Elevated plasma HDL cholesterol in humansRoshni R. Singaraja,1,*, Ian Tietjen,1,* G. Kees Hovingh,?Patrick L. Franchini,* Chris Radomski,* Kenny Wong,** Margaret vanHeek,** Ioannis M. Stylianou,* Linus Lin,** Liangsu Wang,** Lyndon Mitnaul,** Brian Hubbard,** Michael Winther,* Maryanne Mattice,* Annick Legendre,* Robin Sherrington,* John J. Kastelein,?Karen Akinsanya,** Andrew Plump,** and Michael R. Hayden2, ,Xenon Pharmaceuticals Inc.,* Burnaby, BC, Canada; A*STAR Institute and Yong Loo Lin College of Medicine, National University of Singapore, Singapore; Academic Health-related Centre,?University of Amsterdam, Amsterdam, The Netherlands; Merck Analysis Laboratories,** Rahway, NJ; and Centre for Molecular Medicine and Therapeutics, and Child and Household Investigation Institute, University of British Columbia, Vancouver, BC, CanadaAbstract When genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with substantial effects in candidate genes contributing to extreme HDLc in humans, using family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with exceptionally low ( 10th percentile) or high ( 90th percentile) HDLc. Probands were excluded if known mutations existed inside the established HDLc-regulating genes ABCA1, APOA1, LCAT, cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-N-acetyl- -D-galactosamine:polypeptide N-acetylgalactosaminyltransferase two (GALNT2). We identified 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped within the proband’s family members. Familybased association analyses have been performed for variants with enough energy to detect significance at P 0.05 having a total of 627 family members getting assessed. Mutations inside the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor three (LILRA3), and dynein axonemal heavy chain ten (DNAH10) segregated with elevated HDLc levels in households, when no mutations related with low HDLc. Taken collectively, we’ve got identified mutations in 4 novel genes that may play a part in regulating HDLc levels in humans.–Singaraja, R. R., I. Tietjen, G. K. Hovingh, P. L. Franchini, C. Radomski, K. Wong, M. vanHeek, I. M. Stylianou, L. Lin, L. Wang, L.Mitnaul, B. Hubbard, M. Winther, M. Mattice, A. Legendre, R. Sherrington, J.359586-69-9 site J.Formula of Isoxazol-4-ylmethanol Kastelein, K.PMID:24238102 Akinsanya, A. Plump, and M. R. Hayden. Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans. J. Lipid Res. 2014. 55: 1693?701.Supplementary key words higher density lipoprotein ?Mendelian genetics ?lipids ?higher density lipoprotein metabolism ?genetics ?lipoproteinsHeritability estimates of 47?6 for plasma HDL cholesterol (HDLc) levels recommend that genetic variation plays a pivotal function in HDL metabolism (1?). Even so, in spite of major advances in family- and population-based association research (2, four), most genetic causes of intense HDLc levels in humans remain unknown. Cohen et al. (five) reported mutations within the established HDLc genes ABCA1, APOA1, and LCAT in only 12.four of folks with low HDLc (5th percentile). Similarly, we reported that mutations inside the identified HDLc-regulating genes ABCA1, APOA1, and LCAT had been identified in 28.7 of unrelated folks with low HDLc levels ( 10th percentile) (six), consistent withThese studies w.