Genetic insights into coronary heart disease in the Teochew population: Bridging gaps in precision medicine

Abstract

This editorial highlights the study by Xu et al on genetic polymorphisms linked to coronary heart disease (CHD) in the Teochew population. This study adjusted odds ratios for confounding factors including age, sex, hypertension, and diabetes. It identifies the apolipoprotein E ε2 allele and higher lipoprotein (a) kringle IV-2 (KIV-2) copy number as protective factors against CHD. The ε2 allele was found at a lower frequency in CHD patients (8.02%) compared to controls (13.29%), and each additional KIV-2 copy reduced CHD risk by approximately 5% (odds ratio = 0.949). Conversely, solute carrier organic anion transporter family member 1B1 polymorphisms showed no significant link to CHD. These findings underscore the importance of population-specific research, particularly for the Teochew population, where CHD is prevalent. They provide a foundation for precision risk stratification and targeted interventions, including lipoprotein (a)-lowering therapies for those with lower KIV-2 copy numbers. Despite limitations, the study emphasizes the need for further research incorporating multi-omics data and lifestyle factors to enhance personalized CHD prevention, moving away from "one-size-fits-all" approaches. This research is essential for leveraging genetic insights into global CHD prevention.

Key Words: Coronary heart disease; Teochew population; Genetic polymorphisms; Apolipoprotein E; Lipoprotein (a) kringle IV-2; Precision medicine

Core Tip: This editorial emphasizes that APOE ε2 and higher LPA KIV-2 copy number are associated with a reduced risk of coronary heart disease in the Teochew population, highlighting the value of population-specific genetic studies for tailored cardiovascular care.

INTRODUCTION

Coronary heart disease (CHD) remains a leading cause of global mortality and disability, imposing a heavy burden on public health systems worldwide. According to the 2024 heart disease and Stroke Statistics report from the American Heart Association, CHD mortality continues to rise, particularly in low- and middle-income countries, with the elderly population facing the highest risk[1]. In China, the epidemiological landscape of CHD is equally severe: In Chaozhou, a city in southern China with a predominantly Teochew population, the age-standardized mortality rate for CHD ranks second among all causes of death, and the prevalence of CHD in adults aged 20 years and older reaches 1.41%[2,3]. Such data suggest that approximately 3 out of every 200 adults in the region suffer from CHD. This underscores the urgent need to identify region-specific risk factors for CHD, especially in populations with unique genetic and cultural backgrounds like the Teochew people.

CHD is a complex disease driven by the interplay of environmental factors (e.g., hypertension, diabetes, and smoking) and genetic predisposition. Genome-wide association studies have identified over 300 genetic loci associated with CHD risk, highlighting the critical role of genetics in disease susceptibility[4]. However, genetic associations with CHD exhibit substantial population and geographic variability. For instance, polymorphisms in genes involved in lipid metabolism, such as APOE (encoding apolipoprotein E), SLCO1B1 (encoding the drug transporter OATP1B1), and LPA [encoding apolipoprotein (a)], have shown inconsistent associations with CHD across ethnic groups[5-7]. This variability is particularly relevant for the Teochew population, a distinct Han Chinese subgroup in southern China, for which there is limited existing data on CHD-related genetic markers[2,3]. Furthermore, among the numerous genetic loci associated with CHD risk, those related to lipid metabolism possess particularly high clinical value[8-11]. They play a crucial role in the overall management of both chronic coronary syndromes[12-14] and acute coronary syndromes[15-18]. Therefore, identifying key genes and clarifying their genetic polymorphisms related to lipid metabolism that act as protective or risk factors in specific populations can provide clinicians with valuable assessment, management, and treatment strategies for CHD.

Against this backdrop, the recent study by Xu et al[19] proved a correlation between APOE, SLCO1B1, and LPA KIV-2 gene polymorphisms and CHD in the Teochew population, filling a critical knowledge gap. By investigating APOE and SLCO1B1 polymorphisms, as well as LPA KIV-2 copy number variation, in 324 Teochew CHD patients and 143 controls, the study provides the first region-specific evidence of genetic associations with CHD in this understudied population. Its findings, notably that the APOE ε2 allele and higher LPA KIV-2 copy number are protective against CHD, offer actionable insights for precision medicine in southern China. This editorial discusses the significance of these findings, their clinical implications, and future directions to advance CHD prevention and management in population-specific contexts.

THE VALUE OF POPULATION-SPECIFIC GENETIC RESEARCH: WHY THE TEOCHEW STUDY MATTERS

A key strength of Xu et al’s work[19] lies in its focus on the Teochew population, whose genetic and environmental characteristics differ from those of other Chinese subgroups (e.g., Hakka, Mongolian) and global populations. Prior studies on APOE polymorphisms, for example, have reported conflicting results: In non-Hispanic White, compared to other APOE alleles, the APOE ε2 allele is not associated with CHD risk[20]. In Caucasians, the APOE ε2 allele is associated with reduced CHD risk[6], while some Asian studies have suggested it may be a risk factor for premature CHD[21]. Compared with a study based on the Hakka population, there is significant heterogeneity in the frequency of the ε2 allele among populations, even when geographically close to the Teochew population[22]. Similarly, SLCO1B1 polymorphisms have been linked to CHD protection in Mongolians but not in southern Chinese Hakka populations[7,23]. These discrepancies highlight the danger of extrapolating genetic findings across populations and the necessity of region-specific research.

Xu et al[19] reaffirmed that traditional CHD risk factors (e.g., age, sex, hypertension, diabetes) remain independent risk factors in specific populations such as the Teochew population. More significantly, this paper offers valuable insights into the clinical significance of genetic polymorphisms in specific populations. Compared to controls, APOE ε2 allele frequency showed a significant difference (8.02% vs 13.29%, P = 0.012). The number of copies of the KIV-2 gene was significantly lower (23.35 ± 8.78 vs 27.21 ± 9.48; P < 0.01). Xu et al[19] addressed this by rigorously controlling for known confounding factors (e.g., age, sex, hypertension, diabetes) through multivariate logistic regression, ensuring that observed genetic associations were not masked by environmental variables. The study also confirmed Hardy–Weinberg equilibrium in control groups for both APOE and SLCO1B1 polymorphisms, validating the representativeness of those samples. Such methodological rigor strengthens confidence in its conclusions that the APOE ε2 allele [odds ratio (OR) = 0.395, 95%CI: 0.209-0.745] and higher LPA KIV-2 copy number (OR = 0.949, 95%CI: 0.919-0.979) are independent protective factors for CHD in Teochew individuals.

While genetic factors are generally considered difficult to intervene upon as CHD risk factors[24-26], these gene polymorphism-related predictors, being associated with lipid metabolism, provide a breakthrough for interventions targeting CHD risk factors[27-29]. Therefore, integrating these novel risk factors with traditional ones for comprehensive management may enhance the effectiveness of CHD prevention and treatment[30-33]. As new quantitative predictors, these findings will contribute to precision medicine in CHD management, providing personalized guidance for the prevention and treatment of CHD in specific populations. Moreover, for a population where CHD is a top cause of death, these findings are not merely academic; they lay the groundwork for targeted prevention strategies.

CLINICAL TRANSLATION: FROM GENETIC FINDINGS TO PRECISION CARE

The study’s results have immediate implications for CHD prevention, diagnosis, and treatment in the Teochew population and similar southern Chinese groups.

Risk stratification and preventive screening

Identifying genetic protective factors allows for more precise risk stratification. For example, Teochew individuals carrying the APOE ε2 allele or a high LPA KIV-2 copy number may require less intensive screening, while those with a low KIV-2 copy number, and thus higher lipoprotein (a) [Lp(a)] levels, could benefit from earlier, more frequent lipid monitoring. Additionally, such people can benefit more from targeted interventions, such as emerging Lp(a)-lowering therapies. This aligns with global guidelines emphasizing Lp(a) as a causal risk factor for CHD: Kamstrup et al[34] noted that high Lp(a) levels drive atherosclerosis and thrombosis, and Langsted et al[35] linked low LPA KIV-2 copy number to increased all-cause mortality[34,35]. By integrating LPA KIV-2 copy number variation testing into routine CHD risk assessments, clinicians in the Teochew population could identify high-risk individuals before symptom onset.

Personalized statin therapy

While SLCO1B1 polymorphisms were not associated with CHD risk in the Teochew population, the study’s findings on SLCO1B allele frequencies (e.g., *1b: 62.53%, *15: 10.92%) remain clinically relevant[1]. SLCO1B1 encodes OATP1B1, a transporter critical for statin uptake in the liver; polymorphisms like *15 reduce transporter function, increasing statin blood levels and risk of myopathy[36,37]. For Teochew CHD patients prescribed statins, first-line therapy for lipid lowering, SLCO1B1 genotyping could guide dose adjustments: Those with *1a/*15 or *1b/*15 genotypes (intermediate metabolizers) may require lower doses to avoid adverse effects, while extensive metabolizers (*1a/*1a, *1a/*1b, *1b/*1b) could tolerate standard regimens[1,38].

On the other hand, while SLCO1B1 gene polymorphisms may not be directly associated with CHD, they may be relevant to the prognosis of CHD patients. Because they influence the metabolism and side effects of hyperlipidemia medications such as statins, they may serve as a prognostic factor for CHD. For example, this could assess whether statin therapy effectively controls the progression of atherosclerosis in CHD patients. Furthermore, it could be useful to assess whether statin therapy effectively reverses the plaques that cause atherosclerosis. If the interaction between the SLCO1B1 signaling pathway and lipid-lowering drugs could be modulated, thereby achieving a plaque-reversing therapeutic effect, this would be of great benefit to clinical treatment. This personalized approach balances therapeutic efficacy and safety, addressing a longstanding challenge in statin use.

Lipid metabolism guidance

The study also shed light on how APOE genotypes influence lipid profiles in Teochew CHD patients: The APOE E4 group (ε3/ε4, ε4/ε4) had significantly higher triglycerides, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) than the E2 and E3 groups[1]. This aligns with molecular mechanisms: APOE E4 enhances binding to very-low-density lipoprotein, impairing its clearance and promoting atherogenic lipid profiles[39]. For clinicians, this means APOE genotyping could inform lipid-lowering strategies: E4 carriers may need more aggressive LDL-C targets or combination therapy (e.g., statins plus ezetimibe) to mitigate their elevated lipid-related risk.

FUTURE DIRECTIONS: EXPANDING ON GENETIC INSIGHTS

From a clinical perspective, genetic polymorphisms of APOE, SLCO1B1, and LPA KIV-2 are directly associated with residual cardiovascular risk related to lipid levels[40-43]. Even after traditional risk factors such as LDL-C, blood pressure, and blood glucose are controlled through current standard treatments, patients in this population still face a high residual risk of cardiovascular events[44-46]. Multiple studies indicate that while controlling traditional risk factors, precision interventions and management of residual cardiovascular risk based on genetic polymorphism evidence can further reduce the incidence of cardiovascular events[47-51].

While Xu et al’s study is a milestone[19], several avenues remain to deepen our understanding of CHD genetics in the Teochew population and beyond. First, larger, multicenter studies are needed to validate the findings. The study’s sample size (324 cases, 143 controls) limits the power to detect small-effect genetic associations, particularly in subgroups (e.g., poor SLCO1B1 metabolizers; only three cases). Expanding to include Teochew populations across Guangdong and Fujian provinces would enhance generalizability and enable subgroup analyses (e.g., of age-specific or sex-specific genetic effects). Second, research should explore gene–environment interactions. The Teochew population has unique dietary habits (e.g., high salt and seafood consumption) that may modulate genetic risk[2]. For example, could a high-salt diet amplify the atherogenic effects of low LPA KIV-2 copy number? Investigating such interactions would refine risk prediction and enable more tailored lifestyle interventions. Third, longitudinal studies are needed to link genetic markers to CHD prognosis. Xu et al[19] focused on disease incidence, but it remains unclear whether APOE ε2 or high LPA KIV-2 copy number influences outcomes like myocardial infarction recurrence or mortality. Long-term follow-up of genotyped patients could answer this question, guiding post-diagnosis management.

Currently, large-scale real-world clinical public databases such as CHARLS, United Kingdom Biobank, and NHANES have attracted the attention of numerous researchers. The databases cover cardiovascular clinical data from multiple specific populations and may have the potential to provide insights supplementary to genetic research results. Specifically, it should be feasible to validate Xu et al's genetic etiology hypothesis[19] using clinical information from specific populations through appropriate data processing techniques. Mendelian randomization may be among the data processing techniques that avoids confounding factors by randomly assigning genetic variations, enabling more accurate causal inference. Compared with clinical trials, utilizing public clinical databases to promote the clinical translation of genetic research results has significant advantages in terms of time and cost-effectiveness. The use of public clinical databases can also reduce ethical constraints in clinical research and further bridge the gap between controlled research environments and routine medical services.

Finally, integrating multi-omics data (e.g., transcriptomics, metabolomics) would unravel the mechanisms underlying observed genetic associations. For instance, how exactly does higher LPA KIV-2 copy number reduce Lp(a) levels and CHD risk? Identifying intermediate molecular phenotypes could reveal new therapeutic targets for Lp(a)-lowering drugs, which are currently limited[52].

CONCLUSION

Xu et al’s study[19] represents a critical step forward in personalized CHD care for the Teochew population. By identifying population-specific genetic protective factors (APOE ε2, high LPA KIV-2 copy number) and confirming the clinical relevance of SLCO1B1 for statin therapy, the research bridges a gap between global genetic discoveries and local clinical practice. As precision medicine becomes increasingly central to cardiovascular care, studies like this, grounded in population-specific data, will be essential for reducing CHD burden in diverse communities worldwide. For the Teochew population, this work is not just about understanding genetics; it is about empowering clinicians to prevent, diagnose, and treat CHD in a way that honors their unique biological and cultural identity.