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Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, Tanya M.,Musunuru, Kiran,Smith, Albert V.,Edmondson, Andrew C.,Stylianou, Ioannis M.,Koseki, Masahiro,Pirruccello, James P.,Ripatti, Samuli,Chasman, Daniel I.,Willer, Cristen J.,Johansen, C Nature Publishing Group, a division of Macmillan P 2010 Nature Vol.466 No.7307
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P??<??5?????10<SUP>??8</SUP>), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes??GALNT2, PPP1R3B and TTC39B??with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
PtdIns4P synthesis by PI4KIIIα at the plasma membrane and its impact on plasma membrane identity
Nakatsu, Fubito,Baskin, Jeremy M.,Chung, Jeeyun,Tanner, Lukas B.,Shui, Guanghou,Lee, Sang Yoon,Pirruccello, Michelle,Hao, Mingming,Ingolia, Nicholas T.,Wenk, Markus R.,De Camilli, Pietro The Rockefeller University Press 2012 The Journal of cell biology Vol.199 No.6
<P>Plasma membrane phosphatidylinositol (PI) 4-phosphate (PtdIns4P) has critical functions via both direct interactions and metabolic conversion to PI 4,5-bisphosphate (PtdIns(4,5)P<SUB>2</SUB>) and other downstream metabolites. However, mechanisms that control this PtdIns4P pool in cells of higher eukaryotes remain elusive. PI4KIIIα, the enzyme thought to synthesize this PtdIns4P pool, is reported to localize in the ER, contrary to the plasma membrane localization of its yeast homologue, Stt4. In this paper, we show that PI4KIIIα was targeted to the plasma membrane as part of an evolutionarily conserved complex containing Efr3/rolling blackout, which we found was a palmitoylated peripheral membrane protein. PI4KIIIα knockout cells exhibited a profound reduction of plasma membrane PtdIns4P but surprisingly only a modest reduction of PtdIns(4,5)P<SUB>2</SUB> because of robust up-regulation of PtdIns4P 5-kinases. In these cells, however, much of the PtdIns(4,5)P<SUB>2</SUB> was localized intracellularly, rather than at the plasma membrane as in control cells, along with proteins typically restricted to this membrane, revealing a major contribution of PI4KIIIα to the definition of plasma membrane identity.</P>