title: Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload.
abstract: Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93%, P< 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n=7) presented a reduced β-cell function and insulin secretion compared with non-C282Y patients (n=11) (-58% and -73%, respectively, P< 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43±5; non-C282Y: 25±8; controls: 32±7%; P< 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23±5; non-C282Y: 39±10; controls: 26±4%; P< 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined.
authors.affiliation: *Laboratory of Lipids and Lipoproteins, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Junín 956, 1113 Buenos Aires, Argentina.
authors.forename: Tomás
authors.initials: T
authors.lastname: Meroño
authors.affiliation: *Laboratory of Lipids and Lipoproteins, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Junín 956, 1113 Buenos Aires, Argentina.
authors.forename: Fernando
authors.initials: F
authors.lastname: Brites
authors.affiliation: †National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie-Paris 6, AP-HP, Groupe hospitalier Pitié-Salpétrière, ICAN, Paris F-75013, France.
authors.forename: Carolane
authors.initials: C
authors.lastname: Dauteuille
authors.affiliation: †National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie-Paris 6, AP-HP, Groupe hospitalier Pitié-Salpétrière, ICAN, Paris F-75013, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lhomme
authors.affiliation: *Laboratory of Lipids and Lipoproteins, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Junín 956, 1113 Buenos Aires, Argentina.
authors.forename: Martín
authors.initials: M
authors.lastname: Menafra
authors.affiliation: ‡Hepatology Division, Hospital "José de San Martín", University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Arteaga
authors.affiliation: §Department of Hemotherapy and Immunohematology, Hospital "José de San Martín", University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Castro
authors.affiliation: ║Central Laboratory, Italian Hospital of Buenos Aires, Buenos Aires, Argentina.
authors.forename: María Soledad
authors.initials: MS
authors.lastname: Saez
authors.affiliation: ‡Hepatology Division, Hospital "José de San Martín", University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Esteban González
authors.initials: EG
authors.lastname: Ballerga
authors.affiliation: ║Central Laboratory, Italian Hospital of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sorroche
authors.affiliation: §Department of Hemotherapy and Immunohematology, Hospital "José de San Martín", University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Jorge
authors.initials: J
authors.lastname: Rey
authors.affiliation: †National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie-Paris 6, AP-HP, Groupe hospitalier Pitié-Salpétrière, ICAN, Paris F-75013, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lesnik
authors.affiliation: ‡Hepatology Division, Hospital "José de San Martín", University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Juan Andrés
authors.initials: JA
authors.lastname: Sordá
authors.affiliation: †National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie-Paris 6, AP-HP, Groupe hospitalier Pitié-Salpétrière, ICAN, Paris F-75013, France.
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: †National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie-Paris 6, AP-HP, Groupe hospitalier Pitié-Salpétrière, ICAN, Paris F-75013, France.
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
authors.affiliation: ‡Hepatology Division, Hospital "José de San Martín", University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Jorge
authors.initials: J
authors.lastname: Daruich
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D019190:Iron Overload / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007328:Insulin; D008565:Membrane Proteins