Deciphering Teochew population’s genetic protective barrier: Apolipoprotein E- lipoprotein(a) kringle IV type 2 synergy as novel cardioprotective pathway

Abstract

Xu et al provides crucial regional data for precision cardiovascular medicine in East Asia. This study focuses on the Teochew Han population in China for the first time and reveals the synergistic protective effect of the apolipoprotein E ε2 allele and high copy numbers of kringle IV type 2. This discovery holds significant importance for optimizing regional risk assessment models.

Key Words: Apolipoprotein E; Lipoprotein(a) kringle IV type 2; Teochew population; Synergistic effect; Risk stratification

Core Tip: This study identifies a novel synergistic cardiometabolic protective pathway in the genetically distinct Teochew (Chaozhou) Han population of southern China. We demonstrate that the co-presence of the apolipoprotein E (APOE) ε2 allele and high copy number variation of the lipoprotein(a) kringle IV type 2 gene significantly reduces coronary heart disease risk, contrasting with previous reports on APOE ε2 in Asians. This unique gene-environment interaction, potentially modulated by the local seafood-rich diet, offers a population-specific biomarker for optimized coronary heart disease risk stratification. Clinical translation emphasizes integrating APOE/lipoprotein(a) kringle IV type 2 copy number variation screening with solute carrier organic anion transporter family member 1B1 pharmacogenetics to guide precision statin therapy and personalized prevention strategies.

TO THE EDITOR

We highly commend the research conducted by Xu et al[1] on the genetic susceptibility to coronary heart disease (CHD) in the Chaoshan population. This study is the first to confirm in a south Chinese sub - population lacking genetic data that the apolipoprotein E (APOE) ε2 allele and a higher number of lipoprotein(a) [Lp(a)] kringle IV type 2 (KIV-2) copies are protective factors against CHD. Particularly importantly, the researchers found that the number of KIV-2 copies in the CHD group was significantly lower than that in the control group (23.35 ± 8.78 vs 27.21 ± 9.48; P < 0.01). This finding is highly consistent with the pathogenic mechanism proposed by Tasdighi et al[2] in 2024 - a low number of KIV-2 copies mediates the inflammatory response of oxidized phospholipids by increasing the concentration of Lp(a), thereby accelerating atherosclerosis. The KIV-2 domain within the Lp(a) gene is a critical genetic determinant of Lp(a) plasma concentration. Its copy number variation exhibits a well-established inverse correlation with Lp(a) levels; a higher number of KIV-2 repeats is associated with lower Lp(a) concentration, thereby conferring a reduced risk for coronary artery disease.

However, the research method has limitations that urgently need to be examined. Although the (solute carrier organic anion transporter family member 1B1) SLCO1B1 polymorphism did not show an association with CHD, the study overlooked its pharmacogenomic value. The latest guidelines (2024 edition) of the United States Food and Drug Administration mandate that carriers of SLCO1B1 *5/15 avoid high - dose statin therapy[3] (as such variants increase the risk of myopathy by 4.7 times). In the Chaoshan CHD patients, 61.17% carry the 1b allele that affects statin metabolism, and this oversight directly impacts clinical translation.

Notably, the protective effect of APOE ε2 revealed in this study (frequency in the CHD group: 8.02% vs 13.29% in the control group, P = 0.012) contradicts the conclusion of Zhao et al[4] that “ε2 increases the risk of CHD in Asians”. This contradiction may stem from the unique gene - environment interaction in the Chaoshan population: Their diet rich in seafood may regulate lipid metabolism pathways. However, the study did not include dietary covariates in the analysis. Integrating the polygenic risk score, its predictive efficacy far exceeds that of single - gene studies[5,6].

We recommend the following follow-up work: Validating KIV-2 data using long-read sequencing; exploring precision statin use guided by SLCO1B1 genotypes; and systematically analyzing how the characteristic Chaoshan diet (such as fish sauce intake) regulates the protective effect of ε2. This will promote the translation of population genetics into clinical practice.

CLINICAL IMPLICATIONS

Our research has found that in the Chaoshan population, there is an association between the APOE ε2 allele, a higher number of Lp(a) KIV-2 gene copies, and a reduced risk of CHD. This finding holds significant implications for clinical practice. Conducting genetic screening for these specific genetic variations can enhance CHD risk stratification for this unique southern Chinese population. Individuals found to carry the protective APOE ε2 allele or have a higher number of KIV-2 gene copies may benefit from personalized preventive counseling emphasizing a healthy lifestyle. For this low-risk group, the intensity of routine risk factor monitoring may need adjustment, yet vigilance towards other established risk factors remains crucial.

Conversely, the absence of these protective genetic markers, especially when combined with clinical risk factors such as male gender, advanced age, hypertension, diabetes, or a history of smoking (identified as significant in our logistic regression analysis), necessitates enhanced monitoring and active management of modifiable cardiovascular risk factors. Given the confirmed negative correlation between the number of KIV-2 gene copies and Lp(a) levels observed in both our CHD patients and the control group, regular assessment of Lp(a) concentration is strongly recommended. Regardless of the presence of other protective genotypes, if Lp(a) levels are elevated, aggressive strategies for reducing low-density lipoprotein cholesterol (LDL-C) must be adopted. Regardless of the presence of other protective genotypes, if Lp(a) levels are elevated, aggressive strategies for reducing LDL-C must be adopted, because LDL-C is a well-established, modifiable risk factor that directly contributes to atherosclerotic plaque formation and the risk of major adverse cardiac events.

Although the SLCO1B1 gene polymorphism did not show a direct association with CHD susceptibility in our study of the Chaozhou population, genotyping for key variants (especially *5 and *15) remains highly valuable in a therapeutic context. Pharmacogenetic testing of SLCO1B1 before initiating statin therapy is crucial for optimizing treatment outcomes. This testing aids in selecting appropriate statins and determining suitable dosages to minimize the risk of adverse reactions, such as myopathy, thereby enhancing safety and ensuring long - term adherence to secondary prevention and management requirements for diagnosed CHD.

Genetic counseling plays a vital role for families with a history of early - onset or severe congenital heart disease. Detecting the status of the protective APOE ε2 allele or a high number of KIV-2 gene copies in relatives can inform personalized risk assessment and preventive approaches. Discussions regarding the potential use of predictive genetic testing for these specific variants among family members may be appropriate, although it is acknowledged that further validation of population - specific phenotypic penetrance data is required. Ultimately, integrating these Chaozhou - specific genetic markers (APOE ε2 and Lp(a) KIV-2 copy number variation) with established clinical risk prediction models is expected to significantly improve the accuracy of congenital heart disease risk assessment in such populations in southern China. This comprehensive approach enables earlier identification of high-risk individuals, facilitates timely and targeted interventions, and allows for more efficient allocation of medical resources.

ACKNOWLEDGEMENTS

The authors would like to thank He JF from the Second Affiliated Hospital of University of South China for the beneficial discussions on the topics related to this work.