氧化型低密度脂蛋白抗体在抗磷脂综合征中的临床意义

doi:10.19723/j.issn.1671-167X.2022.06.010

摘要/Abstract

摘要：

目的: 探讨氧化型低密度脂蛋白抗体(oxidized low-density lipoprotein antibodies, ox-LDL-Ab)在抗磷脂综合征(antiphospholipid syndrome, APS)中的分布及其临床意义。方法: 共纳入334例患者，包括162例APS患者，122例无血栓或病态妊娠的其他自身免疫性疾病患者作为疾病对照，以及50例健康对照。收集APS患者的临床资料及实验室检查指标，采用酶联免疫吸附试验检测患者的ox-LDL-Ab、IgG/IgA/IgM型抗心磷脂抗体(anticardioli-pin, aCL)、IgG/IgA/IgM型抗β2糖蛋白Ⅰ抗体(anti-β2-glycoprotein Ⅰ, aβ2GPI)。采用统计软件SPSS 27.0分析ox-LDL-Ab与临床及实验室检查指标之间的相关性。结果: APS组60.5%的患者合并血栓，48.1%的患者出现病态妊娠，34.0%的患者合并血小板减少，aCL、aβ2GPI和狼疮抗凝物(lupus anticoagulant, LAC)的阳性率分别为17.9%、34.6%和46.9%。ox-LDL-Ab在APS患者中的滴度和阳性率显著高于健康对照组[滴度：40.8 (25.4~66.0) U/mL vs. 24.1 (12.3~36.5) U/mL, P=0.001；阳性率：67.3% vs. 36.0%, P=0.001]，与疾病对照组的差异无统计学意义[滴度：40.8 (25.4~66.0) U/mL vs. 35.9 (24.2~53.1) U/mL, P=0.118；阳性率：67.3% vs. 61.5%, P=0.318]。aβ2GPI、aCL、ox-LDL-Ab的曲线下面积分别是0.745 (95%CI: 0.692~0.797)、0.666 (95%CI: 0.608~0.724)、0.609 (95%CI: 0.549~0.669)，约登指数(Youden’s index)分别为0.388、0.269、0.132。ox-LDL-Ab在血清阴性APS中的曲线下面积是0.562 (95%CI: 0.480~0.645)，敏感性和特异性分别为63.9%和47.0%，约登指数为0.109。ox-LDL-Ab阳性组aβ2GPI (42.2% vs. 18.9%, P=0.003)和aCL (22.9% vs. 7.5%, P=0.017)的阳性率高于ox-LDL-Ab阴性组。ox-LDL-Ab与血栓形成、冠心病、病态妊娠、高脂血症、低补体血症及LAC阳性率无相关性。结论: ox-LDL-Ab与aCL、aβ2GPI有一定相关性，但与血栓、病态妊娠及冠心病不相关。

关键词: 氧化型低密度脂蛋白抗体, 抗磷脂综合征, 血栓形成, 抗磷脂抗体

Abstract:

Objective: To investigate the significance and distribution of oxidized low-density lipoprotein antibodies (ox-LDL-Ab) in patients with antiphospholipid syndrome (APS). Methods: In this study, 334 patients who were hospitalized in the Department of Rheumatology and Immunology, Peking University People's Hospital were included. There were 162 APS patients, 122 patients with other autoimmune diseases without thrombosis or obstetric disease as disease control and 50 healthy controls. The clinical data and laboratory indicators were retrospectively collected. The ox-LDL-Ab, anticardiolipin (aCL) IgG/IgA/IgM, and anti-β2-glycoprotein Ⅰ (aβ2GPI) IgG/IgA/IgM were detected by enzyme-linked immunosorbent assay (ELISA). The relationship between ox-LDL-Ab and clinical and laboratory parameters were analyzed by SPSS 27.0. Results: In APS group, 60.5% of patients had thrombosis, 48.1% had pregnancy morbidity, 34.0% had thrombocytopenia. The positive rates of aCL, aβ2GPI and lupus anticoagulant (LAC) were 17.9%, 34.6%, and 46.9%, respectively. The ox-LDL-Ab titers and positive rate in APS group were higher than that in healthy controls [titers: 40.8 (25.4-66.0) U/mL vs. 24.1 (12.3-36.5) U/mL, P=0.001; positive rate: 67.3% vs. 36.0%, P=0.001]. The diffe-rences in titers and positive rate of ox-LDL-Ab between APS patients and disease controls were not statistically significant [titers: 40.8 (25.4-66.0) U/mL vs. 35.9 (24.2-53.1) U/mL, P=0.118; positive rate: 67.3% vs. 61.5%, P=0.318]. The area under curve (AUC) for aβ2GPI, aCL, and ox-LDL-Ab were 0.745 (95%CI: 0.692-0.797), 0.666 (95%CI: 0.608-0.724), 0.609 (95%CI: 0.549-0.669), respectively. The Youden's index was 0.388, 0.269, and 0.132, respectively. The AUC for ox-LDL-Ab in seronegative APS patients was 0.562 (95%CI: 0.480-0.645). The sensitivity and specificity of ox-LDL-Ab in seronegative APS patients were 63.9% and 47.0%, respectively, and the Youden's index was 0.109. The ox-LDL-Ab positive group had higher positive rate of aβ2GPI (42.2% vs. 18.9%, P=0.003) and aCL (22.9% vs. 7.5%, P=0.017) than the ox-LDL-Ab negative group. There was no correlation between ox-LDL-Ab and thrombosis, coronary artery disease, pregnancy morbidity, hyperlipidemia, hypocomplementemia, and LAC positivity. Conclusion: Ox-LDL-Ab was correlated with aCL and aβ2GPI, and no association were observed between ox-LDL-Ab and thrombosis, coronary artery disease, and pregnancy morbidity.

Key words: Oxidized low-density lipoprotein antibodies, Antiphospholipid syndrome, Thrombosis, Antiphospholipid antibodies

中图分类号:

R593.2

侯玉珂,蔡青猛,刘香君,贠泽霖,李春,张学武. 氧化型低密度脂蛋白抗体在抗磷脂综合征中的临床意义[J]. 北京大学学报（医学版）, 2022, 54(6): 1117-1122.

Yu-ke HOU,Qing-meng CAI,Xiang-jun LIU,Ze-lin YUN,Chun LI,Xue-wu ZHANG. Clinical significance of oxidized low-density lipoprotein antibody in antiphospholipid syndrome[J]. Journal of Peking University (Health Sciences), 2022, 54(6): 1117-1122.

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参考文献 23

1	Devreese KMJ , Ortel TL , Pengo V , et al. Laboratory criteria for antiphospholipid syndrome: Communication from the SSC of the ISTH[J]. J Thromb Haemost, 2018, 16 (4): 809- 813. doi: 10.1111/jth.13976
2	Conti F , Andreoli L , Crisafulli F , et al. Does seronegative obstetric APS exist? "pro" and "cons"[J]. Autoimmun Rev, 2019, 18 (12): 102407. doi: 10.1016/j.autrev.2019.102407
3	Abreu MM , Danowski A , Wahl DG , et al. The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Anti-bodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features[J]. Autoimmun Rev, 2015, 14 (5): 401- 414. doi: 10.1016/j.autrev.2015.01.002
4	Hulthe J . Antibodies to oxidized LDL in atherosclerosis development: Clinical and animal studies[J]. Clin Chim Acta, 2004, 348 (1/2): 1- 8.
5	Steinberg D . Low density lipoprotein oxidation and its pathobio-logical significance[J]. J Biol Chem, 1997, 272 (34): 20963- 20966. doi: 10.1074/jbc.272.34.20963
6	Salonen JT , Ylä-Herttuala S , Yamamoto R , et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis[J]. Lancet, 1992, 339 (8798): 883- 887. doi: 10.1016/0140-6736(92)90926-T
7	Vaarala O . Antiphospholipid antibodies and atherosclerosis[J]. Lupus, 1996, 5 (5): 442- 447. doi: 10.1177/096120339600500522
8	Ryan M , Owens D , Kilbride B , et al. Antibodies to oxidized lipoproteins and their relationship to myocardial infarction[J]. QJM, 1998, 91 (6): 411- 415. doi: 10.1093/qjmed/91.6.411
9	Bellomo G , Maggi E , Poli M , et al. Autoantibodies against oxidatively modified low-density lipoproteins in NIDDM[J]. Diabetes, 1995, 44 (1): 60- 66. doi: 10.2337/diab.44.1.60
10	Lopez D , Kobayashi K , Merrill JT , et al. IgG autoantibodies against beta2-glycoprotein Ⅰ complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome[J]. Clin Dev Immunol, 2003, 10 (2/3/4): 203- 211.
11	Romero FI , Amengual O , Atsumi T , et al. Arterial disease in lupus and secondary antiphospholipid syndrome: association with anti-beta2-glycoprotein Ⅰ antibodies but not with antibodies against oxidized low-density lipoprotein[J]. Br J Rheumatol, 1998, 37 (8): 883- 888. doi: 10.1093/rheumatology/37.8.883
12	Bec'arevic' M , Andrejevic' S , Miljic' P , et al. Serum lipids and anti-oxidized LDL antibodies in primary antiphospholipid syndrome[J]. Clin Exp Rheumatol, 2007, 25 (3): 361- 366.
13	Miyakis S , Lockshin MD , Atsumi T , et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)[J]. J Thromb Haemost, 2006, 4 (2): 295- 306. doi: 10.1111/j.1538-7836.2006.01753.x
14	Rezende L , Couto NFD , Fernandes-Braga W , et al. OxLDL induces membrane structure rearrangement leading to biomechanics alteration and migration deficiency in macrophage[J]. Biochim Biophys Acta Biomembr, 2022, 1864 (9): 183951. doi: 10.1016/j.bbamem.2022.183951
15	Hartley A , Haskard D , Khamis R . Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis: Novel insights and future directions in diagnosis and therapy[J]. Trends Cardiovasc Med, 2019, 29 (1): 22- 26. doi: 10.1016/j.tcm.2018.05.010
16	Itakura H , Yokoyama M , Matsuzaki M , et al. Relationships between plasma fatty acid composition and coronary artery disease[J]. J Atheroscler Thromb, 2011, 18 (2): 99- 107. doi: 10.5551/jat.5876
17	Yang SH , Li YT , Du DY . Oxidized low-density lipoprotein-induced CD147 expression and its inhibition by high-density lipoprotein on platelets in vitro[J]. Thromb Res, 2013, 132 (6): 702- 711. doi: 10.1016/j.thromres.2013.10.003
18	Strobel NA , Fassett RG , Marsh SA , et al. Oxidative stress biomarkers as predictors of cardiovascular disease[J]. Int J Cardiol, 2011, 147 (2): 191- 201. doi: 10.1016/j.ijcard.2010.08.008
19	Jiang D , Lim W , Crowther M , et al. A systematic review of the association between anti-beta-2 glycoprotein Ⅰ antibodies and APS manifestations[J]. Blood Adv, 2021, 5 (20): 3931- 3936. doi: 10.1182/bloodadvances.2021005205
20	Hayem G , Nicaise-Roland P , Palazzo E , et al. Anti-oxidized low-density-lipoprotein (OxLDL) antibodies in systemic lupus erythematosus with and without antiphospholipid syndrome[J]. Lupus, 2001, 10 (5): 346- 351. doi: 10.1191/096120301667475689
21	Li J , Chi Y , Liu S , et al. Recombinant domain V of β2-glycoprotein Ⅰ inhibits the formation of atherogenic oxLDL/β2-glycoprotein Ⅰ complexes[J]. J Clin Immunol, 2014, 34 (6): 669- 676.
22	Matsuura E , Lopez LR . Autoimmune-mediated atherothrombosis[J]. Lupus, 2008, 17 (10): 878- 887.
23	白玲, 谭雪峰, 刘平. 冠心病患者抗心磷脂抗体与PON、ox-LDL、MDA和SOD的相关性[J]. 心脏杂志, 2014, 26 (4): 453- 455.

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Parameters	APS patients (n=162)	Disease controls (n=122)	Healthy controls (n=50)
Age/years	41.7±15.2	48.8±16.6	42.4±10.3
Gender (female)	143 (88.3)	106 (86.9)	33 (66.0)
Thrombosis	98 (60.5)	0 (0)	0 (0)
Venous thrombosis	61 (37.7)	0 (0)	0 (0)
Deep venous thrombosis	40 (24.7)	0 (0)	0 (0)
Pulmonary embolism	19 (11.7)	0 (0)	0 (0)
Arterial thrombosis	56 (34.6)	0 (0)	0 (0)
Cerebral infarction	35 (21.6)	0 (0)	0 (0)
CAD	8 (4.9)	0 (0)	0 (0)
Atherosclerosis	47 (29.0)	0 (0)	0 (0)
Both venous and arterial thrombosis	19 (11.7)	0 (0)	0 (0)
Pregnancy morbidity	78 (48.1)	0 (0)	0 (0)
Both thrombosis and pregnancy morbidity	14 (8.6)	0 (0)	0 (0)
Livedo reticularis	1 (0.6)	0 (0)	0 (0)
Thrombocytopenia	55 (34.0)	0 (0)	0 (0)
aCL IgG/IgA/IgM (+)	29 (17.9)	0 (0)	0 (0)
aβ2GPI IgG/IgA/IgM (+)	56 (34.6)	2 (1.6)	1 (2.0)
LAC (+)	76 (46.9)	8 (6.6)	0 (0)
Double positive aPLs	29 (17.9)	0 (0)	0 (0)
Triple positive aPLs	34 (21.0)	0 (0)	0 (0)
Triple negative aPLs^*	42 (25.9)	111 (91.0)	49 (98.0)
ox-LDL-Ab (+)	109 (67.3)	75 (61.5)	18 (36.0)

Parameters	ox-LDL-Ab (+)(n=109), n (%)	ox-LDL-Ab (-)(n=53), n (%)	P value
Thrombosis	65 (59.6)	33 (62.3)	0.748
Arterial thrombosis	37 (33.9)	19 (35.8)	0.811
Venous thrombosis	42 (38.5)	19 (35.8)	0.741
Pulmonary embolism	12 (11.0)	7 (13.2)	0.683
Cerebral infarction	22 (20.2)	13 (24.5)	0.548
CAD	5 (4.6)	3 (5.7)	0.719
Pregnancy morbidity^*	54 (55.1)	24 (53.3)	0.844
Neuropsychiatric symptoms	8 (7.3)	7 (13.2)	0.254
Hyperlipidemia	36 (33.0)	14 (26.4)	0.393
Hyper-LDL-C^#	7 (8.1)	4 (9.1)	>0.999
Hypo-HDL-C^#	35 (40.2)	18 (40.9)	0.940
Hyper-TCHO^#	4 (4.5)	3 (6.7)	0.604
aβ2GPI IgG/IgA/IgM (+)	46 (42.2)	10 (18.9)	0.003
aCL IgG/IgA/IgM (+)	25 (22.9)	4 (7.5)	0.017
LAC (+)	50 (45.9)	26 (49.1)	0.703
Thrombocytopenia	35 (32.1)	20 (37.7)	0.478
Hypocomplementemia^△	36 (42.4)	20 (45.5)	0.736

Negative antibody	Sensitivity	Specificity	Youden’s index
aCL	0.632	0.462	0.094
aβ2GPI	0.594	0.467	0.061
aCL+aβ2GPI	0.578	0.470	0.048
aCL+LAC	0.653	0.462	0.115
aβ2GPI+LAC	0.656	0.467	0.123
LAC+aCL+aβ2GPI	0.639	0.470	0.109

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