Lipoprotein(a) (Lp(a)) is one of the most amazing liver-derived lipoprotein particles in humans. During the past decades, more and more convincing evidences have revealed that the plasma Lp(a) levels are largely genetically determined vary widely among individuals.[2,3] Lp(a) is thought to be an independent predictor of cardiovascular and cerebrovascular diseases. For example, high Lp(a) concentrations were associated with an increased risk of coronary artery disease (CAD),[2,5] while low Lp(a) concentrations have been associated with an increased risk of type 2 diabetes (T2DM).
Recently, the impact of Lp(a) on the development and outcomes of cardiovascular diseases (CVD) in Chinese populations has been investigated. This article reviews recent studies regarding Lp(a) and its role in cardiovascular and cerebrovascular diseases in Chinese populations. We searched PubMed and Web of Science using the following keywords: (“Lipoprotein(a)” OR “Lp(a)”) AND “Chinese” to evaluate the available literature, and supplemented by personal communication and references in previous reviews on the subject.
2. Background knowledge of Lp(a)
An Lp(a) particle is a plasma lipoprotein formed by 2 distinct components: (1) a cholesterol-rich low-density lipoprotein (LDL)-like particle covalently bound to 1 molecule of apolipoprotein B-100 (apoB-100) and (2) a unique plasminogen-like glycoprotein particle called apo(a) with a size ranging from 200 to 900 kDa [Figure 1]. The variable size of apo(a) is caused by copy number variations within the LPA gene that determine the number of kringle IV type 2 (KIV-2) repeats, resulting in over 40 isoforms and thus over 40 different sizes of Lp(a) particles. There is an inverse relationship between the number of KIV-2 repeats and the Lp(a) plasma concentration, which might be a result of prolonged intracellular processing and increased intracellular degradation of larger isoforms. As a consequence, the size of apo(a) could significantly impact the hepatic synthesis and secretion of Lp(a), thereby influencing the concentration of circulating Lp(a).
The physiological function of Lp(a) in human remains mysterious. Because of the variable plasma Lp(a) levels between individuals and the fact that individuals with low circulating Lp(a) levels do not have obviously disordered metabolism, some early research had theorized that Lp(a) is of little functional importance in physiological metabolism. However, more recent researches have suggested that Lp(a) participates in the provision of cholesterol for cell proliferation during tissue repair and inhibits fibrinolysis to reduce risk at times of increased bleeding, such as during childbirth. For instance, Boffa and Koschinsky reported that Lp(a) could compete with plasminogen for binding sites, thereby decreasing plasminogen activation and inhibiting fibrinolysis in vitro. Several genetic studies also demonstrated that high plasma Lp(a) concentrations may be associated with the risk of venous thrombosis or venous thromboembolism.[12,13] In addition, Lp(a) participates in the chemotactic activation of monocytes and macrophages, and modulates angiogenesis.[8,10] The potential role of Lp(a) in the development of atherosclerotic cardiovascular disease (ASCVD) is illustrated in Figure 2.
2.3. Epidemiological studies of Lp(a) in the Chinese population
Epidemiological studies indicate that the Chinese population may have distinct Lp(a) levels compared to other populations. Past studies have demonstrated that Lp(a) is an independent risk factor for CVDs.[14,15] A cross-sectional study in a Chinese Han population of 3,462 cases and 6,125 controls suggested that the Lp(a) distribution differed from that in Caucasian populations and that high Lp(a) levels could be modified by several risk factors.
Recently, Dong et al have found single nucleotide polymorphisms in Lp(a) at rs6415084, rs3798221, and rs7770628, which may be responsible for the observed variations in Lp(a) plasma levels between the Han Chinese population, Caucasians, and other populations. Additionally, Xie et al indicated a significant association between plasma Lp(a) levels and gene–gene interactions among the polymorphisms rs1800206, rs135539 in peroxisome proliferator-activated receptor α and rs10865710, rs1805192, and rs4684847 in peroxisome proliferator-activated receptor γ.
Lp(a) alleles are distributed heterogeneously among different ethnic groups. Asian populations tend to have a higher frequency of alleles with higher KIV-2 copy number repeats compared with African and European populations. Moreover, the Lp(a) distribution and risk factors also showed a significantly differentiation in the Chinese Han population.
In addition, Lp(a) levels may vary up to 1,000-fold between individuals. Circulating Lp(a) levels are influenced by many physiological and pathological factors. A retrospective, small observational study in Chinese male patients with premature CAD demonstrated that poor mental health might be related to high Lp(a) levels and increased risk of premature CAD. Other research supports that Lp(a) is an independent risk factor for predicting the presence and severity of new-onset CVD in postmenopausal Chinese women.
In summary, elevated Lp(a) levels may be affected by many distinct factors and the distribution of Lp(a) alleles is different in the Chinese population compared to Western populations. As a whole, the Chinese population has lower plasma Lp(a) levels compared with that in Western populations.
3. Spectrum of Lp(a)-related disease in the Chinese population
Cross-sectional studies have demonstrated that the plasma Lp(a) level is associated with the risk of developing CVDs [22,23] and several epidemiological and genetic studies have identified Lp(a) as an independent risk factor for atherosclerosis.[24,25] Atherosclerosis is one of most common CVDs worldwide and is associated with high morbidity. Previous studies have reported that in the Chinese population, high Lp(a) levels are related to the risk of atherosclerosis and may participate in the pathogenesis of atherosclerosis. A retrospective clinical study in Chinese patients showed that high plasma Lp(a) levels may induce Lp(a) accumulation in the arteries, accelerating atherosclerosis progression, and that Lp(a) accumulation was regulated by LDL-receptor and CXC chemokine receptor 6. Sun et al identified Lp(a) level and KIV-2 copy number as risk factors for atherosclerosis in the Chinese Han population and found that elevated Lp(a) levels might indicate the type of coronary plaque present. Moreover, exposure of endothelial cells to oxidized Lp(a) reduced the expression of desmoglein-1 and desmocollin-2 by generating reactive oxygen species, which may increase the permeability of the endothelial cell monolayer and accelerate the progression of atherosclerosis.
Atherosclerotic plaque in coronary arteries contributes to CAD by facilitating vascular stenosis and occlusion. Several cross-sectional studies have shown that Lp(a) might be an independent predictor for CAD severity in the Chinese population.[29–33] A large Chinese cohort observational study demonstrated that Lp(a) was significantly associated with severity of CAD but not with cardiovascular events. Additionally, Song et al confirmed that the rs6415085 SNP in the Lp(a) gene would increase plasma Lp(a) levels and promote the development of CAD. Chinese patients with 4 haplotypes containing rs9364559 in different blocks in the Lp(a) gene exhibited a higher risk of CAD. For nonobstructive CAD, elevated Lp(a) levels are also independently associated with poor prognosis and may provide a useful metric for risk stratification of Chinese patients.[37,38]
An acute myocardial infarction (AMI) occurs as a result of a reduction in myocardial perfusion, which is typically induced by the rupture or fissuring of an atherosclerotic plaque. Two articles had reported that elevated Lp(a) levels may be associated with AMI in Chinese patients.[40,41] Lp(a) could also act as a biomarker to predict coronary collateral circulation or cardiovascular death in patients with AMI.[42,43] Additionally, Lp(a) interacts with LDL-C in first incident AMI in the Chinese Han population, so that the risk of initial AMI from exposure of elevated Lp(a) combined with elevated LDL-C is much greater than the sum of the risks of each alone.
Lp(a) may also be valuable in clinical diagnosis and treatment of CAD in Chinese patients. High Lp(a) levels are associated with clinical instability and severity of CAD in Chinese patients, especially in patients with both high fibrinogen levels and high Lp(a) levels; in addition, Lp(a) levels may be influenced by LDL-C concentrations in Chinese patients.[33,45–48] A multicenter, prospective study of 7,562 patients with angiography-diagnosed CAD supported circulating Lp(a) concentration as a useful predictor for the risk of recurrent cardiovascular events in real-world treated patients with CAD. In addition, in Chinese patients undergoing coronary angiography, Lp(a) and vitamin D were associated with the severity of CAD.
Percutaneous coronary intervention (PCI) has become one of the most frequently performed therapeutic interventions for patients with CAD. High Lp(a) levels predict an increased incidence of revascularization, platelet aggregation, and thrombogenicity in Chinese patients with CAD after PCI.[52,53] Several studies have reported that plasma Lp(a) concentration and Lp(a) genetic variants are associated with long-term adverse cardiovascular events in patients with chronic kidney disease or CAD who underwent PCI, suggesting that Lp(a) measurements may be useful to stratify Chinese patients according to risk after PCI.[54–60] These findings may provide insight into future clinical applications of Lp(a).
3.2. Calcific aortic valve disease
Calcific aortic valve disease (CAVD) is the most common cause of aortic valve replacement in developed countries. In China, epidemiological data showed that CAVD prevalence remained high and that the number of transcatheter aortic valve implantations increased from 2,000 to 2,015.[62,63]
Several genome-wide association studies and Mendelian randomization studies have revealed that elevated Lp(a) levels are positively associated with CAVD.[64,65] In the Han Chinese population, the rs3798221, rs6415084, and rs7770628 polymorphisms are associated with high plasma Lp(a) levels and increased risk of CAVD. Additionally, elevated Lp(a) levels may also be an independent predictor of severe aortic valve stenosis by echocardiography in the Chinese population, which might be valuable for risk stratification in patients with CAVD.
Basic biomedical studies using primary valvular interstitial cells from Chinese patients have also found that Lp(a) plays an essential role in CAVD. Liu et al demonstrated that Lp(a) combined with oxidized phospholipids to promote the inflammatory response and calcium deposition in aortic valve leaflets. Guo et al also reported that PCSK9 might be an independent predictor of aortic valve calcification and may accelerate CAVD by regulating Lp(a) catabolism. These findings may provide insight into future targeted therapies to prevent CAVD via Lp(a).
Localized blood clotting may contribute to thrombosis in the arterial or venous circulation. Despite the fact that thrombosis is currently a major medical challenge, the underlying mechanisms of the initiation and regulation of thrombosis are still incompletely understood.
Clinical studies in Chinese patients have reported that elevated Lp(a) is associated with the development of thrombosis in many disease states. For instance, a prospective study of 77 Chinese patients showed that the Lp(a) concentration was abnormal in cirrhotic patients with portal and/or splenic vein thrombosis following splenectomy, indicating that monitoring serum Lp(a) levels could be a valuable tool to predict early portal and/or splenic vein thrombosis after splenectomy. Moreover, high Lp(a) plasma level might be an independent risk factor for thrombotic events in Chinese patients with nonvalvular atrial fibrillation and a low CHA2DS2-VASc score. Two prospective cohort studies in Chinese patients also suggested increased serum Lp(a) level as an independent predictor of deep vein thrombosis in patients with spinal cord injuries or acute ischemic stroke, suggesting a possible role of Lp(a) in the pathogenesis of deep vein thrombosis.[71,72]
Central venous thrombosis is a serious and life-threatening complication. A cross-sectional study of 54 Chinese patients on maintenance hemodialysis found that Lp(a) concentration was higher in patients with central venous thrombosis, indicating that Lp(a) might be an important risk factor for central venous thrombosis in Chinese hemodialysis patients.
Several basic studies have also explored the function of Lp(a) in thrombosis. Fu et al isolated Lp(a) from plasma from Chinese donors and demonstrated that Lp(a) could interfere with annexin A5 binding to the procoagulant phosphatidylserine, which translocates to the membrane surface under stress. This study demonstrated that Lp(a) might have a role in the progression of thrombosis and that elevated Lp(a) levels could increase the risk of thrombosis.
The plasma Lp(a) concentration is primarily determined by the synthesis of apo(a) and the assembly of Lp(a) particles. Wu and Lee have found that sequence variations in the apo(a) promoter region may cause variability in its transcription, which could be related to cerebral thrombosis. Taken together, these data indicate that Lp(a) might be related to the process of thrombosis in Chinese patients.
Stroke is the second highest cause of death and a leading cause of disability worldwide, with an increasing morbidity in developing countries. The morbidity of stroke in urban China has increased in recent decades.[78,79] In 2005, an epidemiological study showed that the prevalence of stroke had increased from 0.57% in 1986 to approximately 2.13% in 2013.
Several studies have reported an association between plasma Lp(a) levels and an increased risk of stroke.[81,82] Plasma Lp(a) levels were first demonstrated to be independently associated with stroke in the Chinese population in 2003. This result was also verified by several recent prospective studies and Mendelian randomization studies.[84–89] Moreover, Hong et al found that elevated serum Lp(a) levels could predict the risk of early stroke recurrence in patients with first-ever ischemic stroke.
A retrospective study in Chinese patients with incident chronic peritoneal dialysis identified elevated serum Lp(a) level as a predictor for the risk of hemorrhagic stroke. Additionally, elevated plasma Lp(a) levels may also play a critical role in the pathogenesis of deep vein thrombosis in Chinese patients with acute ischemic stroke. Ma et al found that increased serum Lp(a) could complex with beta2-glycoprotein I in ischemic stroke patients, contributing to the severity and poor clinical outcomes following ischemic stroke.
Circular RNAs are highly expressed in the central nervous system and are involved in the regulation of physiological and pathophysiological processes. Recently, using microarray analysis to examine the circular RNA in plasma samples from Chinese patients with acute ischemic stroke and high plasma Lp(a) levels, Han et al provided translational evidence that circHECTD1 levels could serve as a novel biomarker of and therapeutic target for stroke. As this study remains the only basic research into the function of Lp(a) in stroke to date, the mechanism underlying the effect of Lp(a) concentrations on stroke requires further investigation.
3.5. Type 2 diabetes
While the present review focuses on CVD, the association of Lp(a) with T2DM should be acknowledged as there is a high incidence of CVD in patients with T2DM. In 2020, Muhanhali et al reported that in 798 Chinese patients, low Lp(a) levels were associated with an increased risk of T2DM. This finding was confirmed in a cross-sectional analysis of 10,122 middle-aged and elderly Chinese participants, which suggested an inverse relationship between serum Lp(a) concentrations and the prevalence of T2DM, pre-diabetes, insulin resistance, and hyper-insulinemia. However, another cross-sectional study of 1,604 cases and 7,983 controls from 2017 did not find an association of Lp(a) levels with prevalent T2DM. Similarly, comparing serum Lp(a) levels in Chinese patients with T2DM and in nondiabetic control subjects, Chang et al did not find significantly changed Lp(a) levels in diabetic patients or even in patients with poorly controlled T2DM. Because of these conflicting results, more research is needed to clarify the relationship of Lp(a) and T2DM in the Chinese population.
Complications arising from T2DM have contributed tremendously to mortality and morbidity worldwide. Xuan et al found that elevated Lp(a) levels were independently associated with the risk of incident reduced renal function in Chinese patients with diabetes. Additionally, Lp(a) concentration was positively associated with diabetic retinopathy in patients with T2DM. Wang et al demonstrated that elevated serum levels of β2-glycoprotein I-Lp(a) complexes might reflect underlying chronic pathophysiological processes involved in the development of T2DM complications in Chinese patients. Moreover, Lp(a) might be an independent predictor for recurrent cardiovascular events in T2DM patients. Increased Lp(a) was associated with a greater risk of poor coronary collateralization in Chinese patients with T2DM who had elevated total cholesterol, LDL-C, or non-HDL-C.
Genetic studies have examined the relationship between Lp(a) concentration and the risk of T2DM. Mu-Han-Ha-Li et al found that a high number of LPA KIV-2 repeats were associated with an increased risk of T2DM in a Chinese population at very high cardiovascular risk, which suggested that large Lp(a) isoform size, associated with low Lp(a) concentration, had a causal effect on T2DM. Furthermore, a genetic epidemiological study showed that Lp(a) levels of T2DM patients and their offspring were correlated, indicating a potential genetic control for Lp(a) levels in families with T2DM.
In Chinese patients with both T2DM and CAD or stroke, elevated Lp(a) levels were associated with unfavorable outcomes.[86,107] Elevated Lp(a) levels were also correlated with an increased frequency of peri-procedural myocardial infarction in Chinese male patients with diabetes undergoing PCI. These observations suggest that Lp(a) might act as a marker for risk stratification and as a therapeutic target in patients with T2DM and other diseases.
3.6. Other diseases
Cancer is a major public health problem in developed countries and is an alarming issue in China due to the rapid population growth and socioeconomic development. In several studies on Chinese populations, abnormal Lp(a) levels have been observed and an anti-neoplastic effect has been postulated in various cancers. Wang and Zhang were the first to show a correlation between high Lp(a) levels and adverse clinicopathological features in Chinese patients with prostate cancer. Patients with prostate cancer who have high Lp(a) levels tend to have more aggressive cancer and may require more clinical attention. Elevated serum Lp(a) levels were associated with breast cancer in a Han Chinese population. In Chinese patients, serum Lp(a) concentration was also associated with the presence and stage of lung cancer, and Lp(a) may serve as a biomarker to identify patients who could benefit from recombinant human endostatin treatment with concurrent chemoradiotherapy in stage III lung squamous cell carcinoma.[114,115] The potential impact and specific mechanism of Lp(a) in various cancers remains to be explored in future research.
Familial hypercholesterolemia (FH) is a genetic metabolic disorder characterized by premature ASCVD and incident cardiovascular events.[116,117] Recently, elevated Lp(a) has received increasing interest because of its contribution to CVD in Chinese FH patients. Several clinical studies have reported that plasma Lp(a) levels may be associated with the presence and severity of CVD in patients with heterozygous FH, and the interaction of PCSK9 with Lp(a) may play an important role in CVD pathogenesis and cardiovascular events in Chinese patients.[118–121] Lp(a) measurement might also be helpful for clinical risk stratification of Chinese patients with FH. Furthermore, a novel diagnosis algorithm that includes Lp(a) was designed by a Chinese group, which could provide new insights into FH diagnosis in the Chinese population.
Other diseases have also been associated with circulating Lp(a) concentrations in the Chinese population. A significant correlation was observed between obstructive sleep apnea and decreased Lp(a) levels, which might be relevant to the assessment of metabolic or CVD risk in patients with obstructive sleep apnea. In patients with stable angina pectoris, Lp(a) is significantly positively correlated with the percentage of fibrolipid volume and is negatively correlated with the percentage of fibrous volume, suggesting that Lp(a) concentration could predict the vulnerability of the left main coronary artery plaque. Elevated Lp(a) levels may also contribute to incident reduced renal function in patients with diabetes or hypertension, or in children with nephrotic syndrome.[100,126] Furthermore, increased plasma levels of Lp(a) were associated with premature atherosclerosis in Chinese patients at risk of abnormal semen liquefaction and metabolic syndrome.[127,128]
This review provides an overview of epidemiological and pathological evidence linking Lp(a) to ASCVD in the Chinese population and highlights several specific Lp(a) mutations observed in the Chinese population. A large number of studies have suggested Lp(a) not only as an independent risk factor for ASCVD but also as a novel lipid target for ASCVD regardless of ethnic background. Data from Chinese population may also support the notion that Lp(a) is associated with the incidence and cardiovascular prognosis of ASCVD. In addition, Lp(a) may play an important role in other diseases, such as T2DM, cancer, and FH. The exact mechanisms linking Lp(a) to various diseases remain to be explored. Furthermore, randomized clinical trials are needed to demonstrate causality and assess the clinical benefit of Lp(a)-lowering therapies.
This work was supported by the Capital Health Development Fund (201614035) and CAMS Major Collaborative Innovation 517 Project (2016-I2M-1-011) awarded to Dr. Jianjun Li.
Conflicts of interest
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