title: ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells.
abstract: ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) is a universally confirmed susceptibility gene for asthma and has recently emerged as a crucial modulator in lipid metabolism, inflammation and endoplasmic reticulum (ER) stress-the mechanisms also closely involved in atherosclerosis (AS). Here we first presented the evidence of two single nucleotide polymorphisms regulating ORMDL3 expression (rs7216389 and rs9303277) significantly associated with AS risk and the evidence of increased ORMDL3 expression in AS cases compared to controls, in Chinese Han population. Following the detection of its statistical correlation with AS, we further explored the functional relevance of ORMDL3 and hypothesized a potential role mediating autophagy as autophagy is activated upon modified lipid, inflammation and ER stress. Our results demonstrated that in endothelial cells oxidized low-density lipoprotein (ox-LDL) up-regulated ORMDL3 expression and knockdown of ORMDL3 alleviated not only ox-LDL-induced but also basal autophagy. BECN1 is essential for autophagy initiation and silencing of ORMDL3 suppressed ox-LDL-induced as well as basal BECN1 expression. In addition, deletion of ORMDL3 resulted in greater sensitivity to ox-LDL-induced cell death. Taken together, ORMDL3 might represent a causal gene mediating autophagy in endothelial cells in the pathogenesis of AS.
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Cardiac Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Ma
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Rongfang
authors.initials: R
authors.lastname: Qiu
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics and Cell Biology, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dang
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Jiangxia
authors.initials: J
authors.lastname: Li
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Shan
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xin
authors.affiliation: Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Pan
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Xianli
authors.initials: X
authors.lastname: Bian
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Long
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Cardiac Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Zou
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.affiliation: The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.|Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
authors.forename: Qiji
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D016022:Case-Control Studies; D002681:China; D015331:Cohort Studies; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005838:Genotype; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D034622:RNA Interference; D012307:Risk Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; C099252:oxidized low density lipoprotein