title: Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study.
abstract: OBJECTIVE
  To determine whether biomarkers of oxidized lipoproteins are genetically determined. Lipoprotein(a) (Lp[a]) is a heritable risk factor and carrier of oxidized phospholipids (OxPL).
  
  
  RESULTS
  We measured oxidized phospholipids on apolipoprotein B-containing lipoproteins (OxPL-apoB), Lp(a), IgG, and IgM autoantibodies to malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes in 386 monozygotic and dizygotic twins to estimate trait heritability (h(2)) and determine specific genetic effects among traits. A genome-wide linkage study followed by genetic association was performed. The h(2) (scale: 0-1) for Lp(a) was 0.91±0.01 and for OxPL-apoB 0.87±0.02, which were higher than physiological, inflammatory, or lipid traits. h(2) of IgM malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes were 0.69±0.04, 0.67±0.05, and 0.80±0.03, respectively, and for IgG malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes 0.62±0.05, 0.52±0.06, and 0.53±0.06, respectively. There was an inverse correlation between the major apo(a) isoform and OxPL-apoB (R=-0.49; P<0.001) and Lp(a) (R=-0.48; P<0.001) and OxPL-apoB was modestly correlated with Lp(a) (ρ=0.57; P<0.0001). The correlation in major apo(a) isoform size was concordant (R=1.0; P<0.001) among monozygotic twins but not dizygotic twins (R=0.40; P=0.055). Lp(a) and OxPL-apoB shared genetic codetermination (genetic covariance, ρG=0.774±0.032; P=1.09×10(-38)), although not environmental determination (environmental covariance, ρE=0.081±0.15; P=0.15). In contrast, Lp(a) shared environmental but not genetic codetermination with autoantibodies to malondialdehyde-modified low-density lipoprotein and copper oxidized low-density lipoprotein, and apoB-immune complexes. Sib-pair genetic linkage of the Lp(a) trait revealed that single nucleotide polymorphism rs10455872 was significantly associated with OxPL-apoB after adjusting for Lp(a).
  
  
  CONCLUSIONS
  OxPL-apoB and other biomarkers of oxidized lipoproteins are highly heritable cardiovascular risk factors that suggest novel genetic origins of atherothrombosis.
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Adam X
authors.initials: AX
authors.lastname: Maihofer
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Santica M
authors.initials: SM
authors.lastname: Marcovina
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Miller
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.).
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
authors.affiliation: From the Departments of Medicine (F.R., A.J.S., E.R.M., J.L.W., D.T.O., S.T.) and Psychiatry (A.X.M., C.M.N.), University of California, La Jolla; and University of Washington, Seattle (S.M.M.). stsimikas@ucsd.edu.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000936:Antigen-Antibody Complex / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000276:immunology; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000097:blood / Q000276:immunology; D010743:Phospholipids / Q000097:blood; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000936:Antigen-Antibody Complex; D001055:Apolipoproteins B; D001323:Autoantibodies; D015415:Biomarkers; D008078:Cholesterol, LDL; D008074:Lipoproteins; D010446:Peptide Fragments; D010743:Phospholipids; C093007:apolipoprotein B (3304-3317); D008315:Malondialdehyde
keywords: atherosclerosis; genetics; lipoprotein(a); lipoproteins; oxidation; thrombosis; twins