PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.
PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.
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DOI：
10.1164/rccm.202205-0845oc
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发表时间：
2023-06-01
影响因子：
24.7
通讯作者：
中科院分区：
文献类型：
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作者：
特发性肺纤维化（IPF）是一种破坏性疾病，其特点是治疗选择有限，死亡率高。需要更好地了解IPF进展的分子驱动因素。鉴定和验证IPF存活的分子决定因素。使用配对的基因组和生存数据进行了分阶段的全基因组关联研究。第一阶段病例来自美国和欧洲的中心，第二阶段病例来自范德比尔特大学。Cox比例风险回归用于识别与差异无移植生存（TFS）相关的基因变异。具有名义显著性（P < 5 × 10−5）的I期变异被推进到II期检测和荟萃分析，以确定达到全基因组显著性的变异（P < 5 × 10−8）。下游分析与变异相关的基因和蛋白质达到全基因组意义。经过质量控制，1481例I期病例和397例II期病例纳入分析。经过筛选，在第一阶段测试了9075629个变体，其中158个符合进展标准。在II期发现了与TFS相关的4个具有一致影响方向的变异，其中包括PCSK6（蛋白转化酶枯草素/ keexin 6型）内含子中的一个具有全基因组显著性（风险比为4.11[95%置信区间，2.54-6.67];P = 9.45 × 10−9）。PCSK6蛋白在IPF肺实质中高表达。PCSK6肺染色强度、外周血基因表达和血浆浓度与TFS降低相关。我们发现了四个与IPF存活相关的新变异，其中一个在PCSK6中具有全基因组意义。下游分析表明PCSK6蛋白在IPF的进展中起着潜在的重要作用。
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. To identify and validate molecular determinants of IPF survival. A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 × 10−5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 × 10−8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54–6.67]; P = 9.45 × 10−9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression.
前蛋白转化酶在卵巢癌细胞增殖和肿瘤进展中的影响：PACE4作为治疗靶点的见解。
影响因子：
5
作者：
Longuespee, Remi;Couture, Frederic;Levesque, Christine;Kwiatkowska, Anna;Desjardins, Roxane;Gagnon, Sandra;Vergara, Daniele;Maffia, Michelle;Fournier, Isabelle;Salzet, Michel;Day, Robert
通讯作者：
Day, Robert
评估PACE4同工型作为甲状腺癌的生物标志物。
DOI：
10.1186/s40463-018-0311-x
发表时间：
2018-10-19
期刊：
Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale
影响因子：
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作者：
Fradet L;Temmar R;Couture F;Belzile M;Fortier PH;Day R
通讯作者：
Day R