title: The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients.
abstract: OBJECTIVE
  Hypercholesterolaemia is a major risk factor for atherosclerosis. Cholesterol is modulated by genetic and environmental factors. An important regulatory pathway is controlled by the sterol-regulatory element-binding proteins (SREBPs) and the SREBP cleavage-activating protein (SCAP). Both SREBP-2 and SCAP are candidates to contribute to the development of atherosclerosis. We investigated the possible effects of the variability of proteins involved in this regulatory pathway on plasma lipids among familial hypercholesterolaemia patients.
  
  
  RESULTS
  Single nucleotide polymorphisms (SNPs) in the genes encoding SREBP-2 and SCAP causing amino acid changes at positions 595 (595G/A) and 796 (796I/V), respectively, were genotyped in 801 FH individuals originating from Israel, The Netherlands, and Switzerland. A linear regression model to examine the associations between SREBP-2 and SCAP isoforms and lipid and lipoprotein levels was used. In females, homozygosity either for the SREBP-2-595A or for the SCAP-796I isoform was associated with higher LDL-cholesterol plasma concentrations (14.7 mg/dl and 20.3 mg/dl, respectively). Surprisingly, heterozygosity for the combination SREBP-2-595A/SCAP-796I was associated with a decrease of 30.28 mg/dl in LDL-C (p-value for gene-gene interaction=0.09). No such effect was observed among FH males. Subgroup analysis considering the most frequent (N>/=24) LDL receptor mutations (del191-2, ins313+1-2, C660X, E207K, S285L) revealed further gene-dosage- and gender-dependent effects of the SCAP mutations on LDL-cholesterol concentrations (p=0.0345). These effects were, however, not present when less frequent LDL receptor mutations were investigated.
  
  
  CONCLUSIONS
  These results suggest a possible gene-gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. Further investigation is needed to confirm this effect. A study in a larger FH group or in non-FH hypercholesterolaemic subjects may further define the role of this regulatory mechanism in determining plasma lipid concentration.
authors.affiliation: Internal Medicine Division, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Durst@cc.huji.ac.il
authors.forename: R
authors.initials: R
authors.lastname: Durst
authors.forename: A
authors.initials: A
authors.lastname: Jansen
authors.forename: G
authors.initials: G
authors.lastname: Erez
authors.forename: R
authors.initials: R
authors.lastname: Bravdo
authors.forename: E
authors.initials: E
authors.lastname: Butbul
authors.forename: L
authors.initials: L
authors.lastname: Ben Avi
authors.forename: S
authors.initials: S
authors.lastname: Shpitzen
authors.forename: C
authors.initials: C
authors.lastname: Lotan
authors.forename: E
authors.initials: E
authors.lastname: Leitersdorf
authors.forename: J
authors.initials: J
authors.lastname: Defesche
authors.forename: Y
authors.initials: Y
authors.lastname: Friedlander
authors.forename: V
authors.initials: V
authors.lastname: Meiner
authors.forename: A R
authors.initials: AR
authors.lastname: Miserez
mesh_terms: D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000235:genetics; D004247:DNA / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007557:Israel; D008055:Lipids / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009426:Netherlands; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*; D013557:Switzerland
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; D051782:Sterol Regulatory Element Binding Protein 2; D004247:DNA