Abstract
Background
The rs688 polymorphism in the LDLR gene has been linked to lipid profile alterations, yet its impact in patients at high to very high cardiovascular risk remains unclear.
Objectives
To investigate the association between the LDLR rs688 polymorphism and dyslipidemia in high to very high cardiovascular risk patients.
Methods
This cross-sectional study included patients classified as high or very high cardiovascular risk and matched controls at Can Tho University of Medicine and Pharmacy Hospital. Blood lipid profiles and LDLR rs688 genotyping were assessed using Realtime-PCR.
Results
Among 80 patients (mean age 62.36 ± 10.49 years; 35.0% male), CT and TT genotypes were more frequent compared to controls (37.5% vs. 30.6%, and 15.0% vs. 3.8%, respectively). The T allele was also more prevalent (33.8% vs. 19.1%). Dyslipidemia was present in 68.8% of patients. T allele carriers had higher dyslipidemia rates (90.7% vs. 57.5%), higher LDLc (5.42 ± 1.51 mmol/L vs. 3.19 ± 1.37 mmol/L), and lower HDLc (0.70 ± 0.25 mmol/L vs. 1.03 ± 0.32 mmol/L) compared to C allele carriers. Multivariate analysis identified the T allele (OR = 14.18) and diabetes mellitus (OR = 4.85) as independent predictors of dyslipidemia.
Conclusion
The LDLR rs688 T allele and diabetes mellitus independently increases dyslipidemia risk among patients at high to very high cardiovascular risk.
Keywords: LDLR rs688, Dyslipidemia, Cardiovascular risk
Introduction
Dyslipidemia refers to a condition characterized by elevated cholesterol levels, particularly low-density lipoprotein cholesterol (LDLc), accompanied by decreased high-density lipoprotein cholesterol (HDLc), with or without hypertriglyceridemia. Based on etiology, dyslipidemia is classified into primary and secondary forms, with primary dyslipidemia predominantly associated with genetic alterations [1–3]. Although primary dyslipidemia is less prevalent than secondary causes, it is distinguished by its early onset, severe hypercholesterolemia, poor treatment response, and its propensity to trigger cardiovascular events at younger ages. According to Aikaterini Bilitou, the prevalence of primary hypercholesterolemia has risen from 13.5% in 2009 to 23.5% in 2019, with initial LDLc levels recorded at 4.32 mmol/L, and 19.6% of affected individuals developing atherosclerotic cardiovascular disease (ASCVD) [4]. Genetic polymorphisms play a critical role in cardiovascular disease [5]. Among various genes, LDLR is widely recognized, with multiple reported polymorphisms linked to the initiation of primary dyslipidemia. Recently, Yin-Tso Liu identified a single nucleotide polymorphism (SNP) located at exon 12 of the LDLR gene, rs688, with the T allele associated with abnormal lipid metabolism and the potential development of dyslipidemia. Female gender and CT or TT genotypes were significantly correlated with hypercholesterolemia, with odds ratios (OR) of 1.153 (95% CI = 1.014–1.311) and 1.423 (95% CI = 1.056–1.917), respectively [6]. The rs688 polymorphism impairs exon 12 splicing efficiency [7], leading to altered LDL receptor protein distribution, a reduction in receptor surface expression, decreased LDL cholesterol uptake, and subsequent elevation of plasma cholesterol levels [8].
Patients classified as having high to very high cardiovascular risk often present with a combination of multiple risk factors, existing atherosclerotic cardiovascular disease, and a 10-year mortality risk-according to the SCORE-ranging from 5 to 10%, compared to less than 5% in those at low to moderate risk [3]. This group therefore requires more aggressive treatment strategies. Transitioning from low-moderate to high or very high risk is associated with a significant increase in the likelihood of future cardiovascular events. Genetic abnormalities are increasingly recognized as potential underlying factors that may contribute to the early development of several risk conditions, such as severe hypercholesterolemia and premature atherosclerotic disease, placing affected individuals at high cardiovascular risk from an early stage in life [9]. Primary dyslipidemia appears relatively frequently in this high-risk population [10]. A study conducted in China found that, in addition to increasing LDL-C levels, the rs688 polymorphism also elevated the risk of atherosclerotic cardiovascular events such as ischemic stroke. In this study, the authors reported a significant association between ischemic stroke and rs688 under both the dominant model (TT vs. CC, OR = 1.47, 95% CI: 1.04–2.07) and the recessive model (TT vs. CT + CC, OR = 2.66, 95% CI: 1.37–5.14) [11]. These findings suggest that the rs688 polymorphism in the LDLR gene may influence lipid metabolism disorders in patients at high to very high cardiovascular risk. However, current evidence on this issue remains limited.
Materials and methods
Study design and population
This was a descriptive cross-sectional study involving a convenient sampling method for all patients classified as having high to very high cardiovascular risk attending Can Tho University of Medicine and Pharmacy Hospital between May 2024 and March 2025.
Inclusion and exclusion criteria were established to select appropriate participants. Patients were diagnosed with high to very high cardiovascular risk according to the European Society of Cardiology guidelines [3]. The control group consisted of healthy individuals or those with low to moderate cardiovascular risk, matched for age and gender with the patient group. Exclusion criteria included: (1) severe liver failure (Child-Pugh C) or severe renal impairment (eGFR < 30 mL/min/1.73 m²); (2) current or recent (within three months) lipid-lowering therapy with statins, fibrates, or ezetimibe; (3) severe internal diseases such as cancer, sepsis, or acute coronary syndromes. After the enrollment period, a total of 80 patients and 160 controls were included.
Sample size
The following formula was applied to calculate the required sample size:
 |
n refers to the estimated sample size.
Z is the Z-score corresponding to the standard normal distribution. With a type I error rate of α = 5%, Z(1–α/2) = 1.96, and with a type II error rate of β = 20% (power = 80%), Z(1–β) = 0.84.
p₁ = 23% represents the frequency of the TT genotype of rs688 in the case group with elevated LDL-c, based on the study by Cahua-Pablo et al. (2016) [12], and p₂ = 9.0% represents the corresponding frequency in the control group, as reported by Hussain et al. (2021) [13].
The minimum sample size required was calculated to be n = 80 for each group (cases and controls). To enhance statistical power, we doubled the control group size. Consequently, the study was conducted on 80 cases and 160 controls.
Data collection
Demographic and anthropometric data, including age, gender, and body mass index (BMI), were recorded, with overweight/obesity defined as BMI ≥ 23 kg/m² for Asians [14]. Blood samples for lipid profiles were collected after 8–12 h of fasting, assessed upon hospital admission in the morning. Dyslipidemia was defined by abnormalities in any of the following: total cholesterol ≥ 6.21 mmol/L, triglycerides ≥ 2.31 mmol/L, elevated LDLc ≥ 4.10 mmol/L, or low HDLc < 1.0 mmol/L [3, 15]. A specialized physician performed clinical assessments to document clinical symptoms and risk factors such as hypertension, diabetes mellitus, alcohol consumption, and smoking, as defined by the COMMIT trial [16].
In this study, the control group consisted of healthy individuals undergoing routine health check-ups and patients classified as having low to moderate cardiovascular risk, as defined by the 2019 European Society of Cardiology (ESC) guidelines [3]. This classification includes individuals with a 10-year risk of cardiovascular death below 5.0% according to the SCORE system, those without diabetes, or with diabetes of short duration (less than 10 years) and no evidence of target organ damage or other additional risk factors.
The control group was matched with the case group in terms of anthropometric characteristics.
Genotyping
Peripheral blood samples from both patients and controls were collected simultaneously with lipid testing for genotyping rs688 of the LDLR gene via Realtime PCR, following these steps:
Sample Collection Site: Laboratory Department, Can Tho University of Medicine and Pharmacy Hospital. Testing Site: Molecular Biology Laboratory, Can Tho University of Medicine and Pharmacy. DNA Extraction: Using the Applied Biosystems™ TaqMan™ SNP Genotyping Assay for rs688. Analysis: Realtime PCR was employed to determine the presence of CC, CT, or TT genotypes and C or T alleles.
Statistical analysis
Data analysis was performed using SPSS version 20.0. Qualitative variables were presented as frequencies (percentages), and quantitative variables as mean ± standard deviation (SD) for normally distributed data, or median and interquartile range (IQR) for non-normally distributed data. Normality was assessed using the Kolmogorov-Smirnov test. Comparisons between categorical variables were made using the Chi-square test or Fisher’s exact test. For continuous variables, the Independent Samples T-test or one-way ANOVA was used. Logistic regression models (univariate and multivariate) were applied to identify independent predictors of dyslipidemia.
Ethical approval
All participants were fully informed about the study’s purpose and procedures and provided written informed consent. Participants could withdraw at any stage without any repercussions. Genetic testing costs and related expenses were covered entirely by the research team. The study protocol was approved by the Ethics Committee of Can Tho University of Medicine and Pharmacy and adhered to the Declaration of Helsinki guidelines (No. 24. 2024.HV/PCT-HDDD).
Results
The baseline characteristics of the study population are presented in Table 1. A total of 80 patients were included, with a mean age of 62.36 ± 10.49 years, and males accounting for 35.0%. The proportion of patients classified as high cardiovascular risk was 60.0% (n=48), and very high cardiovascular risk was 40.0% (n=32). Patients with very high cardiovascular risk were older than those with high risk (67.59 ± 9.67 vs. 58.88 ± 9.60 years, p<0.001).
Table 1.
General characteristics of the study population
| Characteristics | Case group (n=80) | Control group (n=160) | Cardiovascular risk in the case group | 1 | p2 | |
|---|---|---|---|---|---|---|
| High risk (n=48) | Very high risk (n=32) | |||||
| Male gender (%) | 28 (35.0) | 64 (40.0) | 14 (29.2) | 14 (43.8) | 0.453 | 0.180 |
| Age (years) | 62.36 ± 10.49 | 61.10 ± 13.37 | 58.88 ± 9.60 | 67.59 ± 9.67 | 0.461 | <0.001 |
| BMI (kg/m²) | 22.40 ± 3.33 | 22.50 ± 3.19 | 22.34 ± 3.14 | 22.50 ± 3.64 | 0.822 | 0.833 |
| Systolic BP (mmHg) | 140.87 ± 23.66 | 119.37 ± 11.69 | 140.21 ± 23.03 | 141.87 ± 24.94 | <0.001 | 0.760 |
| Diastolic BP (mmHg) | 81.25 ± 13.63 | 77.06 ± 9.36 | 81.46 ± 12.37 | 80.94 ± 15.52 | 0.015 | 0.874 |
| Smoking (%) | 23 (28.7) | 29 (18.1) | 10 (20.8) | 13 (40.6) | 0.060 | 0.055 |
| Alcohol consumption (%) | 22 (27.5) | 26 (16.3) | 10 (20.8) | 12 (37.5) | 0.040 | 0.102 |
| Hypertension (%) | 68 (85.0) | 46 (28.7) | 39 (81.3) | 29 (90.6) | <0.001 | 0.344 |
| Diabetes mellitus (%) | 28 (35.0) | 36 (22.5) | 15 (31.3) | 13 (40.6) | 0.039 | 0.389 |
p1 Comparison between the case group and the control group
p2 Comparison between high and very high cardiovascular risk subgroups within the case group
BMI Body Mass Index
Table 2 summarizes the distribution of LDLR rs688 polymorphism. The CT and TT genotypes were more frequent in patients compared to controls (37.5% vs. 30.6% and 15.0% vs. 3.8%, respectively; p<0.05). Similarly, the T allele frequency was higher in patients than in controls (33.8% vs. 19.1%, p<0.05).
Table 2.
Distribution of rs688 genotypes and alleles in patients and controls
| Characteristics | Patient (n=80) | Control (n=160) | p |
|---|---|---|---|
| Genotype | |||
| CC | 38 (47.5) | 105 (65.6) | 0.002 |
| CT | 30 (37.5) | 49 (30.6) | |
| TT | 12 (15.0) | 6 (3.8) | |
| Allele (nx2) | |||
| C | 106 (66.2) | 259 (80.9) | 0.039 |
| T | 54 (33.8) | 61 (19.1) | |
Table 3 shows the distribution of LDLR rs688 polymorphism based on risk factors. Among male patients, the proportion of TT genotype carriers (66.7%) was higher compared to CT (16.7%) and CC (39.5%) genotypes (p=0.007). Regarding comorbidities, diabetes mellitus was more prevalent among T allele carriers (51.8%) compared to C allele carriers (26.4%). Similarly, patients with the TT genotype had a higher diabetes rate (75.0%) compared to CT (33.3%) and CC (23.7%) genotypes (p=0.006).
Table 3.
Distribution of rs688 polymorphism according to risk factors
| Characteristics | Allele (n=160) | p | Genotype (n=80) | p | |||
|---|---|---|---|---|---|---|---|
| Alen C | Alen T | CC | CT | TT | |||
| Male (%) | 35 (33.0) | 21 (38.9) | 0.539 | 15 (39.5) | 5 (16.7) | 8 (66.7) | 0.007 |
| Female (%) | 71 (67.0) | 33 (61.1) | 23 (60.5) | 25 (83.3) | 4 (33.3) | ||
| Smoking (%) | 32 (30.2) | 14 (25.9) | 0.603 | 12 (31.6) | 8 (26.7) | 3 (25.0) | 0.945 |
| Alcohol consumption (%) | 33 (31.1) | 11 (20.4) | 0.225 | 13 (34.2) | 7 (23.3) | 2 (16.7) | 0.465 |
| Hypertension (%) | 85 (80.2) | 51 (94.4) | 0.079 | 29 (76.3) | 27 (90.0) | 12 (100.0) | 0.105 |
| Diabetes mellitus (%) | 28 (26.4) | 28 (51.8) | 0.012 | 9 (23.7) | 10 (33.3) | 9 (75.0) | 0.006 |
Dyslipidemia was observed in 68.8% of patients, with no significant difference between the high and very high cardiovascular risk groups. Patients with very high cardiovascular risk had higher total cholesterol levels compared to those with high risk (7.06 ± 2.62 mmol/L vs. 5.79 ± 2.01 mmol/L, p=0.016) (Table 4).
Table 4.
Lipid disorder characteristics in the study subjects
| Characteristics | Total (n=80) | Cardiovascular risk in the case group | p | |
|---|---|---|---|---|
| High risk (n=48) | Very high risk (n=32) | |||
| Dyslipidemia (%) | 55 (68.8) | 31 (64.6) | 24 (75.0) | 0.325 |
| Elevated Total Cholesterol (%) | 43 (53.8) | 23 (47.9) | 20 (62.5) | 0.200 |
| Total Cholesterol (mmol/L) | 6.30 ± 2.34 | 5.79 ± 2.01 | 7.06 ± 2.62 | 0.016 |
| Elevated LDLc (%) | 42 (52.5) | 23 (47.9) | 19 (59.4) | 0.315 |
| LDLc (mmol/L) | 4.36 ± 1.82 | 4.13 ± 1.83 | 4.71 ± 1.77 | 0.159 |
| Reduced HDLc (%) | 52 (65.0) | 31 (64.6) | 21 (65.6) | 0.924 |
| HDLc (mmol/L) | 0.85 ± 0.33 | 0.86 ± 0.30 | 0.84 ± 0.37 | 0.795 |
| Elevated Triglycerides (%) | 39 (48.8) | 23 (47.9) | 16 (50.0) | 0.855 |
| Triglycerides (mmol/L) | 4.01 ± 3.17 | 4.02 ± 3.64 | 4.00 ± 2.35 | 0.975 |
HDLc High density lipoprotein cholesterol, LDLc Low density lipoprotein cholesterol
Patients carrying the T allele exhibited a higher prevalence of dyslipidemia compared to those with the C allele (90.7% vs. 57.5%, p<0.001). Moreover, T allele carriers had higher LDLc levels and lower HDLc levels compared to C allele carriers (Table 5).
Table 5.
Association Between rs688 polymorphism and dyslipidemia
| Characteristics | Allele (n=160) | p | Genotype (n=80) | p | |||
|---|---|---|---|---|---|---|---|
| C | T | CC | CT | TT | |||
| Dyslipidemia (%) | 61 (57.5) | 49 (90.7) | <0.001 | 16 (42.1) | 29 (96.7) | 10 (83.3) | <0.001 |
| Elevated Total Cholesterol (%) | 45 (42.4) | 41 (75.9) | <0.001 | 11 (28.9) | 23 (76.7) | 9 (75.0) | <0.001 |
| Total Cholesterol (mmol/L) | 4.90 ± 1.89 | 7.56 ± 2.00 | <0.001 | 4.90 ± 1.89 | 7.49 ± 2.16 | 7.73 ± 1.48 | <0.001 |
| Elevated LDLc (%) | 42 (39.6) | 42 (77.8) | <0.001 | 8 (21.1) | 26 (86.7) | 8 (66.7) | <0.001 |
| LDLc (mmol/L) | 3.19 ± 1.37 | 5.42 ± 1.51 | <0.001 | 3.19 ± 1.37 | 5.59 ± 1.50 | 4.99 ± 1.51 | <0.001 |
| Reduced HDLc (%) | 58 (54.7) | 46 (85.2) | <0.001 | 16 (42.1) | 26 (86.7) | 10 (83.3) | <0.001 |
| HDLc (mmol/L) | 1.03 ± 0.32 | 0.70 ± 0.25 | <0.001 | 1.03 ± 0.32 | 0.71 ± 0.27 | 0.66 ± 0.19 | <0.001 |
| Elevated Triglycerides (%) | 49 (46.2) | 29 (53.7) | 0.544 | 17 (44.7) | 15 (50.0) | 7 (58.3) | 0.703 |
| Triglycerides (mmol/L) | 3.40 ± 2.55 | 4.56 ± 3.59 | 0.103 | 3.40 ± 2.55 | 3.93 ± 2.51 | 6.15 ± 5.24 | 0.030 |
HDLc High density lipoprotein cholesterol, LDLc Low density lipoprotein cholesterol
In the multivariate analysis (Table 6), only the T allele of rs688 (OR=14.18, 95% CI=3.13–64.21) and diabetes mellitus (OR=4.85, 95% CI=1.09–21.59) were identified as independent risk factors for dyslipidemia.
Table 6.
Univariable and multivariable logistic regression of age-adjusted factors associated with dyslipidemia
| Factors | Univariate | Multivariate | ||
|---|---|---|---|---|
| OR (95% CI) | p | OR (95% CI) | p | |
| Male | 1.21 (0.44 – 3.31) | 0.705 | - | - |
| rs688 allele T | 17.87 (4.68 – 68.22) | <0.001 | 14.18 (3.13 – 64.21) | <0.001 |
| Systolic BP (mmHg) | 0.99 (0.96 – 1.01) | 0.181 | - | - |
| Diastolic BP (mmHg) | 0.98 (0.95 – 1.02) | 0.363 | - | - |
| Overweight/Obesity | 7.07 (1.89 – 26.39) | 0.004 | 1.42 (0.27 – 7.53) | 0.681 |
| Smoking | 1.95 (0.63 – 6.03) | 0.248 | - | - |
| Alcohol consumption | 1.30 (0.44 – 3.85) | 0.637 | - | - |
| Hypertension | 1.71 (0.49 – 6.05) | 0.402 | - | - |
| Diabetes mellitus | 6.11 (1.64 – 22.83) | 0.007 | 4.85 (1.09 – 21.59) | 0.038 |
CI Confidence interval, OR Odds ratio
Discussion
The LDLR gene encodes the low-density lipoprotein cholesterol (LDL-C) receptor and is located on the short arm of human chromosome 19, specifically at locus 19p13.1 to p13.3.22. It spans approximately 45,000 base pairs (bp) or 45 kilobases, comprising 18 coding exons and 17 intervening non-coding introns. In most tissues, the gene is transcribed into LDL-C receptors, and its expression is regulated by sterol regulatory element-1 (SRE-1). Transcriptional regulatory elements are located in the promoter region upstream of the gene. This region spans more than 177 bp, from position 58 to 234, and contains two critical 7-bp segments where the TATA and CT sequences are essential for gene expression. When intracellular cholesterol levels rise, SRE-binding proteins dissociate from SRE-1, inhibiting LDLR transcription and thereby reducing the number of LDL-C receptors [17]. The rs688 polymorphism of the LDLR gene, located in exon 12, has been reported to be associated with an increased risk of atherosclerotic cardiovascular disease. According to a study by Monika Buraczynska at the Medical University of Lublin, Poland, the frequency of the T risk allele in the general population was found to be 32.0% [18]. In contrast, a 2010 study by Martinelli et al. reported that the TT genotype was present in 20.2% of the control group without coronary artery disease, compared to 21.5% in the disease group [19]. The rs688 polymorphism has also been identified as an independent risk factor for ischemic stroke [20]. A study by Chandan K. Jha in India showed that the rs688 TT genotype and T allele were associated with increased susceptibility to coronary artery disease. Among patients with coronary artery disease, the genotype distribution was 14.0% CC, 65.0% CT, and 21.0% TT, compared to 18.0%, 73.0%, and 9.0% in the control group, respectively. The risk of coronary artery disease associated with the TT genotype was OR = 3.0 (95% CI: 1.43–6.2; p = 0.003) [21]. This polymorphism involves a C >T substitution in exon 12 of the LDLR gene, which may result in functional alterations of the LDL-C receptor protein, leading to dyslipidemia and elevated LDL-C levels regardless of sex [6, 22, 23]. This may serve as an intermediary factor explaining the association between rs688 and atherosclerotic cardiovascular disease. This association was further confirmed in a study from Taiwan by Yin-Tso Liu, which found that female sex, along with the CT and TT genotypes, was significantly associated with hypercholesterolemia, with ORs of 1.153 (95% CI: 1.014–1.311) and 1.423 (95% CI: 1.056–1.917), respectively [6] (Table 7).
Table 7.
Summary of Studies on LDLR rs688 polymorphism
| Author | Sample size | Population | Results |
|---|---|---|---|
| Buraczynska M, et al. (2021) [18] |
ESKD: n=800 Controls: n=500 |
End-stage kidney disease patients |
ESKD: CC 23.0%; CT 53.0%; TT 24.0% Controls: CC 45.0%; CT 47.0%; TT 8.0% |
| Martinelli N, et al. (2010) [19] |
CAD: n=692 non-CAD: n=291 |
Coronary artery disease patients |
CAD: CC 30.1%; CT 48.4%; TT 21.5% non-CAD: CC 37.5; CT 42.3%; TT 20.2% |
| Afzal M, et al. (2024) [24] |
FH: n=120 Controls: n=120 |
Familial hypercholesterolemia patients |
FH: CC 33.0%; CT 42.0%; TT 25.0% Controls: CC 37.0%; CT 41.0%; TT 22.0% |
| Jha C.K, et al. (2018) [21] |
CAD: n=200 Controls: n=200 |
Coronary artery disease patients |
CAD: CC 14.0%; CT 65.0%; TT 21.0% Controls: CC 18.0%; CT 73.0%; TT 9.0% |
| Liu Y.T, et al. (2020) [6] |
Hyperlipidemia: n=5416 Controls: n=12511 |
Hyperlipidemia patients |
Patients (Controls và Hyperlipidemia): Male: CC 65.97%; CT 30.90%; TT 3.13% Female: CC 65.80%; CT 30.84%; TT 3.36% |
CAD Coronary artery disease, ESKD End stage kidney disease, FH Familial hypercholesterolemia, MAF Minor allele frequency
Consistent with previous findings, our study observed that individuals carrying the T allele had a higher prevalence of dyslipidemia, higher LDL-C levels, and lower HDL-C levels compared to those carrying the C allele. Multiple lines of evidence from both experimental and clinical models suggest that the rs688 polymorphism may influence dyslipidemia through various steps in the lipid metabolism pathway. First, rs688 has been shown to impair exon splicing efficiency. According to Haiyan Zhu, the T risk allele of rs688 reduces the efficiency of exon inclusion-particularly exon 12-by decreasing the activity of an exonic splicing enhancer, resulting in elevated total cholesterol and LDL-C levels [7]. Specifically, this polymorphism (C>T) at exon 12 alters two SRp40 binding sites, changing the ESE sequence from the major allele “C” (TGTCAA) to the minor allele “T” (TGTCAA). This substitution reduces the SRp40 binding score from 3.04 to 1.50, well below the binding threshold of 2.67. Using PCR amplification of the LDLR gene from exons 10 to 14, Haiyan Zhu identified a predominant LDLR isoform lacking exon 12, and a less frequent isoform lacking both 11 and 12. Genotype-based splicing analysis revealed that individuals carrying the T allele exhibited lower splicing efficiency, which may result in structurally altered LDL receptors contributing to hyperlipidemia [7].
Second, the T allele of rs688 promotes intracellular accumulation of LDLR protein within lysosomes and reduces LDL-C uptake. The C>T substitution occurs in Exon 12, which encodes part of the epidermal growth factor (EGF) precursor homology domain. This domain is responsible for LDL-C binding and regulates receptor recycling to the cell membrane. Therefore, SNPs at this location are likely to affect both endocytosis and recycling of the LDL receptor [17]. Feng Gao et al. demonstrated that rs688 T allele increases intracellular lysosomal accumulation of LDLR and impairs LDL-C uptake, leading to dyslipidemia [8]. Using Western blot analysis, the authors quantified LDLR protein at the cell surface, intracellular compartments, and lysosomes in individuals with the rs688 polymorphism. They observed that while the total intracellular LDLR protein levels remained unchanged, T allele carriers exhibited increased LDLR accumulation in lysosomes (25.7 ± 0.3%) and reduced expression at the cell surface (21.8 ± 0.6%) compared to C allele carriers. These findings suggest that beyond its impact on exon splicing, rs688 may contribute to dyslipidemia by disrupting LDLR trafficking and recycling within cells [8]. In the multivariable regression model, we found that only the rs688 T allele and diabetes mellitus were independent risk factors for dyslipidemia. The influence of the LDLR genotype on glycemic status has also been reported in previous studies [25]. Di Giacomo Barbagallo et al. investigated the effects of LDLR genotypes on glycemic alterations and atherosclerotic burden in patients with familial hypercholesterolemia (FH). Their study showed that mutations in the LDLR gene may affect glucose metabolism. Specifically, patients were divided into two groups based on genotype: the LDLR group and the non-LDLR (NLDLR) group. The NLDLR group had significantly higher levels of fasting plasma glucose (FPG) and HbA1c compared to the LDLR group. Furthermore, the LDLR group had a higher prevalence of low glycemic state (LGS) than the NLDLR group (44.1% vs. 26.0%, p < 0.01), whereas high glycemic state (HGS) was more frequent in the NLDLR group than in the LDLR group (74.0% vs. 55.9%, p < 0.01). The NLDLR group also showed a higher prevalence of atherosclerotic plaques (93.4% vs. 73.0%, p < 0.05), while coronary artery calcification was more common in the LDLR group (74.7% vs. 48.0%, p < 0.01). These findings suggest that LDLR gene mutations may influence both glycemic control and atherosclerotic processes [25].
Similarly, Da Dalt et al. demonstrated that LDLR gene mutations may contribute to pancreatic β-cell dysfunction and insulin resistance by promoting intracellular cholesterol accumulation [26]. Together, these findings suggest that abnormalities in the LDLR gene may influence both lipid and glucose metabolism. However, further studies are needed to confirm these associations. In the current era of personalized medicine, assessing genetic abnormalities in the context of primary hypercholesterolemia may improve diagnostic accuracy and cardiovascular risk stratification [27]. Several scoring systems that integrate hypercholesterolemia status and genetic risk have been developed. Notably, the Polygenic Risk Score (PRS) aims to quantify the cumulative effect of multiple gene polymorphisms on an individual’s phenotype, potentially enhancing cardiovascular risk prediction from an early age [28]. These scores may also help guide more effective lipid-lowering strategies. Given its observed impact on both lipid levels and glycemic status [18, 21, 22], the LDLR rs688 polymorphism should be considered for inclusion in future cardiovascular risk assessment tools.
The study featured a well-defined process of sample collection with clearly established inclusion and exclusion criteria. All participants were enrolled voluntarily, and genotyping was conducted in a modern molecular biology laboratory, yielding reliable results. The genotypes and alleles of the rs688 polymorphism were clearly described, ensuring reproducibility. An association between the LDLR rs688 polymorphism and dyslipidemia was identified, with the T allele being linked to increased LDL-C levels and, conversely, to reduced HDL-C levels. However, the study was conducted at a single regional hospital with a relatively small sample size, which may limit the generalizability of certain clinical and demographic findings. Although dyslipidemia was evaluated in conjunction with cardiovascular risk factors and comorbidities, the study did not account for the potential influence of ongoing lipid-lowering treatment. As such, it may not fully capture the extent of the rs688 polymorphism's impact on lipid levels. Therefore, larger-scale, multicenter studies that also account for treatment effects are warranted to further confirm the role of the LDLR rs688 polymorphism in dyslipidemia.
Conclusion
Patients at high to very high cardiovascular risk had a higher frequency of the T risk allele of the LDLR rs688 polymorphism compared to the control group (33.8% vs. 19.1%). Carriers of the T allele exhibited a higher prevalence of dyslipidemia, with elevated LDL-C and reduced HDL-C levels compared to individuals carrying the C allele. Finally, in the multivariable model, the rs688 T allele and diabetes mellitus were identified as independent risk factors for dyslipidemia.
Acknowledgements
We would like to thank Can Tho University of Medicine and Pharmacy for creating favorable conditions for this study to be carried out.
Authors’ contributions
Nguyen Trung Kien, Nguyen Thi Thu Sen: Writing – review & editing, Conceptualization. Nguyen Thi Thu Sen, Pham Thi Ngoc Nga, Ngo Hoang Toan, Nguyen Trung Kien: Writing – review & editing, Writing – original draft, Data curation.
Funding
None.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.