{"id":1148,"date":"2022-05-04T15:10:36","date_gmt":"2022-05-04T13:10:36","guid":{"rendered":"https:\/\/rhu-shiva.com\/en\/?p=1148"},"modified":"2022-10-13T16:41:35","modified_gmt":"2022-10-13T14:41:35","slug":"gene-mapping-study-of-extremes-of-cerebral-small-vessel-disease-reveals-trim47-as-a-strong-candidate","status":"publish","type":"post","link":"https:\/\/rhu-shiva.com\/en\/blog\/2022\/05\/04\/gene-mapping-study-of-extremes-of-cerebral-small-vessel-disease-reveals-trim47-as-a-strong-candidate\/","title":{"rendered":"Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate"},"content":{"rendered":"\n<h2 class=\"wp-block-heading\">Authors<\/h2>\n\n\n\n<p> <strong>Aniket Mishra, C\u00e9cile Dupla\u00e0,<\/strong> Dina Vojinovic, Hideaki Suzuki, <strong>Muralidharan Sargurupremraj<\/strong>, Nuno R Zilh\u00e3o, Shuo Li, Traci M Bartz, Xueqiu Jian, Wei Zhao, Edith Hofer, Katharina Wittfeld, Sarah E Harris, Sandra van der Auwera-Palitschka, Michelle Luciano, Joshua C Bis, Hieab H H Adams, Claudia L Satizabal, Rebecca F Gottesman, Piyush G Gampawar, Robin B\u00fclow, Stefan Weiss, Miao Yu, Mark E Bastin, Oscar L Lopez, Meike W Vernooij, Alexa S Beiser, Uwe V\u00f6lker, Tim Kacprowski, <strong>Aicha Soumare<\/strong>, Jennifer A Smith, David S Knopman, Zoe Morris, Yicheng Zhu, Jerome I Rotter, <strong>Carole Dufouil,<\/strong> Maria Vald\u00e9s Hern\u00e1ndez, Susana Mu\u00f1oz Maniega, Mark Lathrop, Erik Boerwinkle, Reinhold Schmidt, Masafumi Ihara,<strong> Bernard Mazoyer,<\/strong> Qiong Yang, Anne Joutel, Elizabeth Tournier-Lasserve, Lenore J Launer, Ian J Deary, Thomas H Mosley, Philippe Amouyel, Charles S DeCarli, Bruce M Psaty,<strong> Christophe Tzourio<\/strong>, Sharon L R Kardia, Hans J Grabe, Alexander Teumer, Cornelia M van Duijn, Helena Schmidt, Joanna M Wardlaw, M Arfan Ikram, Myriam Fornage, Vilmundur Gudnason, Sudha Seshadri, Paul M Matthews, William T Longstreth, Jr, <strong>Thierry Couffinhal, Stephanie Debette<\/strong>. <em>Brain<\/em>, awab432, <a href=\"https:\/\/doi.org\/10.1093\/brain\/awab432\">https:\/\/doi.org\/10.1093\/brain\/awab432<\/a>  <\/p>\n\n\n\n<p><\/p>\n\n\n\n<h2 class=\"wp-block-heading\">Abstract<\/h2>\n\n\n\n<p>Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (<em>n<\/em>\u2009=\u200941\u200a326), whole-exome sequencing (<em>n<\/em>\u2009=\u200915\u200a965), or exome chip (<em>n<\/em>\u2009=\u20095249) data contributed 13\u200a776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5\u2032 UTR region of&nbsp;<em>EFEMP1<\/em>&nbsp;(chr2p16.1) and one probably damaging common missense variant in&nbsp;<em>TRIM47<\/em>&nbsp;(chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer\u2019s disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between&nbsp;<em>TRIM47<\/em>&nbsp;expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of&nbsp;<em>Trim47<\/em>&nbsp;in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing&nbsp;<em>Trim47<\/em>&nbsp;enrichment in brain endothelial cells at single cell level. Functional evaluation of&nbsp;<em>TRIM47<\/em>&nbsp;by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of&nbsp;<em>TRIM47<\/em>&nbsp;in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive&nbsp;<em>in vivo<\/em>&nbsp;explorations and future translational work.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Authors Aniket Mishra, C\u00e9cile Dupla\u00e0, Dina Vojinovic, Hideaki Suzuki, Muralidharan Sargurupremraj, Nuno R Zilh\u00e3o, Shuo Li, Traci M Bartz, Xueqiu Jian, Wei Zhao, Edith Hofer, Katharina<span class=\"excerpt-hellip\"> [\u2026]<\/span><\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"inline_featured_image":false,"footnotes":""},"categories":[2],"tags":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v21.8 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Gene-mapping 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