Jenetik Osteopontin nan pasyan ki gen maladi ren kwonik: etid Alman sou maladi ren kwonik
Jun 07, 2024
Résumé
Remèd fèy òganik pou sante ren
Entwodiksyon
Osteopontin (OPN) kode pa jèn SPP1 la te premye dekri kòm yon glycoprotein ki fè pati fanmi SIBLING (Small Integrin-Binding LIgand N-linked Glycoprotein) an 1985 [1]. OPN eksprime nan yon pakèt tisi tankou osteoblast, osteosit, odontoblast (jwe yon wòl nan mineralizasyon ak resorption zo [2,3]), makrofaj, selil misk lis, ak selil andotelyal, men yo ka jwenn tou nan zòrèy enteryè a, sistèm nève santral, ak plasenta a [1,2]. Malgre ke OPN ka detekte nan anpil kalite selil li se sitou sentèz ak eksprime nan tisi ren. Pwodiksyon OPN ankouraje pa anpil faktè ki gen ladan òmòn paratiwoyid, kalsitriol, kalsyòm, fosfat, ak sitokin. Pwoteyin nan ka mare entegrin atravè yon sekans peptide espesifik, motif arjinin-glycine-aspartic acid (RGD), ki fè entèraksyon ak divès kalite selil posib (atravè chemen kappa B nan faktè nikleyè, [4,5]). Nan ren an, yo ka jwenn entegrin nan kapsil Bowman a, epithelium glomerulèr ak epithelium vaskilè [6,7]. OPN se sentèz nan branch epè monte bouk Henle a ak tib distal la [1,8].
Nan yon revizyon Kaleta (2019), li te ye (pato) wòl fizyolojik nan OPN yo te diskite [1]. Ki baze sou revizyon sa a, wòl fizyolojik OPN nan ren an pa fin konprann ankò, men li te sijere kòm esansyèl pou tubulogenesis [1]. SPP1 mRNA osi byen ke ekspresyon pwoteyin OPN yo te elve nan modèl sitou rat nan maladi ren ak ekspresyon OPN segondè ki gen rapò ak proteinuria, fonksyon ren redwi, ak fibwoz [1]. Yon etid te idantifye divès polimorfism nan rejyon pwomotè SPP1 ki afekte aktivite transcription li yo [9]. Nan tan lontan, plizyè varyant espesifik jèn SPP1 yo te asosye ak patojèn ak pwogresyon diferan maladi ren. Lòt etid ka-kontwòl rapòte sou varyant espesifik nan jèn SPP1 ki asosye ak diferan pasyan maladi ren an konparezon ak yon gwoup kontwòl (sante): Pou egzanp, rs1126616 te repete rapòte kòm yon makè pou nefrit lupus ak imunoglobulin A nefropati [10– 14]. An koneksyon avèk nefropati dyabetik, de SNP yo nan SPP1, rs11730582 ak rs17524488, yo te rapòte [15,16]. Se poutèt sa, nou te rezone ke prezans nan fonksyon ren redwi ka reprezante yon bon anviwònman etid pou etabli plis konpreyansyon nou sou baz jenetik nivo OPN nan maladi ren, kòm kèk mekanis byolojik ta ka ogmante e konsa pi fasil pou detekte, yo te montre anvan [17–19]. Nan Jing et al. [19], pou egzanp, mayitid efè pou loci li te ye yo idantifye nan yon GWAS nan urat serom nan pasyan CKD yo te nan menm jan an oswa pi wo mayitid pase sa yo rapòte nan etid ki baze sou popilasyon an. Etid Alman maladi ren kwonik (GCKD) gen ladan yon gwo kòwòt pasyan CKD [20]. Anplis done demografik ak klinik, done jenetik yo disponib ansanm ak mezi debaz nan OPN serik, ki bay yon anviwònman ideyal pou eksplore jenetik OPN. Pou rezon sa a, nou te fè yon GWAS nan nivo OPN serik nan etid GCKD la
Rezilta Deskripsyon seri analiz GCKD la
Tablo 1 bay yon apèsi sou karakteristik debaz yon kantite varyab chwazi pou kowòt etid GCKD konplè a ak seri analiz GWAS kote patisipan yo ak done konplè sou jenetik, mezi OPN ansanm ak to filtraj glomerulè (eGFR), ak albumin urin. -a-kreyatinin rapò (UACR) yo enkli (S1 Fig). Pa te gen okenn gwo diferans ant kòwòt konplè a ak seri analiz la. An jeneral, seri analiz GWAS la te karakterize pa yon pwopòsyon 60% gason ak yon laj mwayèn 6{{10}}.2 ane (SD: 12.0) , ak valè medyàn nan 46.0 mL / min / 1.73m2 (p25: 37.0; p75: 57.0) pou eGFR ak nan 50.2 mg / g (p25: 9.4; p75: 382.8) pou UACR (Tablo 1). Pami patisipan yo enkli, 35% te gen yon dyabèt melitus, 16% te fimè ak 30% te rapòte yon istwa maladi kadyovaskilè (CVD). Nivo OPN medyàn nan kòwòt konplè a te 29.2 ng/mL (p25: 20.7; p75: 41.9; Tablo 1). Nivo OPN ogmante an mwayèn atravè kategori eGFR ak kategori UACR soti nan yon medyàn nan 25.4 ng/mL pou etap CKD G1/2 rive nan 38.5 ng/mL pou etap CKD G4/5, osi byen ke nan valè OPN medyàn nan 25.6 ng/mL. pou etap UACR A1 vle di valè OPN nan 34.2 ng / mL pou etap UACR A3 (S2 Fig).
Etid asosyasyon nan tout genòm ak amann kat
Nou te fè yon GWAS pou nivo OPN serik (log{{0}}transfòme) lè l sèvi avèk ~ 7.7 milyon varyant otosomal bi-allelic nan etid GCKD ak yon frekans alèl minè (MAF) nan �0.01 (S1). Tablo). Konplo quantile-quantile konpare valè p obsève ak espere nan OPN GWAS la pa t endike enflasyon (faktè enflasyon λ=1.01), ki konsistan avèk absans erè sistematik (S3 Fig). An jeneral, konplo Manhattan te revele twa rejyon enpòtan nan tout genòm ki asosye ak nivo OPN (valè p<5.0E-08; S4 Fig). Besides the three identified regions, the conditional analysis did not reveal additional independent signals (S5 Fig). The respective association results for the three index SNPs (= SNP with the lowest p-value in the respective region) are presented in Table 2. For all three SNPs, the coded allele was present frequently (allele frequency range 0.5– 0.75). The respective coded allele in our cohort decreased OPN levels on average (S6 Fig) with effect estimates per copy of the coded allele ranging from -0.10 to -0.18 (SE: 0.01–0.02; Table 2). One of the index SNPs on chromosome 4 (rs10011284, 4:88833389) is located upstream of SPP1, which encodes the protein OPN itself (Fig 1A). The other index SNP on chromosome 4 (rs4253311, 4:187174683) maps into the KLKB1 gene (intronic variant), encoding the protein prekallikrein (PK) that is converted to kallikrein (KAL); a protease implicated in the surface-dependent activation of coagulation, bradykinin (BK) release, and potentially the renin-angiotensin-aldosterone system (Fig 2A). The index SNP on chromosome 5 (rs2731673, 5:176839898) maps closest to the F12 gene, which encodes coagulation factor XII, a serine protease that cleaves KLKB1-encoded PK to KAL, among other functions and is also related to blood coagulation, fibrinolysis, and the generation of BK (S7 Fig). A summary of annotations combined from different publicly accessible databases and related to all three SNPs is provided in S2 Table. We next tested whether these three index SNPs were associated with serum OPN levels in the Young Finns Study (YFS) cohort, a population-based study with a mean age of 38 years (SD: 5.0) and a mean eGFR of 92.6 mL/min/1.73m2 (SD: 20.7; S1 Methods). Both SNPs on chromosome 4, rs10011284 and rs4253311, were significantly associated with OPN levels showing also direction consistency (Table 2 and Figs 1B and 2B). In contrast, rs2731673 closest to the F12 gene did not replicate in the YFS cohort (S7 Fig). The two replicated SNPs on chromosome 4 explained 1% of OPN levels each within the GCKD study and did not show a non-additive effect on OPN levels (S8 Fig). Moreover, statistical fine-mapping was performed for the two replicated loci to resolve associated loci into potentially causal variants by constructing credible sets that collectively accounted for a 99% posterior probability of containing the variant or variants that cause the association signal (PPA; Material and methods, [21]). However, fine-mapping results are inconclusive as both constructed sets are large, and single variants included only exhibit low PPA estimates (S3 Table)
Analiz kolokalizasyon
Pou aprann plis sou mekanis molekilè ak fenotip ki asosye ki kache siyal asosyasyon yo idantifye pou OPN, nou konpare modèl rezilta OPN GWAS nan rejyon predefini ak estatistik rezime GWAS respektif ki soti nan twa lòt sous lè l sèvi avèk done imen (al gade nan Materyèl ak metòd pou plis detay). Modèl konparab yo ka endike yon baz byolojik komen.
Ekspresyon jèn. Premyèman, nou te fè analiz colocalisation nan OPN GWAS rezime estatistik ki gen rapò ak de repwodwi loci yo ak korespondan GWAS rezime estatistik ekspresyon jèn nan cis lè l sèvi avèk done ki sòti nan pwojè GTEx ak etid NEPTUNE.
(Material and methods). Colocalization (posterior probability of H4 [p12] >0.8) of the OPN association signals were detected with the expression of MEPE in the lung (Fig 3A) and of SPP1 in the pancreas (Fig 3B and S4 Table). Furthermore, colocalization was found between the OPN association signal and expression of F11 in six other tissues (in descending order of H4): tibial artery (Fig 3C), brain cortex, terminal ileum part of the small intestine, muscular of the esophagus, transverse colon, and aortic artery (S4 Table). Except for the colocalization of the OPN signal with an expression of MEPE in the lung, the effect direction of both traits (OPN and gene expression) was concordant (alpha12>0; S4 Tablo). Plasma pwoteòm. Anplis de sa, analiz kolokizasyon yo te fèt lè l sèvi avèk estatistik rezime GWAS nan asosyasyon SNP nan cis ak nan trans ak nivo ~ 3, 000 diferan pwoteyin plasma (pGWAS) rapòte pa Sun et al. (Materyèl ak metòd, [22]). Pandan ke pa gen okenn colocalization prezan pou estatistik rezime GWAS nan OPN ak pwoteyin nan cis, rezilta pGWAS pou 87 pwoteyin ki soti nan divès klas pwoteyin yo te jwenn trans colocalize ak rezilta OPN GWAS pou rs4253311 nan KLKB1 (S5 Table). Pou majorite rezilta colocalisation
Fig 3. Konpare estatistik rezime soti nan OPN GWAS ak tisi GTEx colocalizing: (A) MEPE: OPN ak tisi nan poumon (H4: p12=0.99), (B) SPP1: OPN ak pankreyas (H4: p{{ 6}}.85); (C) F11: OPN ak atè tibial (H4: P12=0.98). Goch: simaye dispèsyon ki konpare valè p asosyasyon ki soti nan tou de sous youn kont lòt (echèl -log10). Anwo adwat: rezilta OPN GWAS pou rejyon ki enterese a. Anba adwat: rezilta GTEx GWAS pou rejyon enterè ògàn respektif la. Koulè reflete korelasyon LD (r2) lè l sèvi avèk popilasyon 1000G EUR kòm referans.
(60/87, 69%), direksyon an efè nan OPN ak pwoteyin te konkordan, ki se pa lefèt ke KKS a aktive patisipe nan yon gwo spectre nan pwosesis, tankou enflamasyon, kansè, maladi kadyovaskilè, osi byen ke (patho). )wòl fizyolojik nan ren ak sistèm nève santral la. Pou pwoteyin kat 86 yo, yo te fè yon analiz anrichisman Gene Ontology (GO) pou evalye si jèn kodaj yo te anrichi an tèm ki reprezante konpozan selilè espesifik ak fonksyon molekilè (Materyèl ak metòd, Tablo S6). Akòz yon estrikti yerarchize nan lis referans, tèm ki enplike yo depann pasyèlman youn sou lòt ki montre egzanp sipèpoze fonksyon molekilè regilasyon ak aktivite òmòn ak reseptè regilasyon (S9 Fig).
Maladi UK Biobank (UKB).
To address the interplay between genetic modulation of OPN levels and phenotypes we further conducted a colocalization analysis with binary UKB disease traits that showed a genome-wide significant association in the GeneAtlas resource [23]. Based on marginal association statistics, no positive colocalization was detected between OPN and various disease traits (S7 Table). Still, for four of seven traits with an association signal different from the OPN signal in the region (H3: p1.2>0.8), yo te detekte yon dezyèm siyal asosyasyon endepandan pou karakteristik maladi respektif la nan UKB. Lè sa a, nou te fè analiz colocalisation adisyonèl ki baze sou estatistik yo jwenn asosyasyon kondisyonèl ak idantifye yon kolokizasyon pozitif ant siyal la asosyasyon OPN nan rs4253311 nan locus KLKB1 ak rs1593 pou tronboz venn gwo twou san fon (DVT; H4: p12=0.96; S7). Tablo ak S10 Fig). Nan GeneAtlas GWAS nan DVT, pi gwo alèl rs1593 (A, frekans alèl=0.87) te asosye ak yon pi gwo risk pou DVT (OSWA=1.2, p-valè 2.4e{{ 18}}), menm jan ak pi gwo alèl rs4253311 (pi gwo alèl: G, frekans alèl=0.51, OSWA=1.13, p-valè=2.6e{{27 }}).
