title: Genetic polymorphisms affecting the phenotypic expression of familial hypercholesterolemia.
abstract: The clinical expression of heterozygous familial hypercholesterolemia (FH) is highly variable even in patients carrying the same LDL receptor (LDL-R) gene mutation. This variability might be due to environmental factors as well as to modifying genes affecting lipoprotein metabolism. We investigated Apo E (2, 3, 4), MTP (-493G/T), Apo B (-516C/T), Apo A-V (-1131T/C), HL (-514C/T and -250G/A), FABP-2 (A54T), LPL (D9N, N291S, S447X) and ABCA1 (R219K) polymorphisms in 221 unrelated FH index cases and 349 FH relatives with defined LDL-R gene mutations. We found a significant and independent effect of the following polymorphisms on: (i) plasma LDL-C (Apo E, MTP and Apo B); (ii) plasma HDL-C (HL, FABP-2 and LPL S447X); (iii) plasma triglycerides (Apo E and Apo A-V). In subjects with coronary artery disease (CAD+), the prevalence of FABP-2 54TT genotype was higher (16.5% versus 5.2%) and that of ABCA1 219RK and KK genotypes lower (33.0% versus 51.5%) than in subjects with no CAD. Independent predictors of increased risk of CAD were male sex, age, arterial hypertension, LDL-C level and FABP-2 54TT genotype, and of decreased risk the 219RK and KK genotypes of ABCA1. These findings show that several common genetic variants influence the lipid phenotype and the CAD risk in FH heterozygotes.
authors.affiliation: Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, I-16132 Genoa, Italy. stefbert@unige.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.forename: Livia
authors.initials: L
authors.lastname: Pisciotta
authors.forename: Lilla
authors.initials: L
authors.lastname: Di Scala
authors.forename: Silvia
authors.initials: S
authors.lastname: Langheim
authors.forename: Antonella
authors.initials: A
authors.lastname: Bellocchio
authors.forename: Paola
authors.initials: P
authors.lastname: Masturzo
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cantafora
authors.forename: Scipione
authors.initials: S
authors.lastname: Martini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Averna
authors.forename: Gianni
authors.initials: G
authors.lastname: Pes
authors.forename: Claudio
authors.initials: C
authors.lastname: Stefanutti
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
mesh_terms: D000328:Adult; D001053:Apolipoproteins / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000032:analysis; D008078:Cholesterol, LDL / Q000032:analysis; D015331:Cohort Studies; D016001:Confidence Intervals; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology* / Q000235:genetics*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016017:Odds Ratio; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011973:Receptors, LDL / Q000235:genetics; D018570:Risk Assessment
chemical_list: D001053:Apolipoproteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011973:Receptors, LDL