title: Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred.
abstract: Plasma lipid and lipoprotein in general reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH in which 69 members were affected with type IIa hyperlipoproteinemia (HLPIIa; high plasma cholesterol) and ten with type IIb hyperlipoproteinemia (HLPIIb; high plasma cholesterol as well as plasma triglyceride). Soluble epoxide hydrolase ( EPHX2, sEH) plays a role in disposition of epoxides in plasma lipoprotein particles. Intrafamilial correlation analysis of the modifier effect of Glu287Arg substitution in the EPHX2 gene was carried out among 79 LDLR mutation carriers and 81 noncarriers. In the carriers, plasma cholesterol levels were elevated among carriers of the 287Arg allele (mean +/- SD=358 +/- 72 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=302 +/- 72 mg/dl) (p=0.0087). Similarly, in the LDLR mutation carriers, the plasma triglyceride levels were elevated among carriers of the 287Arg allele (mean +/- SD=260 +/- 100 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=169 +/- 83 mg/dl) (p=0.020). No such gene-interactive effect was observed among noncarriers of the LDLR mutation. Half of the patients who presented with HLPIIb had inherited a defective LDLR allele as well as an EPHX2-287Arg allele, whereas the majority who presented with HLPIIa had a defective LDLR allele but not an EPHX2-287Arg allele. These results indicate a significant modification of the phenotype of FH with defective LDLR allele by EPHX2-287Arg variation in our studied kindred.
authors.affiliation: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Kawasaki 211-8533, Japan.|Department of Second Internal Medicine, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Kawasaki 211-8533, Japan. memi@nms.ac.jp.|Department of Second Internal Medicine, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan. memi@nms.ac.jp.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
authors.affiliation: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Kawasaki 211-8533, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ezura
authors.affiliation: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Kawasaki 211-8533, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Kawasaki 211-8533, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takada
authors.affiliation: Department of Second Internal Medicine, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishigami
authors.affiliation: Department of Second Internal Medicine, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
authors.affiliation: Cardiovascular Genetics Research Clinic, University of Utah Hearth Science Center, 410 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Yunpei
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Cardiovascular Genetics Research Clinic, University of Utah Hearth Science Center, 410 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Lily L
authors.initials: LL
authors.lastname: Wu
authors.affiliation: Cardiovascular Genetics Research Clinic, University of Utah Hearth Science Center, 410 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Larrinaga-Shum
authors.affiliation: Cardiovascular Genetics Research Clinic, University of Utah Hearth Science Center, 410 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Stephenson
authors.affiliation: Cardiovascular Genetics Research Clinic, University of Utah Hearth Science Center, 410 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.affiliation: Cardiovascular Genetics Research Clinic, University of Utah Hearth Science Center, 410 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
mesh_terms: D000483:Alleles; D002784:Cholesterol / Q000097:blood*; D004851:Epoxide Hydrolases / Q000235:genetics*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014280:Triglycerides / Q000097:blood*; D014589:Utah
chemical_list: D014280:Triglycerides; D002784:Cholesterol; D004851:Epoxide Hydrolases