Surunkali buyrak kasalligi bo'lgan bemorlarda osteopontin genetikasi: Germaniyaning surunkali buyrak kasalligi tadqiqoti Ⅳ
Jun 11, 2024
Plazma proteomasi.
Bundan tashqari, biz GWAS ning umumiy statistikasidan foydalandikplazma oqsillari(pGWAS) Sun va boshqalar tomonidan. [22] OPN va oqsillar o'rtasidagi izchil assotsiatsiya signallarini aniqlash uchun kolokalizatsiya tahlilini o'tkazish uchun cis va transda ta'sir qiladi. GTEx va NephQTL ma'lumotlaridan farqli o'laroq, genom bo'yicha mavjud pGWAS xulosasi ikkala ta'sirni baholashga imkon beradi. Cis-pQTLs bilan kolokalizatsiyani aniqlash uchun har qanday protein-gen mintaqasining (gen hududi ± 500kb, sis mintaqasi) pGWAS umumiy statistikasi chiqarildi. OPN joylashuvi va uning atrofidagi 100kb hududga ko'ra, biz cis pGWAS ekstraktlaridan birortasi bir-biriga o'xshashligini va pGWAS assotsiatsiyasi p-qiymatiga ega ekanligini tekshirdik.<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.
Buyrak salomatligi uchun organik sog'liq oziq-ovqat
Oqsillarni kolokalizatsiya qilish uchun GO uyali komponenti va GO molekulyarining ikkita izohli ma'lumotlar to'plami bilan PANTHER [103] haddan tashqari ko'rsatish testi shaklida Gen ontologiyasi (GO) boyitish tahlili (http://geneontology.org/, [101,102]). funktsiyasi (homo sapiens) sifatida aniqlangan oqsillar tayinlangan boyitilgan toifalarni baholash uchun havolalar o'tkazildi. Umuman olganda, 20 595 ta inson genlari hujayra komponentlari va molekulyar funktsiya bilan bog'liq bo'lgan turli atamalar bilan taqqoslanadi. Agar Fisherning aniq testining Bonferroni tomonidan toʻgʻrilangan p-qiymati va Benjamini-Xochberg protsedurasiga asoslangan notoʻgʻri topish tezligi boʻlsa, kategoriya boyitilgan hisoblanadi.<0.05
UKB kasalliklari. Nihoyat, biz GeneAtlas ma'lumotlar bazasidan (http://geneatlas. Roslin.ed.ac.uk/) GWAS-dan ikkita replikatsiya qilingan OPN lokuslari (±500kb) va genomni ko'rsatadigan barcha UKB ikkilik kasallik belgilari uchun kolokalizatsiya tahlilini o'tkazish uchun foydalandik. keng muhim assotsiatsiyalar (p-qiymati<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). Yuqorida aytib o'tilgan tozalangan va hisoblangan GCKD genotipi ma'lumotlar to'plami GCTA tomonidan LD ma'lumotnomasi sifatida ishlatilgan. Konservativ bo'lish uchun biz kollinearlik chegarasini 0,1 ga o'rnatdik. 1 dan ortiq mustaqil signalga ega bo'lgan lokuslar uchun GCTA COJO-Cond algoritmi tomonidan mintaqadagi boshqa mustaqil SNPlar bilan shartlangan shartli assotsiatsiya statistikasini yaratish uchun taxminiy shartli tahlil o'tkazildi [105]. Nihoyat, kirish sifatida shartli assotsiatsiya statistikasidan foydalangan holda har bir mustaqil SNP uchun kolokalizatsiya tahlillari avvalgidek amalga oshirildi.
Agregatlangan noyob variant sinovi
Umuman olganda, genotiplash (Exome chip), eGFR, UACR va log2 (OPN) o'lchovlari bo'yicha to'liq ma'lumotlarga ega bo'lgan 4,879 GCKD ishtirokchilari yig'ilgan noyob variant testlari tahliliga kiritilgan (S1-rasm). Oldin ta'riflanganidek [106], seqMeta R paketida (v1.6.7, [107]) amalga oshirilgan ikki turdagi noyob variantlarni yig'ish testlari (yuk testi, ketma-ket yadro assotsiatsiyasi testi [SKAT]) ekzom chip ma'lumotlari va log2 yordamida o'tkazildi. (OPN) o'lchovlari (natija). Gen bo'yicha, MAF bilan variantlar<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.
Yosh Finlar tadqiqotida aniqlangan lokuslarning takrorlanishi
GCKD ishtirokchilarining GWAS da aniqlangan uchta OPN lokuslari Yosh Finlar tadqiqotida yurak-qon tomir xavfi (YFS) kohortida replikatsiya uchun sinovdan o'tkazildi. Bu erda plazma OPN 2007 yilda tahlil uchun birinchi marta eritilgan namunalardan fermentga bog'langan immunosorbent tahlili (Human Osteopontin Quantikine kit, R&D Systems, AQSh) bilan o'lchandi. SNPdan keyin 2442 ishtirokchi va 546677 genotip namunalari mavjud edi. QC va hisoblash. Qo'shimcha ma'lumotni S1 usullarida topishingiz mumkin. Tanlangan joy bo'yicha log2 (OPN) ning SNP dozasi (qo'shimchasi) bo'yicha assotsiatsiya tahlili SNPTEST v2.5.4 [89] yordamida yosh, jins va eGFR uchun moslashtirilgan chiziqli regressiya modellarini o'rnatish orqali shakllantirildi. GFR MDRD o'rganish tenglamasi bilan baholandi va jurnal{12}}tahlildan oldin o'zgartirildi [108]. Replikatsiya bir tomonlama assotsiatsiya p-qiymati bilan aniqlandi<0.05/3 (Bonferroni correction for three OPN loci).
Minnatdorchilik Biz CKD bilan og'rigan bemorlarning GCKD tadqiqotida ishtirok etishga tayyorligi uchun minnatdormiz. Turli viloyat markazlari xodimlarining ulkan sa'y-harakatlari yuqori baholanadi. Biz bemorlarga muntazam yordam ko'rsatadigan va GCKD tadqiqoti bilan hamkorlik qiladigan ko'plab nefrologlarga minnatdorchilik bildiramiz. GCKD tergovchilari S1 ma'lumotlarida keltirilgan. Hozirda GCKD tadqiqoti bilan hamkorlik qilayotgan nefrologlarning toʻliq roʻyxati (http://gckd.org) saytida mavjud.
Muallif hissalari kontseptsiyasi: Peggy Sekula, Ulla T. Schultheiss.
Ma'lumotlar kuratori: Yurong Cheng, Yong Li, Nora Sherer, Fransiska Grundner-Kulemann, Terxo Lehtima¨ki, Binisha X. Mishra, Olli T. Raitakari, Mattias Nauck, Kay-Uve Ekardt, Peggi Sekula, Ulla T. Shulteys.
Rasmiy tahlil: Yurong Cheng, Yong Li, Nora Scherer, Fransiska Grundner-Culemann, Binisha X. Mishra, Peggy Sekula, Ulla T. Schultheiss.
Moliyaviy xaridlar: Terho Lehtima¨ki, Olli T. Raitakari, Kay-Uve Ekardt, Peggi Sekula, Ulla T. Shulteys.
Tekshiruv: Binisha H. Mishra, Olli T. Raitakari, Peggy Sekula, Ulla T. Schultheiss.
Metodologiya: Yurong Cheng, Yong Li, Nora Scherer, Fransiska Grundner-Culemann, Binisha X. Mishra, Matthias Nauck, Peggy Sekula, Ulla T. Schultheiss.
Loyiha ma'muriyati: Peggy Sekula, Ulla T. Schultheiss.
Resurslar: Peggy Sekula, Ulla T. Schultheiss.
Dasturiy ta'minot: Yurong Cheng, Yong Li, Binisha H. Mishra, Peggy Sekula, Ulla T. Schultheiss.
Nazorat: Nora Scherer, Fransiska Grundner-Culemann, Peggy Sekula, Ulla T. Schultheiss.
Tasdiqlash: Yurong Cheng, Yong Li, Nora Sherer, Fransiska Grundner-Kulemann, Terxo Lehtima¨ki, Binisha X. Mishra, Olli T. Raitakari, Mattias Nauck, Kay-Uve Ekardt, Peggi Sekula, Ulla T. Shulteys.
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