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Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study.
Arterioscler Thromb Vasc Biol. 2015 Jul; 35(7):1704-11.AT

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).

APPROACH AND 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+Show Affiliations

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.).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.).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.).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.).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.).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.).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.).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.).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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Twin Study

Language

eng

PubMed ID

25953646

Citation

Rao, Fangwen, et al. "Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 35, no. 7, 2015, pp. 1704-11.
Rao F, Schork AJ, Maihofer AX, et al. Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study. Arterioscler Thromb Vasc Biol. 2015;35(7):1704-11.
Rao, F., Schork, A. J., Maihofer, A. X., Nievergelt, C. M., Marcovina, S. M., Miller, E. R., Witztum, J. L., O'Connor, D. T., & Tsimikas, S. (2015). Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(7), 1704-11. https://doi.org/10.1161/ATVBAHA.115.305306
Rao F, et al. Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study. Arterioscler Thromb Vasc Biol. 2015;35(7):1704-11. PubMed PMID: 25953646.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study. AU - Rao,Fangwen, AU - Schork,Andrew J, AU - Maihofer,Adam X, AU - Nievergelt,Caroline M, AU - Marcovina,Santica M, AU - Miller,Elizabeth R, AU - Witztum,Joseph L, AU - O'Connor,Daniel T, AU - Tsimikas,Sotirios, Y1 - 2015/05/07/ PY - 2015/01/12/received PY - 2015/04/14/accepted PY - 2015/5/9/entrez PY - 2015/5/9/pubmed PY - 2015/9/12/medline KW - atherosclerosis KW - genetics KW - lipoprotein(a) KW - lipoproteins KW - oxidation KW - thrombosis KW - twins SP - 1704 EP - 11 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 35 IS - 7 N2 - 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). APPROACH AND 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/25953646/Heritability_of_Biomarkers_of_Oxidized_Lipoproteins:_Twin_Pair_Study_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.115.305306?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -