title: Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred.
abstract: Defect of growth hormone receptor (GHR) is classically known to cause Laron syndrome, characterized by short stature, specific facial appearance, elevated serum growth hormone levels, and decreased insulin-like growth factor I levels. In addition, an increased cardiovascular risk due to elevated plasma total and LDL cholesterol levels marks another feature of the disease. Growth hormone (GH) plays an important role in the regulation of lipoprotein metabolism. GH status was found to be an independent determinant of plasma total cholesterol and triglyceride levels in humans. We studied a total of 207 members of eight-generation extended family of familial hypercholesterolemia (FH) in which affected members presented with various lipoprotein phenotypes. Intra-familial correlation analysis of a modifier effect of a Leu526Ile substitution in GHR gene was carried out among 95 carriers for LDL receptor gene (LDLR) mutation and 112 non-carriers. When plasma high-density lipoprotein cholesterol (HDL-c) levels in the LDLR-mutation carriers were compared, a significant lowering effect of HDL-c was observed with the Leu allele; the values were lowest among Leu/Leu homozygotes (mean +/- SD = 37 +/- 2 mg/dl), highest in Ile/Ile homozygotes (50 +/- 4 mg/dl), and intermediate among Leu/Ile heterozygotes (41 +/- 2 mg/dl) (P = 0.0021). The results indicate a significant modification of the phenotype of FH with the defective LDLR allele, by GHR Leu variation in the kindred studied.
authors.affiliation: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ezura
authors.forename: Shuji
authors.initials: S
authors.lastname: Ono
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iino
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Katayama
authors.forename: Yuanpei
authors.initials: Y
authors.lastname: Xin
authors.forename: Lily L
authors.initials: LL
authors.lastname: Wu
authors.forename: Stacey
authors.initials: S
authors.lastname: Larringa-Shum
authors.forename: Susan H
authors.initials: SH
authors.lastname: Stephenson
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D003062:Codon; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D007532:Isoleucine / Q000235:genetics; D007930:Leucine / Q000235:genetics; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D010949:Plasma; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics; D011986:Receptors, Somatotropin / Q000235:genetics* / Q000378:metabolism
chemical_list: D008076:Cholesterol, HDL; D003062:Codon; D008074:Lipoproteins; D011973:Receptors, LDL; D011986:Receptors, Somatotropin; D007532:Isoleucine; D007930:Leucine