Ere funded by Xenon Pharmaceuticals and Merck Research Laboratories. G.K.H. is definitely the recipient of a Veni Grant (91612122) from the Netherlands Organization for Scientific Analysis (NWO), the CardioVascular Study Initiative (CVON GENIUS 2011-19; Genius), along with the European Union (TransCard: FP7-603091-2). J.J.K. is definitely the recipient with the Lifetime Achievement Award with the Dutch Heart Foundation Excellence (2010T082). R.R.S., I.T., P.L.F., C.R., I.M.S., M.W., M.M., A.L., and R.S. were staff at Xenon Pharmaceuticals at the time of those studies. K.W., M.vH., L.L., L.W., L.M., B.H., K.A., as well as a.P. were staff of Merck at the time of these research. J.J.K. and M.R.H. are founding members of Xenon Pharmaceuticals Inc. Manuscript received 11 March 2014 and in revised kind 1 June 2014. Published, JLR Papers in Press, June two, 2014 DOI 10.1194/jlr.MCopyright ?2014 by the American Society for Biochemistry and Molecular Biology, Inc. This article is offered on the internet at http://jlr.orgAbbreviations: CETP, cholesteryl ester transfer protein; dbSNP, database of SNPs; DNAH10, dynein axonemal heavy chain 10; GALNT2 , UDP-N -acetyl- -D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2; GCKR, glucokinase regulatory protein; GK, glucokinase; GWAS, genome-wide association study; HDLc, HDL cholesterol; HHDL, higher HDL cholesterol or HDL cholesterol 90th percentile; LHDL, low HDL cholesterol or HDL cholesterol 10th percentile adjusted for age and gender; LILRA3, leukocyte immunoglobulin-like receptor 3 subfamily A member 3; LIPG, endothelial lipase; RNASEL, RNase L; SCARB1, scavenger receptor class B member 1.85272-31-7 custom synthesis 1 R.166978-46-7 web R.PMID:28038441 Singaraja and I. Tietjen contributed equally to this operate. 2 To whom correspondence needs to be addressed. e-mail: [email protected] The on the net version of this article (out there at http://jlr.org) contains supplementary information in the kind of 5 tables.Journal of Lipid Study Volume 55,other published information (7, 8). Furthermore, mutations with an HDLc-increasing effect inside the cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-Nacetyl- -D-galactosamine:polypeptide N-acetylgalactosaminyltransferase two (GALNT2) genes were discovered in only 14.six of probands with high HDLc ( 90th percentile) (9). Additionally, only ten?five on the inter-individual variation in lipid levels is explained by widespread genetic variation (10, 11). One significant limitation of identifying novel mutations that lead to large modifications to HDLc is the fact that they’re regularly exceptionally uncommon (i.e., 0.1 within the general population), which precludes testing for associations. Therefore assessing the segregation of genetic variations with apparent Mendelian types of extreme HDLc in households is often a beneficial and well-validated process to examine regardless of whether novel uncommon mutations associate with HDLc phenotypes (6, 9, 12?5). Current advances in sequencing technologies permit parallel sequencing of several genes and in some cases whole exomes or genomes across populations. Nevertheless, a significant challenge to this method is identifying those few mutations that associate with massive changes in HDLc, or any other complex trait, from the numerous extra identified unrelated sequence variations. We propose right here that novel mutations that underlie extreme HDLc levels may be distinguished from other sequence variations found by next-generation sequencing by initially assessing their segregation in households with intense HDLc levels. Right here, we sequenced the exons and exon/intron boundaries of 456 genes that pote.