Analysis with the exome array identifies multiple new independent variants in lipid loci
HUMAN MOLECULAR GENETICS
Authors: Kanoni, Stavroula; Masca, Nicholas G. D.; Stirrups, Kathleen E.; Varga, Tibor V.; Warren, Helen R.; Scott, Robert A.; Southam, Lorraine; Zhang, Weihua; Yaghootkar, Hanieh; Mueller-Nurasyid, Martina; Alves, Alexessander Couto; Strawbridge, Rona J.; Lataniotis, Lazaros; Hashim, Nikman An; Besse, Celine; Boland, Anne; Braund, Peter S.; Connell, John M.; Dominiczak, Anna; Farmaki, Aliki-Eleni; Franks, Stephen; Grallert, Harald; Jansson, Jan-Hakan; Karaleftheri, Maria; Keinanen-Kiukaanniemi, Sirkka; Matchan, Angela; Pasko, Dorota; Peters, Annette; Poulter, Neil; Rayner, Nigel W.; Renstrom, Frida; Rolandsson, Olov; Sabater-Lleal, Maria; Sennblad, Bengt; Sever, Peter; Shields, Denis; Silveira, Angela; Stanton, Alice V.; Strauch, Konstantin; Tomaszewski, Maciej; Tsafantakis, Emmanouil; Waldenberger, Melanie; Blakemore, Alexandra I. F.; Dedoussis, George; Escher, Stefan A.; Kooner, Jaspal S.; McCarthy, Mark I.; Palmer, Colin N. A.; Hamsten, Anders; Caulfield, Mark J.; Frayling, Timothy M.; Tobin, Martin D.; Jarvelin, Marjo-Riitta; Zeggini, Eleftheria; Gieger, Christian; Chambers, John C.; Wareham, Nick J.; Munroe, Patricia B.; Franks, Paul W.; Samani, Nilesh J.; Deloukas, Panos
Abstract
It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were > 1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.
FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Authors: Gai, Junfang; Ji, Meiling; Shi, Chenxi; Li, Wenli; Chen, Simin; Wang, Yeyu; Li, Hao
Abstract
ATP-binding-cassette (ABC) proteins have been recognized as key players in cellular physiological transport processes. ABC transporter A6 (ABCA6) is a member of the ABC subfamily A. Although it was cloned more than 10 years ago, its expression regulation, subcellular localization, and physiologic function remain largely unknown. We here demonstrated that expression of ABCA6 was Forkhead box O (FoxO)-dependent in human endothelial cell line EA.hy926 and human umbilical vein endothelial cells. Two functional FoxO-responsive elements were identified in ABCA6 promoter and characterized in detail. ABCA6 mRNA was suppressed by insulin-like growth factor-1 which stimulates the phosphorylation and inactivation of FoxOs while inhibitor of phosphatidylinositol 3-kinase had the opposite effect. By immunofluorescence and confocal microscopy, ABCA6 protein is localized primarily in an intracellular compartment, likely representing the Golgi apparatus. ABCA6 mRNA was demonstrated to be responsive to cholesterol loading as well as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors in human endothelial cells. Our data provide evidence for an essential role of FoxO proteins in the transcription of ABCA6 in human vascular endothelial cells. Based on its cholesterol responsiveness, a potential involvement of ABCA6 in intracellular lipid transport processes may be anticipated. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.
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