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排序方式: 共有339条查询结果,搜索用时 250 毫秒
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Hagit Hochner Catherine Allard Einat Granot-Hershkovitz Jinbo Chen Colleen M. Sitlani Sandra Sazdovska Thomas Lumley Barbara McKnight Kenneth Rice Daniel A. Enquobahrie James B. Meigs Pui Kwok Marie-France Hivert Ingrid B. Borecki Felicia Gomez Ting Wang Cornelia van Duijn Najaf Amin Jerome I. Rotter John Stamatoyannopoulos Vardiella Meiner Orly Manor Josée Dupuis Yechiel Friedlander David S. Siscovick 《PLoS genetics》2015,11(10)
Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits'' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits. 相似文献
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Marina Caldara Ronn S. Friedlander Nicole L. Kavanaugh Joanna Aizenberg Kevin R. Foster Katharina Ribbeck 《Current biology : CB》2012,22(24):2325-2330
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Tamar Yifhar Irena Pekker Dror Peled Gilgi Friedlander Anna Pistunov Moti Sabban Guy Wachsman John Paul Alvarez Ziva Amsellem Yuval Eshed 《The Plant cell》2012,24(9):3575-3589
Interfering with small RNA production is a common strategy of plant viruses. A unique class of small RNAs that require microRNA and short interfering (siRNA) biogenesis for their production is termed trans-acting short interfering RNAs (ta-siRNAs). Tomato (Solanum lycopersicum) wiry mutants represent a class of phenotype that mimics viral infection symptoms, including shoestring leaves that lack leaf blade expansion. Here, we show that four WIRY genes are involved in siRNA biogenesis, and in their corresponding mutants, levels of ta-siRNAs that regulate AUXIN RESPONSE FACTOR3 (ARF3) and ARF4 are reduced, while levels of their target ARFs are elevated. Reducing activity of both ARF3 and ARF4 can rescue the wiry leaf lamina, and increased activity of either can phenocopy wiry leaves. Thus, a failure to negatively regulate these ARFs underlies tomato shoestring leaves. Overexpression of these ARFs in Arabidopsis thaliana, tobacco (Nicotiana tabacum), and potato (Solanum tuberosum) failed to produce wiry leaves, suggesting that the dramatic response in tomato is exceptional. As negative regulation of orthologs of these ARFs by ta-siRNA is common to land plants, we propose that ta-siRNA levels serve as universal sensors for interference with small RNA biogenesis, and changes in their levels direct species-specific responses. 相似文献
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Wang X Narayanan M Bruey JM Rigamonti D Cattaneo E Reed JC Friedlander RM 《Biochimica et biophysica acta》2006,1762(8):742-754
CARD only protein (Cop) was recently identified as a protein with significant homology with the CARD of caspase-1. We have conducted functional studies on Cop and report on its role as an inhibitor of cell death in a broad range of cell death paradigms. A notable exception in the ability of Cop to inhibit cell death pertains to its inability to inhibit ER stress-mediated cell death. Furthermore, in addition to the known interaction of Cop and caspase-1, we demonstrated a novel interaction of Cop with caspase-4. We propose that Cop's action to prevent TNF-alpha-induced cell death may operate independently of the mitochondrial death pathway. Furthermore, Cop overexpression inhibits Bid cleavage. In summary, Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. Understanding the mechanistic details modulating caspase cell death pathways should provide important information for the development of therapies for diseases featuring aberrant caspase activation. Cop, as an inhibitor of an important apical caspase cell death axis, may provide a tool for modulating pathological cell death. 相似文献
100.
The kidney is a key player of phosphate balance, it determines serum phosphate levels by coupling phosphate reabsorption in the renal proximal tubule, calcitriol synthesis and consequently intestinal phosphate absorption. The identification of fibroblast growth factor 23 (FGF23) as a hormone regulating phosphate and calcitriol metabolism has unveiled the mechanisms that coordinate these renal proximal tubule functions. A bone–kidney axis has emerged that controls bone mineralization. Animal model studies have improved our understanding of phosphate homeostasis and revealed the role of the protein Klotho, which is mandatory to FGF23 action. In this review we detail FGF23 and Klotho implications in physiology and in genetic or acquired disorders. Phosphate ion is involved in vascular and soft tissue calcification and is important for cell proliferation. Disorders of FGF23–Klotho axis alter life-span and the survival in some cancers. 相似文献