title: Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia.
abstract: OBJECTIVE
  The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to the loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG > 10 mmol L(-1) ), it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam.
  
  
  METHODS
  The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls.
  
  
  RESULTS
  In 46 patients (54%), rare DNA sequence variants were identified, comprising variants in LPL (n = 19), APOC2 (n = 1), APOA5 (n = 2), GPIHBP1 (n = 3) and LMF1 (n = 8). In 22 patients (26%), only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype.
  
  
  CONCLUSIONS
  The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n = 3), APOC2 (n = 1) and APOA5 (n = 2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis and may help to guide future individualized therapeutic strategies.
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: R P
authors.initials: RP
authors.lastname: Surendran
authors.forename: M E
authors.initials: ME
authors.lastname: Visser
authors.forename: S
authors.initials: S
authors.lastname: Heemelaar
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Peter
authors.forename: J C
authors.initials: JC
authors.lastname: Defesche
authors.forename: J A
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: M
authors.initials: M
authors.lastname: Hosseini
authors.forename: M
authors.initials: M
authors.lastname: Péterfy
authors.forename: J J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: C T
authors.initials: CT
authors.lastname: Johansen
authors.forename: R A
authors.initials: RA
authors.lastname: Hegele
authors.forename: E S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: G M
authors.initials: GM
authors.lastname: Dallinga-Thie
mesh_terms: D000328:Adult; D000072040:Apolipoprotein A-V; D053304:Apolipoprotein C-II / Q000235:genetics; D001054:Apolipoproteins A / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D015228:Hypertriglyceridemia / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D017720:Molecular Epidemiology; D020125:Mutation, Missense; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D018110:Receptors, Lipoprotein; D012720:Severity of Illness Index
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D053304:Apolipoprotein C-II; D001054:Apolipoproteins A; D002352:Carrier Proteins; C523701:GPIHBP1 protein, human; C546366:LMF1 protein, human; D008565:Membrane Proteins; D018110:Receptors, Lipoprotein; C548261:LPL protein, human; D008071:Lipoprotein Lipase