoopo) o le toe iloiloga lona lima o le Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (). Ae ui i lea, e ui lava i lona taua o le falemaʻi-agafesootai, e itiiti se mea e iloa e uiga i le molecular genetic mechanism i tua atu o le IGD.

O suʻesuʻega masaga lapopoa talu ai nei na fautuaina ai se talaaga faʻavae i le IGD (, ). Vink et al. suʻesuʻeina eseesega o tagata taʻitoʻatasi i le faʻaogaina o le Initaneti ma le 5,247 monozygotic ma dizygotic masaga talavou i le Netherlands Twin Register ma lipotia mai o le 48% o eseesega na faʻamatalaina e mafuaʻaga faʻavae (). Li et al. na matauina le 825 paga o masaga talavou Saina ma lipotia mai o mea faʻapitoa na faʻamatalaina 58-66% o eseesega (). E tusa ai ma lea, polymorphisms o kenera e aofia i le neurotransmission, cognition, ma le gauai e pei o le dopamine receptor D2 gene (DRD2), catecholamine-O-methyltransferase gene (COMT), kenera e feavea'i serotonin (5HTTLPR), ma le cholinergic receptor nicotinic alpha 4 gene (CHRNA4) ua lipotia mai e matua fesoʻotaʻi ma vaisu Initaneti (-). Talu ai nei, Kim et al. su'esu'eina suiga o le sili atu ma le 100 kenera sui e feso'ota'i ma le gaosiga, gaioiga, ma le metabolism o neurotransmitters e ala i le isi augatupulaga fa'asologa o su'esu'ega ma lipotia mai o le rs2229910 o NTRK3 gene e feso'ota'i ma le IGD ().

I le faaopoopo atu i mea tau kenera, ua lauiloa foi o neurobehavioral phenotypes e pulea epigenetically e le coding RNAs e aofia ai microRNAs (miRNAs) (, ). miRNAs o ni molelaula RNA e le faʻapipiʻiina e tasi (e tusa ma le 20-23 nucleotides le umi), e faʻatonutonuina le faʻaalia o kenera-protein e ala i le faʻaleagaina o mRNA ma e taua tele i le pathophysiological process o faʻamaʻi eseese (). O laina o faʻamaoniga ua faʻaalia ai le tele o miRNA i totonu o le tino o le tagata (CNS) ma galue e faʻafetaui lelei le maualuga o faʻamatalaga o latou kenera taulaʻi, lea e aʻafia i le atinaʻeina ma le matua o le CNS system (). O le mea moni, o suʻesuʻega talu ai nei ua faʻaalia ai o faʻamatalaga faʻamatalaga miRNA ua suia i le faiʻai o tagata mamaʻi e iai faʻafitauli o le mafaufau, e faʻapea o latou faʻamatalaga faʻamatalaga e mafai ona avea ma biomarkers mo faʻafitauli o le mafaufau (, , ). Mo se faʻataʻitaʻiga, e ala i suʻesuʻega postmortem, Lopez et al. lipotia o le faʻaaliga o le miR-1202, lea e faʻatonutonuina le faʻaalia o le metabotropic glutamate receptor-4 gene ma vavalo le tali atu i le antidepressant, na faʻaititia i totonu o le tino o le tino o tagata mamaʻi maʻi faʻafitauli tele (). E tusa ai ma le suʻesuʻeina o biomarker, o lenei auala e iai se tapulaʻa manino ona o le faia o se biopsy o le CNS tissue mo le suʻega e le mafai. Talu ai e mafai ona iloa le miRNA i le toto (plasma poʻo le serum), o loʻo faʻasalalau miRNA e iai se faʻamanuiaga faʻapitoa e pei o biomarkers e le faʻaleagaina i maʻi neuropsychiatric. Ae ui i lea, e oʻo mai i le taimi nei, e leai ni suʻesuʻega e uiga i le faʻasalalauina o faʻamatalaga miRNA i le IGD. O le malamalama sili atu i le faʻasalalauina o faʻamatalaga faʻamatalaga miRNA e mafai ona fesoasoani e faʻamalamalamaina le faiga o le atinaʻeina o le IGD ma faʻafaigofie le faʻaliliuga falemaʻi.

I lenei suʻesuʻega, matou te faʻamoemoe e faʻailoa faʻailoga miRNA e fesoʻotaʻi ma le IGD e ala i le matauina o le plasma miRNAs faʻaalia i le va o le IGD ma vaega faʻatonutonu ma suʻesuʻeina o latou aʻafiaga.

Mea ma Metotia

Suesue Mataupu

Na matou suʻesuʻeina le 3,166 talavou (tausaga 12-18 tausaga) faʻaaoga le DSM-V IGD sikoa. Faatasi ai ma i latou, 251 (168 tane ma 83 fafine) na maua i le IGD e tusa ai ma le DSM-V tulaga (). O le aofaʻi o tagata 91 (49 IGDs ma 42 pule) na tuʻuina atu le faʻatagaga faʻamaonia mo lenei suʻesuʻega. Faatasi ai ma i latou, e toafa tagata na le aofia ai e tusa ai ma tulaga faʻapitoa. Mulimuli ane, 87 tagata (45 IGD mataupu ma 42 soifua maloloina tagata taʻitoʻatasi) na lesitala mo lenei suʻesuʻega. Faatasi ai ma i latou, 51 tagata auai (25 IGD maʻi ma 26 pule) na faʻafaigaluegaina e avea ma suʻesuʻega seti mai le 2014 i le 2016. O isi 36 tagata auai (20 IGD maʻi ma 16 pule) na faʻafaigaluegaina e avea ma faʻamaoniga tutoatasi seti mai le 2016. O tagata uma na auai o Korea. tagata taʻitoʻatasi, na lesitala mai le Seoul St. Mary's Hospital (Seoul, South Korea) ma le Seoul National University Boramae Hospital (Seoul, South Korea). O tagata uma na auai na faia se faʻatalanoaga faʻatulagaina e se fomaʻi mafaufau e faʻavae i luga o le Korean Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL) (). O tagata auai uma na faʻamaeʻaina suʻega Block Design ma Vocabulary o le Korean-Wechsler Intelligence Scale for Children, lona 4 lomiga (K-WISC-IV) (). O le impulsiveness na iloiloina e le Barratt Impulsiveness Scale (BIS) (). O fua fa'atatau o Amioga Fa'asaina (BInS) ma Amio Fa'atosinaina (BAS) na fuaina e iloilo ai le uiga o le tagata (). Fa'ata'ita'iga e aofia ai fa'afitauli ogaoga fa'afoma'i ua mavae po'o le taimi nei (fa'ata'ita'iga, ma'i suka ma'i), ma'i neura (fa'ata'ita'iga, fa'alavelave faoa, manu'a o le ulu), fa'aletonu o le mafaufau (fa'ata'ita'iga, ma'i fa'anoanoa tele, fa'alavelave popole), fa'aletonu le mafaufau, po'o so'o se vaila'au fa'asaina (eg. , tapaa, cannabis, ava malosi). O uiga lautele o mataupu suʻesuʻe o loʻo aoteleina ile Laulau Table1.1. O lenei suʻesuʻega na faʻamaonia e le Komiti Faʻatonu Faʻatonu a le Kolisi Faafomai a le Iunivesite Katoliko o Korea (MC16SISI0120). O tagata uma na auai ma o latou matua na tuuina atu le maliega tusitusia.

Laulau 1

Uiga lautele o mataupu su'esu'e.

 mauagaAloaiaTuufaatasi
 
 puleIGDP-valuepuleIGDP-valuepuleIGDP-value
N2625 1620 4245 
Tausaga (tausaga)
Median (min–max)13 (12 - 17)13 (12 - 15)0.75915 (13 - 18)14.5 (12 - 18)0.62814 (12 - 18)14 (12 - 18)0.509
Itula ta'aloga Initaneti ta'i vaiaso (h)
Median (min–max)5.25 (2 - 17)18 (6 - 46)1.27E−6a5.5 (2 - 23)8 (1 - 112)0.3745.5 (2 - 23)14 (1 - 112)1.63E−5a
Tupe maua a aiga ta'i masina (miliona KRW)
Median (min–max)5 (1 - 9)3 (1 - 9)0.5884 (4 - 4)2 (2 - 2)1.0005 (1 - 9)3 (1 - 9)0.460
Aoga (tausaga)
Median (min–max)8 (7 - 9)8 (7 - 9)0.58412 (12 - 12)6 (6 - 13)0.3058 (7 - 12)8 (6 - 13)0.269
K-WISC: mamanu poloka
Median (min–max)10.5 (4 - 17)10 (4 - 16)0.54410 (3 - 16)12.5 (4 - 15)0.12510 (3 - 17)11 (4 - 16)0.598
K-WISC: upu
Median (min–max)9 (5 - 17)7 (5 - 13)0.1749.5 (8 - 15)11.5 (5 - 15)0.5959 (5 - 17)9 (5 - 15)0.527
KS
Median (min–max)24 (17 - 36)37 (22 - 51)3.81E−6a29 (17 - 34)59 (22 - 108)1.2E−5a25 (17 - 36)40 (22 - 108)2.05E−10a
BIS
Median (min–max)63 (35 - 75)67.5 (45 - 81)0.08061 (45 - 79)63 (32 - 82)0.83562 (35 - 79)65 (32 - 82)0.240
maulalo
Median (min–max)31 (15 - 40)31 (13 - 51)0.55836.5 (22 - 48)34 (27 - 52)1.00032 (15 - 48)34 (13 - 52)0.637
BInS
Median (min–max)18 (10 - 26)17.5 (13 - 27)0.64218.5 (12 - 25)20 (13 - 21)0.13818 (10 - 26)19 (13 - 27)0.302
 

IGD, faʻamaʻi faʻaletonu i luga ole Initaneti; KS, Fua Fa'atatau i Vaisu i luga ole Initaneti Korea; BIS, Barratt Impulsivity Scale; BAS, Faiga Fa'agaioiina Amio; BInS, Faiga Fa'asaina Amio; KRW, Won Korea.

aP <0.05 (Su'ega Mann–Whitney–Wilcoxon).

TaqMan Low Density miRNA Array (TLDA) Fa'ata'ita'iga

O le toto pito i tua na aoina mai tagata taʻitoʻatasi ma tuʻuina atu i le fale suʻesuʻe i totonu ole 4 itula e faʻaitiitia ai le lysis o le toto. O le faʻataʻitaʻiga na faʻamalo i le 3,000 rpm mo le 10 min i le vevela o le potu. Ona aoina lea o le supernatant (plasma layer) e aunoa ma le faaleagaina o sela toto. O miRNA fa'asalalau na maua mai e fa'aaoga ai TaqMan miRNA ABC Purification Kit (Human Panel A; Thermo Fisher Scientific, Waltham, MA, USA) e tusa ai ma faatonuga a le kamupani gaosi oloa. I se faapuupuuga, 50 μL o le plasma sample ma le 100 μL o le ABC buffer sa faʻafefiloi. Ina ua mae'a fa'afefiloi ma lo'o fa'amaneta fa'aanti-miRNA fa'atatau, na fa'amama fa'asolo mai miRNA ma lopa fa'atasi ma le 100 µL o le elution buffer. I le vaega o suʻesuʻega, 381 miRNAs na suʻesuʻeina mai 51 plasma samples (25 IGDs ma 26 pule) faʻaaoga le TaqMan miRNA ABC Purification Kit (Human Panel A; Thermo Fisher Scientific, Waltham, MA, ISA) e tusa ai ma faatonuga a le gaosiga. O le Megaplex reverse transcription ma le muai fa'aoso fa'aoso sa faia e fa'ateleina le aofa'i o le cDNA mo fa'amatalaga fa'amatalaga miRNA e fa'aaoga ai le MegaplexPreAmp Primers Human Pool A ma TaqManPreAmp Master Mix (Thermo Fisher Scientific). O le TLDA panel A v2.0 (Thermo Fisher Scientific) na faʻatautaia i luga o le ViiA7 taimi moni PCR system (Thermo Fisher Scientific) e iloilo ai faʻamatalaga o miRNAs. O fa'amaumauga mata'utia na fa'aogaina e fa'aaoga ai le ExpressionSuite Software v1.0.4 (Thermo Fisher Scientific) e fa'amautu ai le tau o le Ct mo miRNA ta'itasi.

Fa'amatalaga Fa'amatalaga mo le TLDA

Na matou fuaina muamua ta'amilosaga (tau Ct) o miRNA ta'itasi. miRNAs faʻatasi ai ma le tau Ct> 35 na manatu e le mafai ona iloa ma le aofia ai mai suʻesuʻega mulimuli ane. O tau Ct uma na faʻatulagaina i le tau Ct o le miR-374b (ΔCt tau), o se tasi o miRNA sili ona faʻaalia o loʻo faʻasalalau i le plasma tagata (). O le log2 fold-change ratio (ΔΔΔCt value) o faʻamatalaga na faʻatatauina i le faʻaaogaina o tau faʻatatau o faʻataʻitaʻiga faʻataʻitaʻiga o se calibrator i le pusa HTqPCR i Bioconductor (). O le faʻatusatusaga faʻatusatusa (RQ) o taʻiala taʻitasi miRNA na faʻamatalaina o le 2−ΔΔCt. Mo faʻataʻitaʻiga faʻataʻitaʻiga o le eseesega o faʻamatalaga i le va o vaega e lua, matou te faʻaaogaina suʻesuʻega fesuiaʻi sui (SVA) e puʻeina ai eseesega e pei o aʻafiaga i faʻataʻitaʻiga e faʻaaoga ai le sva afifi ile Bioconductor (). miRNA ma a P-tau <0.05 na manatu e matua ese lava i le va o vaega e lua.

Gene Set Su'esu'ega Fa'atamaoaigaina

Mo suʻesuʻega faʻatamaoaigaina seti, matou faʻaaogaina ToppFun i ToppGene Suite () e fa'ailoa ai le fa'atamaoaigaina tele o Gene Ontology (GO) () faaupuga, ala, ma fa'ama'i. I le avea ai ma faʻamatalaga mo lenei auala, matou te faʻaaogaina 1,230 faʻasologa o kenera o le sui tauva miRNAs. Na fa'aogaina le su'esu'ega o auala e su'e ai auala taua o kenera taula'i va'ai e tusa ai ma le KEGG, BioCarta, Reactome, GeneMAPP, ma MSigDBi le ToppGene auala. O le taua o faaupuga faʻatamaoaigaina galuega na fuafuaina e faʻavae i luga o le Bonferroni-adjusted P-taua.

Quantitative Reverse Transcription PCR (qRT-PCR) Faʻamaonia ma Toe Faʻatonu

Ina ia faʻamaonia le 10 miRNAs na faʻaalia eseese i le tulaga o le suʻesuʻeina, na faia le qRT-PCR e faʻaaoga ai le TaqMan MicroRNA Assay (miR-15b-5p, #000390; miR-26b-5p, #000407; miR-29b-3p, # 000413; miR-125b-5p, #000449; -200p, #3; ma le miR-002300-337p, #5) ma le ViiA002156 system (Life Technologies) e tusa ai ma le faʻasologa o le gaosiga. E sefulu nanograms o le RNA atoa na fa'aliliuina i le cDNA muamua fa'atasi ai ma fa'amatalaga fa'apitoa miRNA e fa'aaoga ai le TaqMan MicroRNA Reverse Transcription Kit (#411, Life Technologies), sosoo ai ma le PCR taimi moni ma TaqMan Probes. O le RQ o miRNA taʻitasi na faʻamatalaina e 5−ΔCt, lea o le ΔCt o le eseesega i le taamilosaga o le laasaga mo le faʻataʻitaʻiga o loʻo fesiligia, faʻatatau i le miRNA endogenous (miR-374b-5p, #001319). O tali uma a le PCR na fa'atinoina i le fa'atolu, ma o latou tau Ct sa ave fa'atatau. Na matou fuafuaina le log2 fold-change ratio (ΔΔCt) o miRNA taʻitasi i le auala tutusa e pei o le suʻesuʻega faʻavae. O se suʻega Mann-Whitney-Wilcoxon e le faʻataʻitaʻia na faia e suʻe ai le eseesega i tulaga faʻaalia o miRNA i vaega e lua ma se faʻailoga. P-taua ole 0.05.

Western Analysis

O faʻataʻitaʻiga taʻitasi taʻitasi na faʻaumatia muamua le 14 pito i luga o polotini maualuga (albumin, immunoglobulin G, immunoglobulin A, serotransferrin, haptoglobin, alpha-1 antitrypsin, fibrinogen, alpha-2 macroglobulin, alpha-1 acid glycoprotein, immunoglobulin M, apolipoprotein AI. , apolipoprotein A-II, faʻapipiʻi C3, ma transthyretin) e faʻaaoga ai le koluma MARS-14 (4.6 × 50 mm, Agilent Technology, Santa Clara, CA, ISA) aʻo leʻi faia le suʻesuʻega i sisifo. O le vaega le saisaitia na maua mai le koluma MARS-14 na faʻapipiʻiina i le faʻaogaina o le Amicon Ultracel-3 centrifugal filter (3 kDa cutoff), ona faʻamautu lea o le faʻaogaina o le porotini e faʻaaoga ai le bicinchoninic acid method. Ole aofaʻi tutusa (mai le 10 i le 30 μg) o le faʻatonuga ma le IGD serum samples na vavae ese i luga o le 4-20% Mini-PROTEAN TGX precast gel (Bio-Rad, CA, USA) ma faʻafeiloaʻi i se polyvinylidene difluoride membrane. O le isi, na poloka le membrane i le TBS-T (190 mM NaCl, 25 mM Tris-HCl, pH 7.5, ma le 0.05% Tween 20) faʻatasi ai ma le 5% susu susu mamago i le vevela o le potu mo le 30 min. Ona fa'auluina lea o pa'u i fa'ama'i muamua e faasaga i le DPYSL2 (1: 500, Novus Biologicals, Littleton, CO, ISA), GABRB2 (1: 1000, Abcam, Cambridge, MA, ISA), ma le CNR1 (1: 100, Santa Cruz Biotechnology. , Inc., Santa Cruz, CA, ISA), DUSP4 (1:500, MybioSource, San Diego, CA, ISA), ma le PI15 (1:500, MybioSource, San Diego, CA, ISA) i le TBS-T ma le 5 % susu mago e le ga'o i le 4°C i le po, ona fa'atasi ai lea ma fa'amago lona lua talafeagai po'o le isumu povi (1:1,000, Santa Cruz Biotechnology) po'o le 'oti-lapiti (1:1,000, Cell Signaling, Beverly, MA, ISA. ) fa'atasi i le horseradish peroxidase i le vevela o le potu mo le 1 itula. Fa'ailoga fa'ailoga na faia e fa'aaoga ai le chemiluminescence fa'atasi ai ma le ECL reagent (GE healthcare, Piscataway, NJ, USA). Sa matou fuaina i'uga o le poloka i sisifo e fa'aaoga ai le TotalLab 1D analysis software (Non-linear Dynamics, Newcastle upon Tyne, UK). Ona fuafua lea o le fua faatatau o le densitometry e ala i le vaevaeina o le tau o le densitometry o faataitaiga taitasi e pei ona faamatalaina i se isi mea (). I le avea ai o se faʻatonuga mo le faʻavasegaina, o se faʻataʻitaʻiga faʻataʻitaʻi mai le 46 IGD ma faʻataʻitaʻiga faʻataʻitaʻiga na faʻaaogaina mo suʻega uma. Na fa'amauina le taua o fa'amaumauga i le fa'aaogaina o le su'ega Mann-Whitney-Wilcoxon e le o parametric ma se fa'ailoga. P-taua ole 0.05.

i'uga

Uiga o Mataupu Suesue

O lo'o fa'aalia i luga o le Laulau a'ia'i le tulaga fa'aletagata ma le falema'i o mata'upu su'esu'e Table1.1. Pe a matou faʻatusatusaina le IGD ma vaega faʻatonutonu e tusa ai ma le Korean Internet Addiction Proneness Scale (K- Fua) e pei ona faamatalaina i se isi mea (, ), o le vaega IGD na faʻaalia ai le maualuga maualuga o le tau o le K-Scale nai lo le vaega e pulea (37 vs. 24, P = 3.81 × 10-6) (Laulaula (Table1) .1). Ole taimi ole vaiaso fa'aalu ile initaneti ile vaega ole IGD e sili atu le umi nai lo le pule (18 vs. 5.25 h, P = 1.27 × 10-6). E leai se eseesega tele i le va o vaega e lua i le matutua, tupe maua a le aiga i masina taitasi, umi o aoaoga, mamanu poloka, ma faaiuga o su'ega upu o le K-WISC, BIS, BInS, ma le BAS.

MiRNAs Fa'aalia Eseese i le Va IGD ma Pule

Ina ia maua miRNAs e fesoʻotaʻi ma IGD, na matou faʻaaogaina se laʻasaga lua (suʻesuʻe ma faʻamaonia tutoatasi) auala. O le mamanu su'esu'e ma le fuafuaga atoa o lo'o fa'aalia ile Ata S1 ile Mea Fa'aopoopo. I le tulaga suʻesuʻe, matou suʻesuʻeina faʻamatalaga faʻamatalaga miRNA o 51 faʻataʻitaʻiga (25 IGDs ma 26 pule) faʻaaoga le miRNA array o loʻo iai 384 miRNAs. O tulaga faʻaalia o 10 miRNAs na maua e matua ese lava le eseesega i le va o le IGD ma vaega faʻatonutonu (Laulau (Table2) .2). Fa'aaliga fa'atusa tulaga o nei 10 miRNA o lo'o fa'aalia i le Ata Figure1.1. Faatasi ai ma i latou, e lua (hsa-miR-423-5p ma hsa-miR-483-5p) na faʻasalaina ma valu (hsa-miR-15b-5p, hsa-miR-26b-5p, hsa-miR-29b-3p, hsa-miR-125b-5p, hsa-miR-200c-3p, hsa-miR-337c-5p, hsa-miR-411-5p, ma hsa-miR-652-3p) na faʻalaloina i le vaega IGD.

Laulau 2

Fa'aaliga eseese microRNAs (miRNAs) ma suiga gaugau.

miRNAmauagaAloaiaTuufaatasi
 
 P-valueGagau suigaP-valueGagau suigaP-valueGagau suiga
hsa-miR-15b-5p0.0330.8290.6941.1190.3810.947
hsa-miR-26b-5pa0.0080.8710.0490.8410.0130.857
hsa-miR-29b-3p0.0050.4000.5601.1870.0890.647
hsa-miR-125b-5p0.0210.5820.2900.9500.0690.723
hsa-miR-200c-3pa0.0110.3360.0030.5422.93 × 10-50.415
hsa-miR-337c-5p0.0090.3850.5820.8720.0200.553
hsa-miR-411-5p0.0040.3220.3361.2820.1580.595
hsa-miR-423-5p0.0261.3870.1890.9550.5181.175
hsa-miR-483-5p0.0181.8610.7651.4130.2111.647
hsa-miR-652-3pa0.0190.7150.0490.8770.0110.782
 

amiRNAs matua suia i le mauaina ma faʻamaonia seti i se faiga faifai pea.

 

O se faila i fafo o loʻo uuina se ata, faʻataʻitaʻiga, ma isi igoa. Object object o le fpsyt-09-00081-g001.jpg

Tulaga fa'aaliga fa'atusa o 10 fa'aaliga fa'aalia miRNA. Fa'atusatusaga fa'atatau (RQ) na fa'amanino i le miR-374b-5p.

qRT-PCR Fa'amaonia o le sui tauva miRNAs

Ina ia faʻamaonia le 10 sui miRNAs, matou te faia le qRT-PCR faʻatasi ai ma se seti faʻamaonia tutoʻatasi (20 IGDs ma 16 pule) (Table S1 i Mea Faʻaopoopo). Tolu o nei miRNAs (hsa-miR-200c-3p, hsa-miR-26b-5p, ma hsa-miR-652-3p) na matua faʻaititia i le IGD vaega o le seti faʻamaonia (Laulau). (Table2) .2). E tolu isi miRNAs (hsa-miR-337c-5p, hsa-miR-125b, ma le hsa-miR-423-5p) na faʻalaloina foi i le vaega IGD ae le o se mea taua. O totoe miRNA e fa (hsa-miR-15b-5p, hsa-miR-29b-3p, hsa-miR-411-5p, ma hsa-miR-423-5p) na faʻaalia faʻafeagai i le seti faʻamaonia. Ina ua matou tuʻufaʻatasia le suʻesuʻeina ma faʻamaonia seti (o le aofaʻi o 45 IGD mataupu ma 42 faʻatonuga), o le tolu faʻamaonia miRNAs sa taua tele (Laulau). (Table2) .2). O faʻamatalaga auʻiliʻili, nofoaga o chromosomal, faʻasologa matutua, ma faʻaaliga faʻaalia i le CNS o nei miRNA e tolu o loʻo maua ile Laulau S2 ile Mea Faʻaopoopo.

Aafiaga Synergistic o Suiga Faʻatasi o le tolu miRNA i luga ole IGD Risk

Ina ia iloilo le aʻafiaga tuʻufaʻatasia o miRNA e tolu, na matou matauina le faʻatusatusaina o faʻatusatusaga (ORs) o vaega laiti e fa (faatasi ai ma 0, 1, 2, poʻo 3 miRNA suiga). MiRNA suiga na faʻamatalaina e le RQ tau e pei ona faʻamatalaina i le Vaega "Mea ma Metotia.” Talu ai ona o faʻailoga miRNA uma e tolu na faʻatulafonoina i le vaega IGD, o se miRNA o loʻo i lalo ifo o le tasi le tau o le RQ na teteʻeina e pei o se suiga. O fa'amatalaga au'ili'ili o mata'upu su'esu'e ta'itasi RQ tau mo miRNA e tolu o lo'o maua ile Laulau S3 ile Mea Fa'aopoopo. Mo vaega laiti taʻitasi, o faʻalavelave na faʻatatauina o le fua faatatau o numera o faʻatonuga i le IGDs, ona faʻatatauina lea o OR taʻitasi e ala i le vaevaeina o faʻalavelave o vaega taʻitasi e ala i faʻalavelave o le vaega laiti e aunoa ma ni suiga miRNA. O tagata taʻitoʻatasi e tolu suiga o le miRNA na faʻaalia se lamatiaga 22 taimi maualuga atu nai lo i latou e leai se suiga o le miRNA (OR 22, 95% CI 2.29-211.11). ORs na faʻaalia le faʻatupulaia o faʻataʻitaʻiga ma le numera o miRNA ua suia mai le 0 i le 3 (r2 = 0.996) (Ata (Figure22).

O se faila i fafo o loʻo uuina se ata, faʻataʻitaʻiga, ma isi igoa. Object object o le fpsyt-09-00081-g002.jpg
Odds ratios (ORs) i le numera o fa'ailoga microRNA (miRNA) fa'alalolalo. O tau o lo'o i luga a'e o fua fa'atatau o ORs (95% taimi fa'alagolago).

GO ma Ala Su'esu'ega o Genes Sini o le sui tauva miRNAs

Ina ia maua se faʻamatalaga i galuega a le tolu miRNA faʻailoga e matua faʻaititia i le IGD vaega, o latou kenera taulaʻi na valoia e faʻaaoga ai le miRWalk 2.0 database (). Ole aofaʻi ole 1,230 genes na faʻaalia i taimi uma e avea ma faʻataʻitaʻiga pito i lalo e fa algorithms (miRWalk, miRanda, RNA22, ma Targetscan) faʻaaogaina le miRWalk database (-) (Laulau S4 i Mea Faaopoopo). O suʻesuʻega faʻatamaoaigaina faʻatupu faʻasologa e faʻaaoga ai ToppFun i ToppGene Suite na faʻaalia ai o kenera taulaʻi o na miRNA na matua fesoʻotaʻi ma auala faʻaleleia neural e pei o le "Axon guide" ma GO faaupuga e pei o le "neurogenesis" (Table S5 i Mea Faʻaopoopo).

Fa'aaliga o Kenera Fa'atatau

Faatasi ai ma genes taulaʻi i lalo o le tolu miRNA, 140 na valoia i le taimi e tasi mo le lua pe sili atu miRNAs (Table S4 i Mea Faʻaopoopo). Ina ia suʻesuʻe pe o latou faʻaaliga faʻapolotini maualuga o kenera taulaʻi i lalo e eseese i le va o le IGD ma vaega faʻatonutonu, matou te filifilia 2 genes (DUSP4 ma PI15), lea o loʻo valoia e avea ma sini pito i lalo o 3 miRNA uma ma faʻaopoopoga 3 genes (GABRB2, DPYSL2, ma CNR1) mai i latou na valoia mo 2 miRNAs ma faia suʻesuʻega i sisifo ma faʻataʻitaʻiga plasma mai 28 IGDs ma 28 faʻatonutonu avanoa mo le suʻega. Na matou faʻatusatusaina faʻamatalaga o sini e lima i le va o le IGD ma vaega faʻatonutonu e ala i le fuaina o le malosi faʻaili ma le eria e pei ona faʻamatalaina i isi mea (). Faatasi ai ma i latou, o tulaga faʻaalia o le DPYSL2 (28 IGDs ma le 28 pule, P = 0.0037) ma GABBR2 (27 IGDs ma 28 pule, P = 0.0052) na sili atu le maualuga i le IGD vaega (Ata (Figure3) .3). Ae ui i lea, e le mafai ona matou matauina faʻamatalaga eseese o le CNR1 (P = 0.0853), DUSP4 (P = 0.5443), ma le PI15 (P = 0.6346).

 

O se faila i fafo o loʻo uuina se ata, faʻataʻitaʻiga, ma isi igoa. Object object o le fpsyt-09-00081-g003.jpg

Western blot images ma pusa-dot-plots fa'aalia fa'aaliga o (A) DPYSL2 ma (B) GABRB2. O le DPYSL2 ma le GABRB2 proteins na faʻaalia ai le tele o eseesega i latou tulaga faʻaalia i le va o le Initaneti taʻaloga taʻaloga (IGD) ma faʻataʻitaʻiga faʻataʻitaʻiga (P-taua <0.05). O palatini e lua na faʻaalia i tulaga maualuga i faʻataʻitaʻiga IGD.

Talanoaga

Ua lipotia mai o miRNA o loʻo aʻafia i le atinaʻeina o neuronal (, ), ma faʻaaliga eseese o faiʻai miRNA o loʻo matauina i faʻamaʻi faʻapitoa e pei ole schizophrenia (). O le mea lea, e talafeagai le faʻasalalauina o faʻamatalaga miRNA e mafai ona avea ma faʻamatalaga aoga mo le IGD. O miRNA faʻasalalau ua fautuaina e fai ma faʻailoga mo faʻafitauli eseese o le neuropsychiatric (-); ae ui i lea, o le molecular mechanisms i tua atu o le atinaʻeina o le IGD e tele lava ina le iloa e ui lava i lona taua ile falemaʻi ma agafesootai. Aemaise lava, e leai ni suʻesuʻega i luga ole IGD-sociated miRNAs. O le sini o lenei suʻesuʻega e lua. Muamua, na matou taumafai e suʻe plasma miRNAs e fesoʻotaʻi ma IGD. Lona lua, na matou iloiloina le faʻaogaina o meaola o sui o le miRNA e ala i le suʻesuʻeina o faʻamatalaga porotini ma le GO o faʻasologa o loʻo i lalo. E ala i le suʻesuʻeina o genome-lautele o faʻamatalaga faʻamatalaga o le miRNA ma faʻamaoniga i lalo o sui tauva, na matou iloa ai o faʻamatalaga o miRNA e tolu (hsa-miR-200c-3p, hsa-miR-26b-5p, ma le hsa-miR-652-3p) sa matua maualalo i IGD maʻi nai lo pule. E ui lava o faʻataʻitaʻiga faʻataʻitaʻiga o isi sui e fitu miRNA e leʻi toe faʻaaogaina i le faʻamaoniga, e mafai ona sese le leaga ona o le laʻititi laʻititi laʻititi i lenei suʻesuʻega. I lo matou iloa, o le lipoti muamua lea i luga o le ono mafai ona avea faʻamatalaga faʻamatalaga toto miRNA e mafai ona aoga biomarkers mo IGD. O le tuʻufaʻatasia o faʻailoga miRNA e tolu e mafai ona avea o se meafaigaluega faʻalavelave faʻafuaseʻi mo le vave iloa o tagata e lamatia i le IGD.

O miRNA na faʻaalia i lenei suʻesuʻega ua lipotia mai e aʻafia i faʻafitauli eseese o le neuropsychiatric. O le faʻaalia o le hsa-miR-200c i totonu o le toto ua lipotia mai e faʻaititia i le tele o faʻafitauli o le mafaufau e pei o le schizophrenia () ma vaega tetele o le atuatuvale (). miR-200c na lipotia mai e sili atu ona faʻaalia i vaega ninii synaptic nai lo le aofaʻi atoa o le muai () ma e fa'apea fo'i ona feso'ota'i ma le oti o sela neura (). Faʻavae i luga o nei lipoti talu ai, o le miR-200c o loʻo aʻafia i le neurodevelopment ma e mafai ona fesoʻotaʻi ma faʻafitauli o le neuropsychiatric pe a faʻalavelave lona faʻaaliga. E tele suʻesuʻega ua fautuaina ai le fesoʻotaʻiga i le va o le miR-652 ma le lamatiaga o faʻafitauli o le neuropsychiatric. E tutusa ma la tatou auala, e iloa ai biomarkers toto mo schizophrenia, Lai et al. faia suʻesuʻega TLDA faʻatasi ma maʻi schizophrenia ma faʻatonuga masani, ma maua ai e fitu miRNAs e aofia ai le hsa-miR-652 na faʻaalia eseese i tagata maʻi schizophrenia (). I le suʻesuʻega mulimuli ane, na latou mamanuina se faʻataʻitaʻiga faʻataʻitaʻiga e faʻaaoga ai faʻamatalaga faʻamatalaga miRNA ma faʻamaonia lelei le schizophrenia mai le pulea masani (). O le suiga o le faʻaaliga o le hsa-miR-652 na matauina foi i le ava malosi (). Hsa-miR-26b na maua e faʻagaoioia i le taimi o le eseesega o sela neuronal (). Perkins et al. lipotia mai o le hsa-miR-26b na faʻaititia i le pito i luma o le faʻamaʻi o tagata maʻi schizophrenia ().

E ui lava e leai se faʻamaoniga tuusaʻo e lagolago ai le sootaga i le va o le faʻalavelave faʻaalia o nei miRNAs ma le pathophysiology o le IGD, e mafai ona tatou faʻapea o le dysregulation o nei miRNAs e mafai ona fesoʻotaʻi ma le pathophysiology o le IGD e faʻavae i luga o lipoti muamua i luga o genes lalo ifo na tatou valoia. . O nisi o kenera i lalo ole tolu miRNA pei ole GABRB2, CNR1, NRXN1, ma DPYSL2 o loʻo lipotia mai e fesoʻotaʻi ma faʻafitauli o le neuropsychiatric. Gamma-aminobutyric acid (GABA) o se neurotransmitter inhibitory tele i le CNS. Disregulation o le GABA receptor, o loʻo aʻafia i faʻafitauli o le neuropsychiatric e aofia ai vaisu, popole, ma le atuatuvale (), o vaega autu foi ia o le IGD (). Genetic polymorphisms i GABA receptor genes ua lipotia mai e fesoʻotaʻi ma vaisu o le ava ma le schizophrenia (, ). Dihydropyrimidinase-like 2 (DPYSL2) o se sui o le collapsin response mediator protein family, lea e taʻalo i le microtubule faʻapotopotoga, faʻailoga synaptic, ma le faʻatonutonuina o le tuputupu aʻe o le axonal. O lea la, o lenei mole mole ua fautuaina e avea o se biomarker mo faʻafitauli o le mafaufau (, ). Polymorphism i le DPYSL2 na lipotia mai foi le kenera e fesootaʻi ma le faʻaaogaina o le ava malosi (). O lipoti talu ai ma a matou faʻamatalaga o loʻo fautua mai ai o le faʻaalia o le GABRB2 ma le DPYSL2, faʻataʻitaʻiga pito i lalo o miRNAs lalo ifo, ei ai aʻafiaga mo le faʻamaʻiina o faʻafitauli o le neuropsychiatric e aofia ai le IGD. Cannabinoid receptor type 1 (CNR1) o se presynaptic heteroreceptor lea e faʻaogaina ai le tuʻuina atu o le neurotransmitter ma faʻalavelave i faʻailoga cannabinoid e fesoʻotaʻi ma faʻalavelave neuropsychiatric eseese (). Genetic polymorphism o CNR1 ua iloa le kenera e feso'ota'i ma le fa'alagolago i vaila'au i Caucasians (). I se faʻataʻitaʻiga o isumu, o le faʻagaoioia o le ventral hippocampus CNR1 e faʻalavelaveina amioga masani masani ma le malamalama (). O suiga fa'aletagata i le aiga NRXN ua iloa e a'afia i fa'afitauli eseese o le neuropsychiatric e aofia ai vaisu ().

Ina ia suʻesuʻeina le faʻaogaina o meaola o sui e tolu miRNA i se auala sili atu ona tuusaʻo, na matou suʻesuʻeina le faʻamatalaga o le polotini o latou kenera taulaʻi lalo. Ona o le faʻatapulaʻaina o le maua o faʻataʻitaʻiga plasma, o le 140 masani sui tauva (valoʻaina o lalo ifo o le 2 pe sili atu miRNAs), na matou suʻesuʻeina 5 sini (GABRB2, DPYSL2, CNR1, DUSP4, ma PI15) e ala i sisifo ma faʻamaonia lena faʻamatalaga o GABRB2. ma le DPYSL2 na sili atu le maualuga i le vaega IGD. O lipoti talu ai ma a matou faʻamatalaga o loʻo fautua mai ai o le faʻaalia o le GABRB2 ma le DPYSL2, faʻataʻitaʻiga pito i lalo o miRNAs lalo ifo, e ono i ai ni aʻafiaga mo le faʻamaʻiina o faʻafitauli o le neuropsychiatric e aofia ai le IGD. O taunuʻuga o le GO ma le suʻesuʻeina o auala o auala atinaʻe neural e lagolagoina ai le neurobiological implication o faʻailoga miRNA. O le isi suʻesuʻega mataʻina o le aʻafiaga faʻatasi o suiga faʻatasi o miRNAs. O tagata taʻitoʻatasi o loʻo i ai le faʻatonutonuina o 3 miRNA uma na faʻaalia le 22 taimi sili atu le lamatiaga nai lo i latou e leai ni faʻatonuga, ma o le ORs na faʻateleina i se fua faʻalagolago. E ui o le CI mo nei suiga e tolu na lautele ona o le faʻatapulaʻaina o le lapoʻa faʻataʻitaʻiga, o le faʻamaonia manino lelei (r2 = 0.996) e lagolagoina le aʻafiaga faʻatasi o miRNA e tolu.

E ui lava na matou mauaina faʻailoga miRNA e fesoʻotaʻi ma le IGD ma tagata taʻitoʻatasi ma suiga uma miRNA e tolu na i ai se lamatiaga 22 taimi maualuga atu nai lo i latou e aunoa ma ni suiga miRNA, e tele tapulaa i lenei suʻesuʻega. Muamua, o le laʻititi laʻititi laʻititi na faʻateleina ai le avanoa e misi ai isi faʻailoga taua miRNA. Lona lua, talu ai e leʻi lava a matou faʻamatalaga e faʻamalamalama ai pe o le plasma miRNA profiles o se mafuaʻaga poʻo se aʻafiaga, e le mafai ona matou faʻamaonia matafaioi faʻapitoa o nei faʻailoga e le faʻaleagaina i se falemaʻi. O isi fa'amatalaga miRNA ma a latou su'esu'ega o gafa i lalo e fa'aaoga ai le fai'ai o le tagata mai le faletupe o le fai'ai e mafai ona maua ai se tali sa'o. Ole su'esu'ega ole fai'ai fa'atasi ai ma se fa'ata'ita'iga manu fa'aletonu ta'aloga e fesoasoani fo'i. Lona tolu, ona o le utiuti o le maua o faʻataʻitaʻiga plasma, na matou suʻesuʻeina naʻo le lima molelaula sui tauva i lalo. O le su'esu'eina atili o fa'amoemoega i lalo ma se seti fa'ata'ita'iga tele o le a fesoasoani e malamalama atili ai i le masini mole mole o le IGD.

I le aotelega, e ala i le suʻesuʻeina o genome-lautele o faʻamatalaga faʻamatalaga o le miRNA ma le faʻamaonia tutoatasi, na matou maua ai ni miRNA e tolu IGD (hsa-miR-200c-3p, hsa-miR-26b-5p, ma le hsa-miR-652-3p). O le tele o latou genes i lalo o loʻo lipotia mai e aʻafia i faʻafitauli eseese o le neuropsychiatric, ma faʻamaonia faʻataʻitaʻiga o suiga faʻaalia o nei kenera i lalo e lagolagoina le aʻafiaga o miRNA o loʻo faʻaalia i lenei suʻesuʻega. Na matou iloa o tagata taʻitoʻatasi o loʻo i lalo le tulafono ole tolu miRNA e maualuga le lamatiaga ole IGD. Faʻatasi ai ma faʻafitauli faʻapitoa faʻapitoa poʻo le siosiomaga ma faʻataʻitaʻiga faʻataʻitaʻiga, oa tatou suʻesuʻega e mafai ona faafaigofieina vave fesoasoani e fesoasoani ai i tagata e maualuga atu le lamatiaga o le IGD.

Talosaga Tetele

O lenei suʻesuʻega na faʻamaonia e le Komiti Faʻatonu Faʻatonu a le Kolisi Faafomai a le Iunivesite Katoliko o Korea (MC16SISI0120). O tagata uma na auai ma o latou matua na tuuina atu le maliega tusitusia.

Tusitala Tusitala

ML ma HC e tutusa le sao i lenei pepa. ML, D-JK, ma Y-JC na fuafuaina le suʻesuʻega. SJ, S-MC, YP, DC, ma JL na faia faʻataʻitaʻiga ma faʻamaumauga faʻamaumauga. O le J-WC, S-HP, J-SC, ma le D-JK na aoina mai faʻataʻitaʻiga toto ma faʻamatalaga falemaʻi. ML, HC, S-HY, ma le Y-JC su'esu'e fa'amaumauga. ML, HC, S-HY, ma Y-JC na faʻamatalaina tusitusiga. Na vaavaaia e le Y-JC le poloketi.

Feteʻenaʻiga o Tupulaga e Tetee ai

Fai mai tusitala o le suʻesuʻega sa faia i le leai o soʻo se fefaʻatauaʻiga faʻapisinisi pe tau tupe e mafai ona avea o se feteenaʻiga e ono aʻafia ai.

Faamatalaga Faʻamatalaga

 

Faatupeina. O lenei galuega na lagolagoina e se fesoasoani mai le Brain Research Program e ala i le National Research Foundation of Korea (NRF), faʻatupeina e le Matagaluega o Saienisi ma ICT ma Fuafuaga o le Lumanai (NRF-2015M3C7A1064778).

 

 

Faaopoopoga mea

O Mea Faaopoopo mo lenei tusiga e mafai ona maua i luga ole laiga ile http://www.frontiersin.org/articles/10.3389/fpsyt.2018.00081/full#supplementary-material.

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