Cardiovascular disease (CVD) remains the leading cause of mortality globally, accounting for 31% of annual deaths worldwide, and primarily includes coronary heart disease (CHD) (1). Statins, the cornerstone of dyslipidemia management, reduce cardiovascular events by 20%–30% through low-density lipoprotein cholesterol (LDL-C) lowering (2). However, interindividual variability in therapeutic response and adverse musculoskeletal effects, particularly in elderly populations, remain critical challenges (3). Emerging evidence implicates genetic polymorphisms in SLCO1B1, encoding the hepatic transporter OATP1B1, as key determinants of statin pharmacokinetics and toxicity (4). Specifically, the c.521T>C and c.388A>G variants impair OATP1B1-mediated hepatic uptake, elevating systemic statin exposure by 2–5-fold and increasing myopathy risk (5, 6). Similarly, the SLCO1B1 c.388A>G polymorphism has been consistently linked to altered OATP1B1 function, thereby affecting statin transport efficiency and potentially influencing drug exposure and clinical outcomes (7).

Despite consensus on these pharmacogenetic associations, critical knowledge gaps persist. First, while current guidelines endorse statins for primary prevention in adults aged 40–75 years (8), and a meta-analysis by Gencer et al. (9) has confirmed that statin use in individuals aged >75 years can effectively delay the progression of cardiovascular diseases and reduce the risk of mortality. However, relevant research on adverse reactions such as myopathy induced by statin administration in this population is still scarce. Additionally, existing literature (10) has verified that the SLCO1B1 genotype can guide the clinical use of statins, but evidence supporting genotype-guided dosing in patients >75 years remains sparse, with randomized controlled trials (RCTs) including <3% of this demographic (11). Second, ethnic disparities in allele frequencies—exemplified by the c.521C allele prevalence ranging from 28.3% in Amerindians to 5.7% in African-descent Brazilians and 14.8% in those of European ancestry—complicate extrapolation of existing pharmacogenetic data to admixed or understudied populations (12). Notably, no studies have systematically evaluated SLCO1B1-mediated statin outcomes in elderly Han Chinese.

Accordingly, this study addresses these gaps through two primary objectives: (1) to determine whether SLCO1B1 polymorphisms independently predict CHD susceptibility in Southern Han Chinese, and (2) to evaluate genotype-dependent effects on statin efficacy and safety in this understudied demographic.

This study demonstrates that age, diabetes, and hypertension act as independent genetic risk factors for CHD in the southern Han Chinese population, with findings congruent with established CHD risk markers and providing robust validation of prior epidemiological evidence (13). Notably, our research further identifies the SLCO1B1 c.521C allele as a distinct genetic determinant for CHD in this cohort (OR = 1.37, 95% CI: 1.06–1.77, P = 0.02), which is consistent with investigations by MO, Q et al (14). As a transmembrane transporter, OATP1B1 mediates hepatic uptake and clearance of endogenous substrates including bilirubin and bile acids. Clinical study (15) have postulated that the SLCO1B1 521C allele induces structural alterations in OATP1B1, leading to diminished substrate binding affinity and reduced transport efficiency. This functional impairment compromises hepatic processing of lipophilic molecules, exacerbating dyslipidemia through mechanisms such as increased retention of triglyceride-rich lipoproteins and reduced reverse cholesterol transport. Consequently, the c.521C allele-driven dysfunction may establish a genetic predisposition to CHD by promoting atherogenic lipid profiles and vascular inflammation. In this context, implementing time-sensitive primary prevention strategies—such as intensified lipid-lowering therapy and lifestyle interventions—for individuals harboring the c.521C allele may counteract the genetic risk and attenuate disease incidence and progression.

In the field of CHD prevention and management, strategies predominantly encompass lifestyle modifications and lipid-lowering interventions. Within the domain of dyslipidemia therapy, low-density lipoprotein cholesterol (LDL-C) has been firmly established as a pivotal risk factor for CHD, with robust evidence demonstrating that lower LDL-C concentrations are inversely associated with reduced incidence and mortality from cardiovascular events (16). A meta-analytic synthesis (17) has underscored that each 1 mmol/L (38.7 mg/dL) reduction in LDL-C is accompanied by a 22% relative risk reduction in major vascular and coronary artery events. These data reinforce the indispensable role of achieving and maintaining low LDL-C levels in effectively mitigating the initiation and progression of CHD pathogenesis. Since the advent of statins, these agents have emerged as the clinical gold standard for lipid-lowering therapy owing to their hypolipidemic efficacy, being widely deployed in the management of dyslipidemia and primary/secondary prevention of CHD (18, 19). Notwithstanding, the clinical applicability of statins in geriatric populations remains a subject of debate due to potential side effects such as myotoxicity. Although meta-analyses have confirmed that statin use in elderly individuals aged ≥75 years can effectively reduce the incidence of cardiovascular diseases (9), evidence regarding the safety of such drugs in this specific population remains insufficient. Geriatric individuals constitute a distinct therapeutic cohort with age-related metabolic derangements that diverge significantly from younger populations, rendering their pharmacotherapeutic management susceptible to multifactorial influences. Therefore, our investigation was designed to focus on geriatric patients with age >75 years.

Our findings demonstrate that statin therapy in this demographic predominantly elicits reductions in plasma TC and LDL-C concentrations, with negligible effects on HDL-C and TG. These data suggest that the use of statins in adults aged over 75 years can effectively reduce LDL and TC, thereby preventing and treating CHD. Additionally, we found that routine doses of statins in older adults did not provoke severe hepatotoxicity (aspartate transaminase/alanine transaminase elevation: P > 0.05) or myopathic complications (creatine kinase levels: P > 0.05). These safety observations are consistent with dose-dependent hepatotoxicity patterns and the low adverse event rates reported for standard/low-dose regimens (20, 21), suggesting that statin use at routine or low doses is safe in elderly.

With the continuous advancement of pharmacogenomics, personalized medication has garnered increasing attention. Previous studies have demonstrated that the SLCO1B1 gene influences the hepatic transport of statins by encoding OATP1B1, thereby affecting their pharmacological efficacy. However, current conclusions regarding the impact of SLCO1B1 gene polymorphisms on the lipid-modifying effects and adverse reactions of statins remain inconsistent. Our study revealed that the c.521T>C polymorphism in the SLCO1B1 gene had no significant effect on the lipid-lowering efficacy of statins in older adults, with no significant differences in the percentage changes of blood lipid levels across genotypes (P > 0.05). These results are consistent with those reported by Kim Y et al (22). Additionally, statins exhibited more pronounced lipid-lowering effects in patients carrying the c.388A allele. In contrast, Wu et al. found that individuals with the c.388G allele showed greater reductions in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) after 4 weeks of simvastatin treatment (23), which is inconsistent with the findings of our study. The reasons for this are unclear but we hypothesize that this discrepancy could be attributed to the relatively small sample size of patients harboring the c.388A allele in our study. Notably, a recent study has proposed that c.521T>C is unrelated to statin-induced myotoxicity side effects (24). Our study further demonstrates that neither the SLCO1B1 c.521T>C nor c.388A>G polymorphisms exert significant effects on hepatic function markers (AST, ALT) or muscular safety parameters (CK) in elderly patients (all P > 0.05). These findings substantiate the reliable safety profile of standard-dose statin therapy across diverse SLCO1B1 genotypes in elderly populations. Furthermore, no statistically significant sex-specific differences were observed in the association between the SLCO1B1 c.521T>C genotype and statin therapeutic response or adverse outcomes in this study (all interaction P > 0.05). This finding diverges from earlier reports such as that by Bosco et al (25), which suggested that the genotype effect of SLCO1B1 rs4149056 could be more pronounced in women than men. Several factors may account for this discrepancy. First, population characteristics differed: our cohort was restricted to older adults (age > 75 years), whereas the study by Bosco et al. included predominantly younger participants. Age-related physiological changes—including alterations in hepatic and renal function, sex-hormone profiles, and body composition—could mask or modify sexually dimorphic pharmacogenetic relationships. Second, limitations in statistical power must be acknowledged; the relatively small sample size of the statin-treated group (n = 57) reduces the ability to detect modest gene-by-sex interactions, thereby increasing the risk of a type II error. In summary, while our results provide preliminary support for a sex-independent effect of the SLCO1B1 c.521T>C variant in an elderly population, they also underscore the need for future prospective, adequately powered studies conducted in well-defined geriatric cohorts under uniform treatment protocols to clarify the complex interplay of sex and age in this pharmacogenetic association.

In summary, this paper represents the SLCO1B1 c.521C allele as a novel genetic risk marker for CHD while affirming the lipid-lowering efficacy and safety of conventional statin regimens in elderly populations. SLCO1B1 genotyping may hold limited utility for personalizing statin therapy in older adults receiving standard doses, and such genotyping may be unnecessary in this population. These findings provide valuable insights for optimizing cardiovascular risk management in geriatric populations through genetic profiling and personalized statin regimens.

Notably, as a retrospective study, there are several limitations to our study. First, this study focuses on the Han Chinese population in South China, and its applicability to other ethnic groups requires further research and validation. Second, the small sample size of the elderly subgroup may reduce the power to detect small effect sizes, thereby reducing the likelihood of obtaining conclusive results. In particular, the low allele frequency of c.388A, which makes the observed enhanced lipid-lowering effect associated with this allele may be coincidental. Third, the present investigation adopted a surrogate marker-driven paradigm for both efficacy and safety assessments. While this approach permits precise quantification of pharmacological effects, it inherently fails to address the clinically paramount question of whether observed biochemical improvements translate into reduced cardiovascular event rates, nor does it adequately reflect treatment tolerability from the patient perspective. Forth, although the interaction analysis did not demonstrate statistical significance, the overall sample size of the treatment group (n = 57) was limited, and the subgroup sizes became even smaller after cross-stratification by sex and genotype, resulting in insufficient statistical power to detect gene-by-sex interactions. Consequently, conclusions regarding sex differences should be considered exploratory. Despite these limitations, the present study still identifies SLCO1B1 c.521C as a genetically meaningful marker with clinical utility for cardiovascular disease (CVD) prevention in southern Han Chinese population. It also confirms that the efficacy of statins in elderly individuals aged over 75 years is independent of genotype, which suggests that the need for pharmacogenetic testing in statin therapy for elderly patients is limited.