Cov noob caj noob ces ntawm Osteopontin hauv cov neeg mob uas muaj kab mob raum tsis zoo: German Chronic Kidney Disease Study Ⅳ
Jun 11, 2024
Plasma proteome
Tsis tas li ntawd, peb siv GWAS cov txheeb cais cov ntsiab lus ntawmplasma proteins(pGWAS) by Sun et al. [22] los khiav colocalization tsom xam los txheeb xyuas cov teeb liab sib xws ntawm OPN thiab cov proteins nrog cov teebmeem hauv cis thiab hauv trans. Hauv kev sib piv rau cov ntaub ntawv los ntawm GTEx thiab NephQTL, genome-wide muaj pGWAS cov ntsiab lus tso cai rau kev ntsuam xyuas ntawm ob qho tib si. Txhawm rau txheeb xyuas colocalization nrog cis-pQTLs, pGWAS cov ntsiab lus cov txheeb cais ntawm ib cheeb tsam pro-tein-gene (gene region ± 500kb, cis region) tau muab rho tawm. Raws li OPN qhov chaw thiab thaj tsam 100kb nyob ib puag ncig nws, peb tau kuaj xyuas yog tias ib qho ntawm cis pGWAS rho tawm sib tshooj thiab muaj lub koom haum pGWAS p-tus nqi ntawm<0.05/2 (Bonferroni correction for two OPN loci). For all hereby selected proteins, we then extracted the protein-gene-region from the OPN GWAS summary statistics and ran colocalization within the protein-gene-region. For potential colocalization with trans-pQTLs, we selected all proteins with pGWAS association p-values <0.05/2/3,000 (Bonferroni correction for the two OPN loci and number of proteins evaluated in pGWAS) within a 100kb region around an OPN-associated index SNP. For all hereby selected proteins, colocalization analyses were conducted within the ±500kb region of the OPN-associated index SNP.
Organic Health Food For raum Health
Rau colocalizing proteins, ib tug Gene ontology (GO) enrichment tsom xam (http://geneontology. org/, [101,102]) nyob rau hauv daim ntawv ntawm ib tug PANTHER [103] overrepresentation xeem nrog ob annotation cov ntaub ntawv teev ntawm GO cellular tivthaiv thiab GO molecular muaj nuj nqi (homo sapiens) raws li cov ntaub ntawv tau ua los ntsuas cov khoom muaj txiaj ntsig uas tau txheeb xyuas cov proteins raug muab rau. Zuag qhia tag nrho, 20,595 tib neeg cov noob tau piav qhia rau ntau cov ntsiab lus ntsig txog cov khoom siv ntawm tes thiab kev ua haujlwm molecular. Ib qeb yog suav tias muaj kev nplua nuj yog tias ob qho tib si, Bonferroni-kho p-tus nqi ntawm Fisher qhov kev xeem thiab qhov kev tshawb pom tsis tseeb raws li Benjamini-Hochberg tus txheej txheem, yog<0.05
UKB cov kab mob. Thaum kawg, peb siv GWAS los ntawm GeneAtlas database (http://geneatlas. Roslin.ed.ac.uk/) los ua colocalization tsom xam rau ob replicated OPN loci (± 500kb) thiab tag nrho UKB binary kab mob zoo uas pom genome- cov koom haum tseem ceeb (p-value<5.0E-08) in at least one of the two replicated OPN loci. Overall, GeneAtlas comprises GWAS results of 660 binary disease traits of ~450,000 UKB participants [23]. In addition, we adopted the conditional colocalization analysis approach which was first applied in a GWAS of plasma proteome [104].
Performing colocalization on conditionally independent association statistics could reveal true colocalization signals that were missing when using marginal association statistics in the presence of multiple independent association signals. We applied the GCTA COJO Slct algorithm to identify independent association signals in the OPN region for the seven traits [105], which showed a trait association signal different from the OPN signal (H3: p1.2>{{0}}.8). Cov ntaub ntawv uas tau muab ntxuav thiab imputed GCKD genotype tau hais ua ntej tau siv los ua LD siv los ntawm GCTA. Peb teem lub collinearity txiav tawm ntawm 0.1 los ua conservative. Rau loci nrog ntau tshaj 1 lub teeb liab ywj siab, kwv yees qhov kev ntsuas ntsuas tau ua los ntawm GCTA COJO-Cond algorithm los tsim kom muaj kev koom tes nrog cov txheeb cais uas tau teev tseg rau lwm tus SNPs hauv cheeb tsam [105]. Thaum kawg, kev txheeb xyuas colocalization tau ua raws li ua ntej rau txhua tus SNPs ywj siab siv cov ntaub ntawv txheeb xyuas cov koom haum raws li cov tswv yim.
Aggregated tsawg variant xeem
Zuag qhia tag nrho, 4,879 GCKD cov neeg koom nrog ua tiav cov ntaub ntawv ntawm genotyping (Exome chip), eGFR, UACR, thiab log2 (OPN) kev ntsuas tau suav nrog hauv kev tshuaj xyuas ntawm qhov sib txawv tsis tshua muaj qhov sib txawv (S1 Fig). Raws li yav dhau los tau piav qhia [106], ob hom kev xeem sib txawv tsis tshua muaj kev sib sau ua ke (bur den test, sequence kernel Association test [SKAT]) tau ua tiav hauv R pob seqMeta (v1.6.7, [107]) tau ua los ntawm exome chip data thiab log2. (OPN) kev ntsuas (qhov tshwm sim). Rau cov noob, hloov pauv nrog MAF<1% and having a major effect on the gene product (nonsynonymous, stop gain/loss, splicing; "qualifying variants") as annotated by dbNSFP v.2.0 were aggregated [24,25]. Results were filtered to retain genes with cumulative minor allele count (MAC) �10 and with �2 contributing variants per gene. Analyses were adjusted for age, sex, log(eGFR), and log(UACR). To adjust for multiple testing, the statistical significance level was corrected for the number of assessed genes (N = 17,575) and the two conducted tests: 0.05/(2×17,575) = 1.4E-06. Moreover, analyses were repeated for significantly associated genes additionally adjusted for the two replicated OPN loci.
Kev rov ua dua ntawm kev txheeb xyuas qhov chaw nyob hauv Young Finns Study
Peb qhov OPN loci tau txheeb xyuas hauv GWAS ntawm GCKD cov neeg koom tau raug sim rau kev rov ua dua tshiab hauv Cardiovascular Risk hauv Young Finns Study (YFS) pawg. Ntawm no, plasma OPN tau ntsuas los ntawm enzyme-linked immunosorbent assay (Human Osteopontin Quantikine kit, R&D Systems, USA) los ntawm cov qauv thawed thawj zaug rau kev ntsuam xyuas hauv 2007. Cov qauv ntawm 2,442 tus neeg koom thiab 546,677 SNP tom qab kev tshuaj ntsuam genotyped ntxiv. QC thiab imputation. Cov ntsiab lus ntxiv tuaj yeem pom hauv S1 Txoj Kev. Raws li qhov chaw xaiv, koom nrog kev txheeb xyuas ntawm log2(OPN) ntawm SNP ntau npaum li cas (ntxiv) tau tsim los ntawm kev haum cov qauv kev hloov pauv hloov kho rau hnub nyoog, poj niam txiv neej, thiab eGFR los ntawm kev siv SNPTEST v2.5.4 [89]. GFR tau kwv yees nrog MDRD txoj kev sib npaug thiab teev{12}} hloov ua ntej kev tshuaj ntsuam [108]. Kev rov ua dua tau txhais los ntawm ib qho kev koom nrog ib sab p-tus nqi<0.05/3 (Bonferroni correction for three OPN loci).
Kev lees paub Peb ua tsaug rau qhov txaus siab ntawm cov neeg mob CKD los koom nrog GCKD txoj kev kawm. Kev siv zog loj ntawm kev kawm cov neeg ua haujlwm ntawm ntau lub chaw hauv cheeb tsam tau txais txiaj ntsig zoo heev. Peb ua tsaug rau ntau tus kws kho mob nephrologists uas muab kev saib xyuas niaj hnub rau cov neeg mob thiab koom tes nrog GCKD txoj kev tshawb fawb. GCKD Cov Kws Tshawb Fawb tau teev nyob rau hauv S1 Cov Ntaub Ntawv. Daim ntawv teev tag nrho ntawm cov kws kho mob nephrologists tam sim no koom tes nrog GCKD txoj kev tshawb fawb muaj nyob ntawm (http://gckd.org).
Sau Kev Koom Tes Kev Ntseeg: Peggy Sekula, Ulla T. Schultheiss.
Cov ntaub ntawv curation: Yurong Cheng, Yong Li, Nora Scherer, Franziska Grundner-Culemann, Terho Lehtima¨ki, Binisha H. Mishra, Olli T. Raitakari, Matthias Nauck, Kai-Uwe Eckardt, Peggy Sekula, Ulla T. Schultheiss.
Kev tsom xam: Yurong Cheng, Yong Li, Nora Scherer, Franziska Grundner-Culemann, Binisha H. Mishra, Peggy Sekula, Ulla T. Schultheiss.
Kev nrhiav nyiaj txiag: Terho Lehtima¨ki, Olli T. Raitakari, Kai-Uwe Eckardt, Peggy Sekula, Ulla T. Schultheiss.
Kev Tshawb Fawb: Binisha H. Mishra, Olli T. Raitakari, Peggy Sekula, Ulla T. Schultheiss.
Methodology: Yurong Cheng, Yong Li, Nora Scherer, Franziska Grundner-Culemann, Binisha H. Mishra, Matthias Nauck, Peggy Sekula, Ulla T. Schultheiss.
Kev tswj hwm qhov project: Peggy Sekula, Ulla T. Schultheiss.
Cov peev txheej: Peggy Sekula, Ulla T. Schultheiss.
Software: Yurong Cheng, Yong Li, Binisha H. Mishra, Peggy Sekula, Ulla T. Schultheiss.
Saib xyuas: Nora Scherer, Franziska Grundner-Culemann, Peggy Sekula, Ulla T. Schultheiss.
Validation: Yurong Cheng, Yong Li, Nora Scherer, Franziska Grundner-Culemann, Terho Lehtima¨ki, Binisha H. Mishra, Olli T. Raitakari, Matthias Nauck, Kai-Uwe Eckardt, Peggy Sekula, Ulla T. Schultheiss.
Cov ntaub ntawv
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