title: Segregation of LIPG, CETP, and GALNT2 mutations in Caucasian families with extremely high HDL cholesterol.
abstract: To date, few mutations are described to underlie highly-elevated HDLc levels in families. Here we sequenced the coding regions and adjacent sequence of the LIPG, CETP, and GALNT2 genes in 171 unrelated Dutch Caucasian probands with HDLc≥90th percentile and analyzed segregation of mutations with lipid phenotypes in family members. In these probands, mutations were most frequent in LIPG (12.9%) followed by GALNT2 (2.3%) and CETP (0.6%). A total of 6 of 10 mutations in these three genes were novel (60.0%), and mutations segregated with elevated HDLc in families. Interestingly, the LIPG mutations N396S and R476W, which usually result in elevated HDLc, were unexpectedly found in 6 probands with low HDLc (i.e., ≤10th percentile). However, 5 of these probands also carried mutations in ABCA1, LCAT, or LPL. Finally, no CETP and GALNT2 mutations were found in 136 unrelated probands with low HDLc. Taken together, we show that rare coding and splicing mutations in LIPG, CETP, and GALNT2 are enriched in persons with hyperalphalipoproteinemia and segregate with elevated HDLc in families. Moreover, LIPG mutations do not overcome low HDLc in individuals with ABCA1 and possibly LCAT and LPL mutations, indicating that LIPG affects HDLc levels downstream of these proteins.
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Tietjen
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: Chris
authors.initials: C
authors.lastname: Radomski
authors.forename: Amina
authors.initials: A
authors.lastname: Barhdadi
authors.forename: Jason
authors.initials: J
authors.lastname: McEwen
authors.forename: Elden
authors.initials: E
authors.lastname: Chan
authors.forename: Maryanne
authors.initials: M
authors.lastname: Mattice
authors.forename: Annick
authors.initials: A
authors.lastname: Legendre
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Franchini
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000368:Aged; D017398:Alternative Splicing; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D008076:Cholesterol, HDL / Q000235:genetics*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D008049:Lipase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D044465:White People; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008049:Lipase; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C577836:ABCA1 protein, human; C506642:CETP protein, human; C410382:LIPG protein, human