title: High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin.
abstract: Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles "Del" and "4G". The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G) are at high risk for the onset of CVDs.
authors.affiliation: Reviva Regenerative Medicine Center, Human Genetic Center, Middle East Institute of Health Hospital, Bsalim, Lebanon; Laboratory of Applied Biotechnology, Azm Center for the Research in Biotechnology and its Applications, Doctoral School for Sciences and Technology, Lebanese University, Tripoli, Lebanon.
authors.forename: Jeanne d'Arc
authors.initials: Jd
authors.lastname: AlBacha
authors.affiliation: Reviva Regenerative Medicine Center, Human Genetic Center, Middle East Institute of Health Hospital, Bsalim, Lebanon.
authors.forename: Mira
authors.initials: M
authors.lastname: Khoury
authors.affiliation: Department of Biology, Faculty of Science, Section III, Lebanese University, El Kobeh, Lebanon.
authors.forename: Charbel
authors.initials: C
authors.lastname: Mouawad
authors.affiliation: Department of Biology, Faculty of Science, Section III, Lebanese University, El Kobeh, Lebanon.
authors.forename: Katia
authors.initials: K
authors.lastname: Haddad
authors.affiliation: Department of Biology, Faculty of Science, Section III, Lebanese University, El Kobeh, Lebanon.
authors.forename: Samar
authors.initials: S
authors.lastname: Hamoui
authors.affiliation: Reviva Regenerative Medicine Center, Human Genetic Center, Middle East Institute of Health Hospital, Bsalim, Lebanon.
authors.forename: Albert
authors.initials: A
authors.lastname: Azar
authors.affiliation: Reviva Regenerative Medicine Center, Human Genetic Center, Middle East Institute of Health Hospital, Bsalim, Lebanon; Laboratory of Applied Biotechnology, Azm Center for the Research in Biotechnology and its Applications, Doctoral School for Sciences and Technology, Lebanese University, Tripoli, Lebanon.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Fajloun
authors.affiliation: Reviva Regenerative Medicine Center, Human Genetic Center, Middle East Institute of Health Hospital, Bsalim, Lebanon; Department of Biology, Faculty of Science, Section III, Lebanese University, El Kobeh, Lebanon.
authors.forename: Nehman
authors.initials: N
authors.lastname: Makdissy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000069059:Atorvastatin / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D007861:Lebanon; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017257:Ramipril / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D000069059:Atorvastatin; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril