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Article

Glucose-6-Phosphate Dehydrogenase Deficiency and Cardiovascular Risk in Familial Hypercholesterolemia: A Retrospective Cohort Study

by
Alessandra Errigo
1,
Maria Pina Dore
1,2,
Elettra Merola
1 and
Giovanni Mario Pes
1,*
1
Dipartimento di Medicina, Chirurgia e Farmacia, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy
2
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Lipidology 2025, 2(4), 22; https://doi.org/10.3390/lipidology2040022
Submission received: 28 August 2025 / Revised: 15 October 2025 / Accepted: 7 November 2025 / Published: 11 November 2025
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Abstract

Background: Familial hypercholesterolemia (FH) is a monogenic disorder causing markedly elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerosis. Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in antioxidant defense via NADPH production. G6PD deficiency, an X-linked disorder impairing redox homeostasis, may contribute to cardiovascular disease (CVD) risk. This study examined whether G6PD deficiency increases CVD risk in FH patients. Methods: We retrospectively analyzed 217 FH patients. Clinical data included demographics, lipid profiles, G6PD status, and atherosclerotic CVD outcomes (coronary, cerebrovascular, or peripheral arterial disease). In a subset, FH was confirmed by LDLR gene sequencing, and G6PD Mediterranean and Seattle variants were genotyped. Cumulative CVD prevalence was compared between G6PD-deficient and G6PD-normal FH patients. Multivariable logistic regression was adjusted for age, sex, body mass index, high blood pressure, and smoking. Results: Participants (mean age 47 years, 60% female) had markedly elevated LDL-C (mean 292 mg/dL at diagnosis). Atherosclerotic CVD was present in 119 (55%) patients. G6PD-deficient FH patients had a significantly higher CVD prevalence than those with normal G6PD activity (77.4% vs. 39.8%, p < 0.0001). LDL-C levels were higher in the G6PD-deficient group than in the non-deficient group, and this difference reached statistical significance in the univariate analysis. In the multivariable analysis, G6PD deficiency remained an independent CVD predictor (adjusted OR 3.57, 95% CI 1.30–9.83) after controlling for conventional risk factors. Conclusions: In FH, hereditary G6PD deficiency is associated with a markedly increased risk of atherosclerotic CVD. A pro-oxidative state in G6PD-deficient FH patients may play a role in premature atherogenesis. G6PD status may represent a cardiovascular risk modifier in FH, warranting further research into underlying mechanisms and targeted management.

Graphical Abstract

1. Introduction

Familial hypercholesterolemia (FH) is one of the most common monogenic metabolic disorders, characterized by impaired clearance of LDL cholesterol from the circulation. Pathogenic variants in genes encoding key proteins of LDL metabolism, most often the LDL receptor (LDLR) [1] but also apolipoprotein B (APOB) [2], PCSK9 [3], and LDLR adaptor protein 1 (LDLRAP1) [4], chronically elevate plasma LDL-C levels. Consequently, FH patients develop premature atherosclerotic plaques in arterial walls, with a significantly increased risk of early-onset cardiovascular disease (CVD) [5]. Prior studies and meta-analyses indicate that untreated heterozygous FH individuals may experience approximately a 2- to 3-fold higher risk of CVD compared to individuals with normal LDL levels [6,7,8,9,10].
Beyond traditional risk factors [11], various genetic modifiers can influence CVD risk in FH [12,13,14,15,16,17]. Notably, genes involved in inflammation and oxidative stress responses have been implicated [18]. One such modifier is the enzyme glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.46), which plays a central role in the pentose phosphate pathway by generating NADPH to fuel the glutathione antioxidant system [19]. In G6PD-deficient cells, the limited availability of NADPH impairs the regeneration of reduced glutathione (GSH) from its oxidized form (GSSG), thereby shifting the redox balance toward oxidative stress. Erythrocytes, which rely solely on G6PD for NADPH production, are especially vulnerable; hence, the well-known hemolytic anemia triggered by infections, certain drugs, or fava bean ingestion in G6PD deficiency. Notably, defects in intracellular glutathione metabolism have also been reported in FH patients, linking oxidative stress to the pathophysiology of FH [20,21].
G6PD deficiency is the most common X-linked enzyme defect, affecting an estimated 400 million people worldwide. Its prevalence is particularly high in regions historically endemic for malaria due to balanced selection (the G6PD Mediterranean variant, for example, reaches a frequency of nearly 10–15% in Sardinia) [22]. Traditionally, G6PD deficiency was thought to protect against CVD due to a “statin-like” effect, as some earlier studies noted lower serum cholesterol levels in G6PD-deficient individuals [19]. Indeed, earlier epidemiological studies paradoxically reported lower rates of ischemic heart disease in G6PD-deficient cohorts [23]. However, more recent evidence strongly contradicts that view [24]. Extensive contemporary studies have instead found that G6PD deficiency correlates with higher CVD risk. For example, a U.S. military cohort study (17,338 subjects) showed nearly 39% higher odds of coronary heart disease among G6PD-deficient individuals [25]. In an Italian population study (Sardinia, 9604 subjects), G6PD deficiency was associated with a 71% increase in CVD risk after propensity matching [26]. Likewise, a Chinese stroke registry found G6PD deficiency linked to greater large-artery atherosclerotic stroke prevalence (OR 1.53, 95%CI 1.09–2.17) [27]. These and other reports have shifted the consensus toward G6PD deficiency being a risk factor for atherosclerosis rather than protective [24]. The pro-atherogenic effect is biologically plausible: G6PD-deficient endothelial and vascular smooth muscle cells experience increased oxidative stress and nitric oxide dysregulation, which can promote endothelial dysfunction, inflammation, and plaque formation. In fact, most experimental evidence (e.g., G6PD-knockdown mice or cell models) shows that reduced G6PD activity is associated with greater oxidative damage and may play a modifying role in atherogenesis [28]. These adverse effects on the arterial wall likely outweigh any mild cholesterol-lowering effect from G6PD deficiency.
Given this emerging recognition of G6PD deficiency as a contributor to CVD risk, we hypothesized that it could have an especially pronounced impact on FH patients, a population already predisposed to aggressive atherosclerosis. Sardinia offers a unique setting to test this hypothesis: the island has both a relatively high prevalence of FH (including founder LDLR variants) [29] and one of the world’s highest frequencies of G6PD deficiency [22]. Moreover, prior work in Sardinian FH families hinted that co-inherited genetic traits (e.g., beta-thalassemia) can modulate the FH phenotype [29].
We therefore aimed to determine whether hereditary G6PD deficiency is associated with increased cardiovascular risk in FH and to explore the potential underlying mechanisms of any observed association.

2. Materials and Methods

2.1. Study Design and Participants

We retrospectively reviewed digitized medical records of 21,777 patients evaluated between 2002 and 2017 at the University of Sassari Gastroenterology Center, a tertiary referral center in Northern Sardinia. Patients with a diagnosis of FH according to the Simon Broome criteria [30] were selected, including both “definite” and “possible” FH cases as defined by those criteria. In practice, this meant that genetic confirmation or the presence of tendon xanthomas was not strictly required for inclusion, as long as other clinical criteria were met. Specifically, patients fulfilled the Simon Broome FH diagnostic criteria if they had:
  • personal and family history of early onset of coronary, cerebrovascular, and peripheral vascular diseases;
  • LDL-C levels (calculated using the Friedewald formula [31]) exceeding 190 mg/dL without treatment or >100 mg/dL following treatment with maximum doses of statins (40–80 mg atorvastatin), or above the age- and sex-specific 95th percentile for the local population;
  • tendon xanthomas or evidence of severe hypercholesterolemia in a first-degree relative.
We excluded individuals with incomplete medical histories or missing lipid profile data or G6PD status and acknowledged that a subset of patients was diagnosed clinically rather than genetically. The patient selection process is illustrated in Figure 1.
Data on the presence of atherosclerotic manifestations were extracted from the records and used for the analysis.

2.2. Clinical and Laboratory Data of Participants

Clinical data collected from each record included age (at last follow-up or at the time of CVD event), sex, body mass index (BMI), smoking status (never vs. current/former), blood pressure, and fasting lipid profile (total cholesterol, LDL-C, HDL-C, non-HDL-C, and triglycerides). Medication use was reported, particularly lipid-lowering therapies (statins or ezetimibe). The presence of other comorbid conditions (e.g., hypertension) was recorded.

2.3. Assessment of Cardiovascular Disease Outcomes

The primary outcome was the occurrence of atherosclerotic CVD documented in the patient’s history. We defined CVD broadly to include any of the following manifestations: (i) coronary heart disease (non-fatal myocardial infarction, acute coronary syndrome, or history of coronary revascularization), (ii) stable angina pectoris with objective evidence of ischemia, (iii) ischemic stroke or transient ischemic attack of atherosclerotic origin, (iv) peripheral arterial disease with claudication or revascularization, and (v) other atherosclerotic disease such as aortic aneurysm or significant carotid artery stenosis. We did not count isolated xanthomas or valvular disease as CVD outcomes. CVD events were determined based on documentation by cardiovascular specialists in the records (e.g., angiographic reports, imaging studies, or hospital discharge summaries). If a patient reached the last available follow-up with no documented CVD events, they were considered free of CVD for our analysis.

2.4. Genetic Analysis

Molecular genetic testing was performed in a subset of patients to confirm the FH diagnosis. Genomic DNA was extracted from peripheral blood leukocytes. A rapid screening for known Sardinian founder pathogenic variants was performed by PCR amplification with allele-specific primers and restriction enzyme digestion (Supplementary Table S1 lists PCR primers and restriction enzymes used for rapid LDLR variants screening). Positive results were confirmed by the Sanger sequencing of the corresponding LDLR exons/introns. The two most prevalent LDLR variants identified in our cohort were a single-base substitution at the intron 3 donor splice site (c.313+1G>A, known as FH Elverum, [32]) and a single guanine deletion at nucleotide 1778 in exon 12 (FH Sassari-1 variant), both of which are known founder variants in Sardinia and other populations [29]. Other less frequent LDLR variants were found in only one or two families each (e.g., c.346T>C, c.415G>A, c.828C>G), making genotype–phenotype correlation difficult for those rare variants [29]. Where available, we noted the American College of Medical Genetics (ACMG) or ClinVar classification of each LDLR variant: the common splice site and frameshift variants mentioned above are classified as pathogenic, and most of the missense variants are considered likely pathogenic. We did detect one intronic LDLR variant, c.1706-10G>A, which is classified as likely benign by expert consensus (ClinVar), suggesting that patient’s FH phenotype may have been due to other causes. Supplementary Table S2 lists LDLR variants identified among study participants.
We also assessed each patient’s G6PD genotype. In Sardinia, two G6PD gene variants account for >95% of G6PD deficiency cases due to a founder effect: the Mediterranean variant (c.563C>T, p.Ser188Phe), a severe Class II allele, and the Seattle variant (c.844G>C, p.Asp282His) a Class III allele. For genotyped patients, we noted whether they carried the G6PD Mediterranean or Seattle variant (hemizygous in males, homozygous or heterozygous in females). Technical details are provided in the Supplementary Data [33].

2.5. Glucose-6-Phosphate Dehydrogenase Status Determination

All patients underwent evaluation for G6PD deficiency as part of their workup, given the high regional prevalence of G6PD variants. Quantitative G6PD enzyme activity was measured in peripheral blood using a standard kinetic assay at 37 °C, which involved determining the ratio of G6PD activity to 6-phosphogluconate dehydrogenase (6PGD) activity in red blood cells [34,35]. This coupled enzyme assay (Brewer’s test) normalizes G6PD activity to an internal 6PGD control, ensuring reliability even with varying red cell counts. Results were interpreted per the established reference ranges [36]: severe deficiency (<10% of normal activity) and intermediate deficiency (10–80% of normal) were grouped together for analysis, with patients above the threshold considered G6PD-normal. In all deficient patients, confirmatory molecular tests of G6PD deficiency were assessed, focusing on the two Sardinian variants (Mediterranean and Seattle) that account for >95% of cases. The PCR protocol for G6PD variant screening was described previously [37].

2.6. Statistical Analysis

All data were analyzed using SPSS 22.0 (Chicago, IL, USA). For all tests, the significance cut-off was set at 0.05. A priori power calculations assumed that the prevalence of G6PD deficiency in our sample would be at most 15% and that CVD events in the non-deficient FH population could range between 30% and 50%. Under these assumptions, a total sample size of n = 200 (170 normal/30 deficient) patients provides at least 78.7% power to detect odds ratios of 3.25 or more at a 2-sided significance level of 5%. Continuous variables were presented as mean ± standard deviation, and categorical variables as counts and percentages. Group comparisons (e.g., FH patients with vs. without G6PD deficiency) were made using the unpaired Student’s t-test for continuous variables and the chi-square test (or Fisher’s Exact Test when appropriate) for categorical variables. To reduce covariate imbalance and more accurately estimate the effect of G6PD on CVD risk, a propensity score matching (PSM) analysis was conducted using the MatchIt package in R (version 4.5.0; http://www.r-project.org/, accessed on 6 October 2025) with age, sex, BMI, smoking, and high blood pressure as matching variables. Each FH patient was matched to one control (1:1 matching) using greedy nearest-neighbor matching within a caliper of ±0.2 SD of the propensity score. Covariate balance in the matched dataset was assessed to ensure comparability between groups. Multivariable analysis of CVD outcomes was performed with binary logistic regression. Covariates in the adjusted model included age, sex, BMI category, smoking status, and high blood pressure. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Given the historical dataset, some variables had missing values; these cases were excluded listwise in relevant analyses.

2.7. Ethical Approval

Ethical review and approval were waived for this study due to its retrospective observational design, in accordance with Italian law (GU No. 76, 31 March 2008). The procedures performed were consistent with the ethical standards of the Declaration of Helsinki.

3. Results

3.1. Baseline Characteristics of the Cohort

A total of 217 patients with heterozygous FH were included (131 females, 60.4%). Table 1 summarizes major clinical characteristics.
The mean age at last evaluation was 46.9 ± 19.3 years (males 44.9 ± 18.7, females 47.8 ± 19.6). Briefly, males and females had similar BMI distributions (overall, 59% had a BMI <25 kg/m2; 36% were overweight, 5% obese). A higher proportion of males were ever-smokers compared to females (43.0% vs. 24.4%, p = 0.006). Treated hypertension was noted in 36.9% of patients (43.0% of males, 32.8% of females; difference not significant). Nearly all patients (86.6%) were receiving statin therapy, and 13% were on adjunctive ezetimibe. As expected in FH, lipid profiles before therapy were markedly abnormal (Table 1). Mean total cholesterol was 364.2 ± 84.9 mg/dL and LDL-C 291.9 ± 82.5 mg/dL, consistent with a heterozygous FH phenotype, while HDL cholesterol and TG were in the mid-normal range. Lipid differences between male and female FH patients in our cohort were not significant.
Thirty-one patients (14.3% of the cohort) had G6PD deficiency (either severe or intermediate enzyme deficiency), which is in line with the frequency of G6PD-deficient individuals in the general Sardinian population [38]. Interestingly, G6PD deficiency was actually a bit more frequent in females (22 of 131 females, 16.8%) than in males (9 of 86 males, 10.5%) in our FH cohort, although this sex difference was not statistically significant (p = 0.19). This pattern reflects the inclusion of heterozygous female carriers with intermediate enzyme levels in the “deficient” group.
Table 2 displays the main clinical features of study participants stratified according to G6PD status.
The most striking finding of our study was the large difference in CVD prevalence between FH patients with G6PD deficiency and those with normal G6PD activity. Among the 31 FH patients with G6PD deficiency, 24 (77.4%) had experienced at least one atherosclerotic CVD event. In contrast, only 74 of 186 FH patients with normal G6PD had any CVD history (39.8%). This nearly two-fold difference in cumulative CVD prevalence (77.4% vs. 39.8%) was highly significant (chi-square p < 0.0001).
Notably, in our cohort, FH patients with G6PD deficiency did not have lower cholesterol levels than those with normal G6PD activity. On the contrary, their pretreatment LDL-C tended to be significantly higher: mean untreated total cholesterol was 407 mg/dL in G6PD-deficient FH patients vs. 357 mg/dL in G6PD-normal FH patients, and mean LDL-C was 356 mg/dL vs. 283 mg/dL, respectively (p < 0.01 for both comparisons). Thus, there was no lipid-lowering effect of G6PD deficiency evident in this FH cohort. This finding does not alter the overall conclusions of the study, but rather reinforces the potential biological link under investigation. HDL-C and triglycerides did not differ significantly between the G6PD-deficient and G6PD-normal groups (Table 2). Among the 217 patients who underwent genetic testing, an FH-causing variant was confirmed in 126 of them (these included the common LDLR variants as described). There were no statistically significant differences regarding sex distribution, BMI, and smoking habits.
To formally test whether G6PD deficiency was independently associated with CVD after accounting for other factors, we performed a multivariable logistic regression analysis (Table 3). In an unadjusted (univariate) logistic model, FH patients with G6PD deficiency had over five times the odds of CVD compared to those with normal G6PD (reflecting the 77% vs. 40% prevalence difference).
After adjusting for the major covariates (age, sex, BMI category, hypertension, and smoking), G6PD deficiency remained significantly associated with CVD. The adjusted OR for CVD associated with G6PD deficiency was 3.57 (95% CI 1.30–9.83) in our model, indicating that even after controlling for those risk factors (including the older age of the G6PD-deficient group), FH patients with G6PD deficiency had more than threefold higher odds of having had CVD. In other words, G6PD deficiency appeared to carry additional risk on top of the conventional risk factors. All the traditional risk factors in the model behaved as expected: ever-smoking, hypertension, and obesity, were also independently associated with higher odds of CVD (Table 3). We note that the logistic model included 98 CVD events for five covariates (nearly 19 events per predictor); a propensity score matching demonstrated that the cardiovascular risk associated with G6PD deficiency remains significant even after controlling for age as a confounder (Supplementary Table S4). This suggests our findings are robust despite the modest sample size of the deficient subgroup.

3.2. Molecular Genetic Findings and CVD Risk

In the total of 217 FH patients a molecular defect was found in 126 (58%), with complete data on LDLR variants and clinical outcomes (56 with CVD, 70 without CVD). The spectrum of LDLR variants in these patients was consistent with prior reports from Sardinia [29] (Table S3 of Supplementary Data). Two LDLR variants were particularly prevalent: the intron 3 splice donor variant c.313+1G>A was present in 41 patients (32%), and the exon 12 frameshift variant 1778delG (denoted Fs572) in 61 patients (nearly 48%). The remaining patients had one of several rarer LDLR variants (e.g., c.346T>C in nine patients, c.1195G>A in three, c.1301C>G in one, c.1798G>T in eleven), but the numbers were too small to assess CVD risk for each specific variant.
An exploratory cross-tabulation suggested some differences in variant frequency between those with and without CVD: for example, the c.313+1G>A LDLR variant was relatively more frequent in FH patients with CVD (found in 24 of 41, 58.5%) than in those without CVD (17 of 119, 14%). In contrast, the 1778delG variant appeared less often among those with CVD (22 of 98, 22%) compared to those without CVD (39 of 119, 33%). This context raises the hypothesis that FH patients with the 1778delG variant might have somewhat lower CVD risk than those with the c.313+1G>A variant, although our sample is too limited for firm conclusions.
Notably, considering the LDLR variant, G6PD deficiency was disproportionately present in FH patients with CVD (Table S3 of Supplementary Data). For instance, among the 41 FH patients carrying the c.313+1G>A variant, 12 were G6PD-deficient, and all but one had CVD. Similarly, of the 61 patients with the 1778delG variant, six were G6PD-deficient and all but one of these deficient patients had CVD.
Supplementary Table S3 provides a breakdown of each patient’s LDLR variant alongside their G6PD genotype (wild-type B allele, Med, or Seattle). There was no obvious one-to-one correspondence; G6PD variants were scattered among different LDLR genotypes without a consistent pattern of cosegregation. This finding suggests that the relationship between G6PD deficiency and CVD in FH is not due to any particular LDLR variant linkage, but rather an independent effect of the G6PD status.
In the cluster represented by the LDLR c.313+1G>A variant, four hemizygous males with the G6PD Mediterranean variant (nucleotide 563 C→T, amino acid S188F) were detected, and another 11 males bore the wild allele B. Moreover, 8 females were heterozygous for the G6PD Mediterranean variant, and 18 females bore the wild-type alleles. The second, relatively more numerous, cluster represented by the LDLR 1778delG variant included one hemizygous male with the G6PD Mediterranean variant, one hemizygous male with the G6PD Seattle variant, and 25 males with the wild-type allele. The other LDLR variants were associated with G6PD variants in a dispersed manner.

4. Discussion

Our findings show that G6PD deficiency was significantly associated with increased risk of atherosclerotic CVD in patients with FH (77% vs. 39%, p < 0.0001). To our knowledge, this is the first analysis focusing on the interplay between these two conditions. Even after adjusting for classical risk factors (including the older age of the G6PD-deficient group), G6PD deficiency remained associated with substantially increased odds of CVD (adjusted OR 3.57, 95% CI 1.30–9.83). Although numbers are small, this observation suggests that within any given FH genotype, the presence of G6PD deficiency may confer higher CVD risk, regardless of which LDLR variant an FH patient has.
These results align with and extend the growing body of evidence in non-FH populations that G6PD deficiency is a detrimental factor for cardiovascular health. They also question earlier assumptions that G6PD deficiency might protect against CVD via modest cholesterol reduction [23]. In our FH cohort, G6PD-deficient individuals did not have lower LDL-C. Thus, any theoretical lipid-lowering effect of G6PD deficiency was certainly insufficient to offset the adverse effects of chronic hypercholesterolemia.
Several prior studies in diverse populations have similarly found that G6PD deficiency is associated with a higher CVD risk. For instance, Thomas et al. reported that U.S. military personnel with G6PD deficiency had an adjusted OR of 1.39 for coronary artery disease [25]. In previous work, we examined a Sardinian cohort and found an OR of 1.71 for composite CVD in G6PD-deficient individuals [26]. Ou et al. observed a higher prevalence of large-artery stroke in Chinese patients with G6PD deficiency (OR nearly 1.53) [27]. A narrative review by our team concluded that G6PD downregulation generally facilitates atherogenesis in susceptible individuals [24]. Our findings in FH patients align with these reports. In fact, the impact of G6PD deficiency was expected to be even more pronounced in FH, as FH imposes a heavy baseline atherosclerotic burden against which any additional pro-oxidative stress could have amplified consequences. The FH population can be considered a “natural human model” of accelerated atherosclerosis (analogous to LDLR-knockout mice), wherein secondary factors can be tested for their effect. G6PD deficiency appears to be one such factor worsening atherosclerotic outcomes in this high-risk setting.
Mechanistically, the reasons for G6PD deficiency promoting atherogenesis are compelling. G6PD is the primary source of NADPH in many cell types, and NADPH is required for regenerating reduced glutathione (GSH) via glutathione reductase (Figure 2). GSH is a critical intracellular antioxidant that protects endothelial cells and macrophages from oxidative injury. In FH, oxidative stress is already raised due to excessive LDL oxidation and inflammation in arterial walls. A concomitant G6PD deficiency might exacerbate this by impairing the GSH/GSSG recycling and other NADPH-dependent antioxidant systems. Endothelial cells with G6PD inhibition produce more superoxide and less nitric oxide, leading to endothelial dysfunction [39]. In vivo, G6PD-deficient mice show increased susceptibility to oxidative tissue damage and accelerated vascular pathology under stress conditions. Of particular relevance, a recent experiment by Jain et al. demonstrated that following cardiac ischemia–reperfusion injury, G6PD-deficient mouse hearts exhibited greater damage, which was inversely correlated with myocardial GSH levels [40]. This underscores the importance of adequate G6PD activity (and thus NADPH availability) for cardiovascular resilience against oxidative stress. In the setting of FH, in which plaques form and progress partly due to oxidative and inflammatory processes, a chronic NADPH/GSH deficit could plausibly accelerate plaque development and instability.
The reasons why some older studies suggested a protective effect of G6PD deficiency are worth discussing. One hypothesis was the “pseudo-statin” effect: G6PD-deficient individuals might have lower hepatic cholesterol synthesis, slightly reducing circulating cholesterol (as in some rodent models) [19]. Some earlier Sardinian observations of lower ischemic heart disease in G6PD-deficient males are now thought to have been influenced by differences in statin use or baseline risk profiles [41]. However, newer and larger analyses controlling for confounders have not supported any net cardioprotective effect of G6PD deficiency. Our data clearly show no intrinsic LDL-C reduction in G6PD-deficient FH patients (their LDL levels were just as high or higher), and their outcomes were worse, not better. This finding is consistent with the current consensus that G6PD deficiency, overall, promotes rather than prevents atherogenesis. Another intriguing aspect is the age-dependent expression of CVD risk in G6PD deficiency. We previously observed that in the general Sardinian population, the CVD risk associated with G6PD deficiency became significantly elevated only around age 60, with little difference at younger ages [26].
The particular G6PD variants prevalent in our cohort might also play a role. The G6PD Mediterranean variant (Ser188Phe), common in Sardinia, results in a severe (90–95%) enzyme activity reduction (Class II) [37]. In contrast, the G6PD A—variant common in African populations is a milder Class III deficiency (10–15% residual activity) [42]. It has been hypothesized that the severity of G6PD deficiency correlates with the cardiovascular impact. Indeed, a U.S. military study (with mostly African American G6PD A—individuals) found a smaller risk increase (OR 1.3–1.4), whereas studies involving the Mediterranean variant (in Italy and the Middle East) often reported higher ORs [24]. Our findings with the Mediterranean variant in FH show a very pronounced unadjusted effect (nearly 70% higher CVD prevalence), implying that a severe G6PD deficiency can substantially worsen an already high-risk situation. This context raises an interesting clinical question: should we genotype or screen FH patients for G6PD deficiency as part of risk stratification? Recommending this routinely is premature, but if our findings are confirmed in further research, knowing a patient’s G6PD status could alert clinicians that such an FH patient has even greater urgency for aggressive CVD prevention (e.g., intensive LDL-lowering, strict control of other risk factors, and perhaps targeted antioxidant therapies). Conversely, assessing whether individuals with milder G6PD variants (or intermediate enzyme activity) have a proportionally smaller impact on FH outcomes would be informative.

Study Limitations

Our study has several limitations. First, its retrospective design using clinical record data is subject to inherent biases and cannot establish temporal relationships between G6PD deficiency and CVD events, which is critical for causal inference. Some patients’ records were compiled several years ago, during a period when diagnostic and treatment practices had undergone significant evolution. Second, not all FH diagnoses were genetically confirmed; around 42% were clinical-only, which is lower than the 80% in other cohorts [43]. While clinical criteria are widely used and validated, lack of genetic confirmation may introduce heterogeneity. In addition, as noted in the FH literature, roughly 30–40% of clinically diagnosed FH patients have no identifiable pathogenic mutation [44,45]; thus, we cannot rule out a possible misclassification (e.g., polygenic hypercholesterolemia labeled as FH). It is possible that some clinically diagnosed FH patients did not carry an LDLR/APOB/PCSK9 variant (phenocopies), though the stringent clinical criteria make this unlikely. Regardless, any misclassification would tend to dilute differences and should not create a false association with G6PD status. Third, the sample size of G6PD-deficient FH patients was modest (n = 31 enzyme-deficient, 13 of whom also had genotype data). The unavoidable small sample size of this study limits the statistical power, meaning that our multivariable model should be interpreted cautiously. Although residual confounding is possible, it is notable that the association remained relatively strong despite adjusting for the major known confounders. Additionally, our focus was on manifest CVD; we did not systematically assess subclinical atherosclerosis (e.g., carotid intima-media thickness or coronary calcium). Fourth, our study did not include measurements of oxidative markers such as glutathione, malondialdehyde (MDA), or others, which will be the object of future analyses. However, Andrews et al. reported that G6PD-deficient patients exhibit significantly higher levels of lipid and protein oxidation products (MDA and protein carbonyls) [28]. Fifth, although PSM may not be the optimal approach for genetic traits, our use of it was intended to provide reassurance about confounding rather than to suggest causal inference.
Despite these limitations, the study also has strengths. It examines a unique high-risk population (FH patients in Sardinia) with a high prevalence of the exposure of interest (G6PD deficiency), providing a clearer signal than might be seen in the general population. All patients were managed at a single specialized center, which likely standardized the workup and CVD definitions. We also had the opportunity to validate findings in a genotyped subset, reinforcing that the G6PD–CVD link was not an artifact of some peculiar subgroup (for instance, it held even among genetically confirmed FH patients).
From a clinical perspective, clinical findings suggest that FH patients who also have G6PD deficiency deserve particular attention. They might benefit from more aggressive therapy to mitigate oxidative stress. For instance, high-dose antioxidant vitamin supplementation has generally not improved outcomes in unselected patient groups, but perhaps in this genetically predisposed subgroup, it could be worth testing as a hypothesis.
In conclusion, our study presents intriguing preliminary evidence for an important clinical association but requires additional validation and mechanistic data before definitive conclusions can be drawn about clinical management implications. G6PD deficiency may contribute to increased CVD risk via loss of protection against oxidative stress, extending this knowledge to patients with familial hypercholesterolemia. FH patients who inherit a G6PD-deficient genotype appear to have an adverse synergistic risk profile for atherosclerotic disease. Future prospective studies or pooled registries of familial hypercholesterolemia could assess outcomes in larger cohorts of G6PD-deficient patients. Ultimately, a deeper understanding of this gene–gene interaction may pave the way for personalized risk management in familial hypercholesterolemia and related disorders.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/lipidology2040022/s1, Table S1: Oligonucleotide primers and restriction enzymes used for the rapid screening of LDLR variants [32,46,47]; Table S2: LDLR variants identified in study participants; Table S3: LDLR variants according to G6PD genotype; Table S4: PS-matched analysis with 1:1 ratio. Covariate distribution among the study participants, by glucose-6-phosphate dehydrogenase (G6PD) status.

Author Contributions

Conceptualization, A.E. and G.M.P.; methodology, G.M.P.; software, G.M.P.; validation, M.P.D., A.E., E.M. and G.M.P.; formal analysis, G.M.P.; investigation, A.E.; resources, M.P.D.; data curation, M.P.D.; writing—original draft preparation, A.E.; writing—review and editing, A.E., E.M., G.M.P. and M.P.D.; visualization, G.M.P.; supervision, M.P.D.; project administration, M.P.D.; funding acquisition, M.P.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki. Ethical review and approval were waived for this study due to its retrospective observational design, in accordance with Italian law (GU No. 76, 31 March 2008).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on reasonable request from the corresponding author.

Acknowledgments

This paper is dedicated to the memory of Stefano Bertolini, an Italian lipidologist with great experience and humanism, who twenty years ago strongly contributed to the development of studies on familial hypercholesterolemia in Sardinia.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
6PGD6-phosphogluconate dehydrogenase
APOBApolipoprotein B
BMIBody Mass Index
CVDCardiovascular disease
FHFamilial Hypercholesterolemia
G6PDGlucose-6-phosphate dehydrogenase
HDL-CHigh Density Lipoprotein Cholesterol
LDL-CLow Density Lipoprotein Cholesterol
LDLRLow Density Lipoprotein Receptor
LDLRAP1Low-Density Lipoprotein Receptor Adaptor Protein 1
NADPHReduced Nicotinamide Adenine Dinucleotide Phosphate
OROdds Ratio
PCSK9Proprotein Convertase Subtilisin/Kexin type 9
TGTriglycerides

References

  1. Sudhof, T.C.; Goldstein, J.L.; Brown, M.S.; Russell, D.W. The LDL receptor gene: A mosaic of exons shared with different proteins. Science 1985, 228, 815–822. [Google Scholar] [CrossRef]
  2. Cladaras, C.; Hadzopoulou-Cladaras, M.; Nolte, R.T.; Atkinson, D.; Zannis, V.I. The complete sequence and structural analysis of human apolipoprotein B-100: Relationship between apoB-100 and apoB-48 forms. EMBO J. 1986, 5, 3495–3507. [Google Scholar] [CrossRef]
  3. Abifadel, M.; Varret, M.; Rabes, J.P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 2003, 34, 154–156. [Google Scholar] [CrossRef] [PubMed]
  4. Garcia, C.K.; Wilund, K.; Arca, M.; Zuliani, G.; Fellin, R.; Maioli, M.; Calandra, S.; Bertolini, S.; Cossu, F.; Grishin, N.; et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 2001, 292, 1394–1398. [Google Scholar] [CrossRef]
  5. Santos, R.D.; Gidding, S.S.; Hegele, R.A.; Cuchel, M.A.; Barter, P.J.; Watts, G.F.; Baum, S.J.; Catapano, A.L.; Chapman, M.J.; Defesche, J.C.; et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: A consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol. 2016, 4, 850–861. [Google Scholar] [CrossRef]
  6. Akioyamen, L.E.; Genest, J.; Chu, A.; Inibhunu, H.; Ko, D.T.; Tu, J.V. Risk factors for cardiovascular disease in heterozygous familial hypercholesterolemia: A systematic review and meta-analysis. J. Clin. Lipidol. 2019, 13, 15–30. [Google Scholar] [CrossRef]
  7. Yu, Y.; Chen, L.; Zhang, H.; Fu, Z.; Liu, Q.; Zhao, H.; Liu, Y.; Chen, Y. Association Between Familial Hypercholesterolemia and Risk of Cardiovascular Events and Death in Different Cohorts: A Meta-Analysis of 1.1 Million Subjects. Front. Cardiovasc. Med. 2022, 9, 860196. [Google Scholar] [CrossRef]
  8. Cui, Y.; Li, S.; Zhang, F.; Song, J.; Lee, C.; Wu, M.; Chen, H. Prevalence of familial hypercholesterolemia in patients with premature myocardial infarction. Clin. Cardiol. 2019, 42, 385–390. [Google Scholar] [CrossRef] [PubMed]
  9. Khan, T.Z.; Breen, J.; Neves, E.; Grocott-Mason, R.; Barbir, M. Prevalence of cardiovascular events in genetically confirmed versus unconfirmed familial hypercholesterolaemia. Glob. Cardiol. Sci. Pract. 2020, 2020, e202024. [Google Scholar] [CrossRef] [PubMed]
  10. Masana, L.; Zamora, A.; Plana, N.; Comas-Cufi, M.; Garcia-Gil, M.; Marti-Lluch, R.; Ponjoan, A.; Alves-Cabratosa, L.; Elosua, R.; Marrugat, J.; et al. Incidence of Cardiovascular Disease in Patients with Familial Hypercholesterolemia Phenotype: Analysis of 5 Years Follow-Up of Real-World Data from More than 1.5 Million Patients. J. Clin. Med. 2019, 8, 1080. [Google Scholar] [CrossRef]
  11. Malone, R.; Savage, S.; Crowley, V.; Hennessy, M.; O’Connor, P.; Kennedy, C. Risk Factors and Modifiers for Cardiovascular Disease Assessment of Patients with Heterozygous Familial Hypercholesterolaemia. J. Clin. Med. 2024, 13, 2270. [Google Scholar] [CrossRef]
  12. Bertolini, S.; Pisciotta, L.; Di Scala, L.; Langheim, S.; Bellocchio, A.; Masturzo, P.; Cantafora, A.; Martini, S.; Averna, M.; Pes, G.; et al. Genetic polymorphisms affecting the phenotypic expression of familial hypercholesterolemia. Atherosclerosis 2004, 174, 57–65. [Google Scholar] [CrossRef]
  13. Calandra, S.; Bertolini, S.; Pes, G.M.; Deiana, L.; Tarugi, P.; Pisciotta, L.; Li Volti, S.; Li Volti, G.; Maccarone, C. Beta-thalassemia is a modifying factor of the clinical expression of familial hypercholesterolemia. Semin. Vasc. Med. 2004, 4, 271–278. [Google Scholar] [CrossRef]
  14. Jansen, A.C.; van Aalst-Cohen, E.S.; Tanck, M.W.; Cheng, S.; Fontecha, M.R.; Li, J.; Defesche, J.C.; Kastelein, J.J. Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1475–1481. [Google Scholar] [CrossRef]
  15. Oosterveer, D.M.; Versmissen, J.; Schinkel, A.F.; Langendonk, J.G.; Mulder, M.; Sijbrands, E.J. Clinical and genetic factors influencing cardiovascular risk in patients with familial hypercholesterolemia. Clin. Lipidol. 2010, 5, 189–197. [Google Scholar] [CrossRef]
  16. van der Net, J.B.; Oosterveer, D.M.; Versmissen, J.; Defesche, J.C.; Yazdanpanah, M.; Aouizerat, B.E.; Steyerberg, E.W.; Malloy, M.J.; Pullinger, C.R.; Kastelein, J.J.; et al. Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia. Eur. Heart J. 2008, 29, 2195–2201. [Google Scholar] [CrossRef] [PubMed]
  17. Versmissen, J.; Oosterveer, D.M.; Hoekstra, M.; Out, R.; Berbee, J.F.; Blommesteijn-Touw, A.C.; van Vark-van der Zee, L.; Vongpromek, R.; Vanmierlo, T.; Defesche, J.C.; et al. Apolipoprotein isoform E4 does not increase coronary heart disease risk in carriers of low-density lipoprotein receptor mutations. Circ. Cardiovasc. Genet. 2011, 4, 655–660. [Google Scholar] [CrossRef]
  18. Radovanovic, J.; Banjac, K.; Obradovic, M.; Isenovic, E.R. Antioxidant enzymes and vascular diseases. Explor. Med. 2021, 2, 544–555. [Google Scholar] [CrossRef]
  19. Hecker, P.A.; Leopold, J.A.; Gupte, S.A.; Recchia, F.A.; Stanley, W.C. Impact of glucose-6-phosphate dehydrogenase deficiency on the pathophysiology of cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 2013, 304, H491–H500. [Google Scholar] [CrossRef] [PubMed]
  20. Cortes, R.; Martinez-Hervas, S.; Ivorra, C.; De Marco, G.; Gonzalez-Albert, V.; Rojo-Martinez, G.; Saez, G.; Carmena, R.; Ascaso, J.F.; Real, J.T.; et al. Enhanced reduction in oxidative stress and altered glutathione and thioredoxin system response to unsaturated fatty acid load in familial hypercholesterolemia. Clin. Biochem. 2014, 47, 291–297. [Google Scholar] [CrossRef] [PubMed]
  21. Ganjali, S.; Keshavarz, R.; Hosseini, S.; Mansouri, A.; Mannarino, M.R.; Pirro, M.; Jamialahmadi, T.; Sahebkar, A. Evaluation of Oxidative Stress Status in Familial Hypercholesterolemia. J. Clin. Med. 2021, 10, 5867. [Google Scholar] [CrossRef] [PubMed]
  22. De Vita, G.; Alcalay, M.; Sampietro, M.; Cappellini, M.D.; Fiorelli, G.; Toniolo, D. Two point mutations are responsible for G6PD polymorphism in Sardinia. Am. J. Hum. Genet. 1989, 44, 233–240. [Google Scholar]
  23. Cocco, P.; Todde, P.; Fornera, S.; Manca, M.B.; Manca, P.; Sias, A.R. Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency. Blood 1998, 91, 706–709. [Google Scholar] [CrossRef]
  24. Dore, M.P.; Parodi, G.; Portoghese, M.; Pes, G.M. The Controversial Role of Glucose-6-Phosphate Dehydrogenase Deficiency on Cardiovascular Disease: A Narrative Review. Oxidative Med. Cell. Longev. 2021, 2021, 5529256. [Google Scholar] [CrossRef] [PubMed]
  25. Thomas, J.E.; Kang, S.; Wyatt, C.J.; Kim, F.S.; Mangelsdorff, A.D.; Weigel, F.K. Glucose-6-Phosphate Dehydrogenase Deficiency is Associated with Cardiovascular Disease in U.S. Military Centers. Tex. Heart Inst. J. 2018, 45, 144–150. [Google Scholar] [CrossRef]
  26. Pes, G.M.; Parodi, G.; Dore, M.P. Glucose-6-phosphate dehydrogenase deficiency and risk of cardiovascular disease: A propensity score-matched study. Atherosclerosis 2019, 282, 148–153. [Google Scholar] [CrossRef]
  27. Ou, Z.; Chen, Y.; Li, J.; Ouyang, F.; Liu, G.; Tan, S.; Huang, W.; Gong, X.; Zhang, Y.; Liang, Z.; et al. Glucose-6-phosphate dehydrogenase deficiency and stroke outcomes. Neurology 2020, 95, e1471–e1478. [Google Scholar] [CrossRef]
  28. Andrews, P.H.; Zimring, J.C.; McNamara, C.A. Clinical associations and potential cellular mechanisms linking G6PD deficiency and atherosclerotic cardiovascular disease. NPJ Metab. Health Dis. 2025, 3, 16. [Google Scholar] [CrossRef]
  29. Deiana, L.; Garuti, R.; Pes, G.M.; Carru, C.; Errigo, A.; Rolleri, M.; Pisciotta, L.; Masturzo, P.; Cantafora, A.; Calandra, S.; et al. Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia: A study of patients with familial hypercholesterolemia from Sardinia. Arterioscler. Thromb. Vasc. Biol. 2000, 20, 236–243. [Google Scholar] [CrossRef] [PubMed]
  30. Harada-Shiba, M.; Arai, H.; Ohmura, H.; Okazaki, H.; Sugiyama, D.; Tada, H.; Dobashi, K.; Matsuki, K.; Minamino, T.; Yamashita, S.; et al. Guidelines for the Diagnosis and Treatment of Adult Familial Hypercholesterolemia 2022. J. Atheroscler. Thromb. 2023, 30, 558–586. [Google Scholar] [CrossRef]
  31. Friedewald, W.T.; Levy, R.I.; Fredrickson, D.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 1972, 18, 499–502. [Google Scholar] [CrossRef]
  32. Leren, T.P.; Solberg, K.; Rodningen, O.K.; Tonstad, S.; Ose, L. Two founder mutations in the LDL receptor gene in Norwegian familial hypercholesterolemia subjects. Atherosclerosis 1994, 111, 175–182. [Google Scholar] [CrossRef]
  33. Errigo, A.; Bitti, A.; Galistu, F.; Salis, R.; Pes, G.M.; Dore, M.P. Relationship between Glucose-6-Phosphate Dehydrogenase Deficiency, X-Chromosome Inactivation and Inflammatory Markers. Antioxidants 2023, 12, 334. [Google Scholar] [CrossRef] [PubMed]
  34. Minucci, A.; Giardina, B.; Zuppi, C.; Capoluongo, E. Glucose-6-phosphate dehydrogenase laboratory assay: How, when, and why? IUBMB Life 2009, 61, 27–34. [Google Scholar] [CrossRef]
  35. Roper, D.; Layton, M.; Rees, D.; Lambert, C.; Vulliamy, T.; De la Salle, B.; D’Souza, C.; British Society for Haematology. Laboratory diagnosis of G6PD deficiency. A British Society for Haematology Guideline. Br. J. Haematol. 2020, 189, 24–38. [Google Scholar] [CrossRef]
  36. Mosca, A.; Paleari, R.; Rosti, E.; Luzzana, M.; Barella, S.; Sollaino, C.; Galanello, R. Simultaneous automated determination of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities in whole blood. Eur. J. Clin. Chem. Clin. Biochem. 1996, 34, 431–438. [Google Scholar] [CrossRef] [PubMed]
  37. Fiorelli, G.; Meloni, T.; Palomba, V.; Manoussakis, C.; Villa, S.; Cappellini, M.D. Gene frequency of glucose-6-phosphate dehydrogenase (G6PD) polymorphic variants in Sardinia. Gene Geogr. 1990, 4, 139–142. [Google Scholar] [PubMed]
  38. Pes, G.M.; Errigo, A.; Bitti, A.; Dore, M.P. Effect of age, period and birth-cohort on the frequency of glucose-6-phosphate dehydrogenase deficiency in Sardinian adults. Ann. Med. 2018, 50, 68–73. [Google Scholar] [CrossRef]
  39. Leopold, J.A.; Dam, A.; Maron, B.A.; Scribner, A.W.; Liao, R.; Handy, D.E.; Stanton, R.C.; Pitt, B.; Loscalzo, J. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat. Med. 2007, 13, 189–197. [Google Scholar] [CrossRef]
  40. Jain, S.K.; Parsanathan, R.; Levine, S.N.; Bocchini, J.A.; Holick, M.F.; Vanchiere, J.A. The potential link between inherited G6PD deficiency, oxidative stress, and vitamin D deficiency and the racial inequities in mortality associated with COVID-19. Free Radic. Biol. Med. 2020, 161, 84–91. [Google Scholar] [CrossRef]
  41. Sanna, G.D.; Canonico, M.E.; Siciliano, R.; Guarino, S.; Montereggi, F.; Ponti, E.; Corda, G.; Talanas, G.; Parodi, G. Impact of glucose-6-phosphate dehydrogenase deficiency on the severity of coronary atherosclerosis in patients with acute coronary syndromes. J. Cardiovasc. Med. 2021, 22, 813–817. [Google Scholar] [CrossRef]
  42. Luzzatto, L.; Ally, M.; Notaro, R. Glucose-6-phosphate dehydrogenase deficiency. Blood 2020, 136, 1225–1240. [Google Scholar] [CrossRef]
  43. Garg, A.; Fazio, S.; Duell, P.B.; Baass, A.; Udata, C.; Joh, T.; Riel, T.; Sirota, M.; Dettling, D.; Liang, H.; et al. Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort. J. Endocr. Soc. 2020, 4, bvz015. [Google Scholar] [CrossRef]
  44. Warden, B.A.; Fazio, S.; Shapiro, M.D. Familial Hypercholesterolemia: Genes and Beyond; MDText.com, Inc.: South Dartmouth, MA, USA, 2024. [Google Scholar]
  45. Zubieliene, K.; Valteryte, G.; Jonaitiene, N.; Zaliaduonyte, D.; Zabiela, V. Familial Hypercholesterolemia and Its Current Diagnostics and Treatment Possibilities: A Literature Analysis. Medicina 2022, 58, 1665. [Google Scholar] [CrossRef] [PubMed]
  46. Hobbs, H.H.; Brown, M.S.; Goldstein, J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum. Mutat. 1992, 1, 445–466. [Google Scholar] [CrossRef] [PubMed]
  47. Errigo, A.; Carru, C.; Petrazzini, A.; Meloni, G.; Addis, L.; Filigheddu, G.; Pettinato, S.; Manca, S.; Cossu, M.; Pala, P.G.; et al. Screening rapido di mutazioni responsabili di ipercolesterolemia familiare dominante nella popolazione sarda. G. dell’Arterioscler. 2002, 27, 211–215. [Google Scholar]
Lipidology 02 00022 g001
Figure 1. Selection of study patients. This flow diagram shows the inclusion and exclusion of patients. Patients meeting Simon Broome criteria for FH were identified from 21,777 clinical records. After excluding those with incomplete records or missing laboratory data (lipid profile or G6PD assay), 217 FH patients were included in the study. Abbreviations: FH, familial hypercholesterolemia; G6PD, glucose-6-phosphate dehydrogenase.
Figure 1. Selection of study patients. This flow diagram shows the inclusion and exclusion of patients. Patients meeting Simon Broome criteria for FH were identified from 21,777 clinical records. After excluding those with incomplete records or missing laboratory data (lipid profile or G6PD assay), 217 FH patients were included in the study. Abbreviations: FH, familial hypercholesterolemia; G6PD, glucose-6-phosphate dehydrogenase.
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Lipidology 02 00022 g002
Figure 2. Mechanisms mediating the impact of G6PD deficiency on accelerated atherogenesis in FH patients.
Figure 2. Mechanisms mediating the impact of G6PD deficiency on accelerated atherogenesis in FH patients.
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Table 1. Demographic and clinical features of 217 FH patients with and without cardiovascular disease.
Table 1. Demographic and clinical features of 217 FH patients with and without cardiovascular disease.
Clinical FeaturesMalesFemalesTotal
No. of patients (%)86 (39.6)131 (60.4)217
Age (years)44.9 ± 18.747.8 ± 19.646.9 ± 19.3
Body mass index, n (%)
<25 kg/m248 (55.8)79 (60.3)127 (58.5)
25–29.930 (34.9)48 (36.6)78 (35.9)
≥308 (9.3)4 (3.1)12 (5.5)
Smoking, n (%)
Never smokers49 (57.0)99 (75.6)148 (68.2)
Current or former smokers37 (43.0)32 (24.4)69 (31.8)
Cardiovascular disease, n (%)
None40 (46.5)55 (42.0)95 (43.8)
Myocardial infarction24 (27.9)26 (19.8)50 (23.0)
Angina4 (4.7)7 (5.3)11 (5.1)
Stroke2 (2.3)5 (3.8)7 (3.2)
Peripheral disease4 (4.7)11 (8.4)15 (6.9)
Others12 (14.0)27 (20.6)39 (18.0)
High blood pressure, n (%)
None49 (57.0)88 (67.2)137 (63.1)
Yes37 (43.0)43 (32.8)80 (36.9)
Lipid profile, mg/dL
TC 1370.0 ± 82.8360.4 ± 86.3364.2 ± 84.9
LDL-C 2299.3 ± 80.6287.1 ± 83.2291.9 ± 82.5
HDL-C 346.3 ± 12.453.3 ± 13.750.5 ± 13.6
Non-HDL-C323.8 ± 80.9309.8 ± 85.0315.4 ± 83.5
TG 4122.8 ± 72.5113.3 ± 63.8117.0 ± 67.3
Treatment, n (%)
Only statins65 (75.6)123 (93.9)188 (86.6)
Both statins and ezetimibe21 (24.4)8 (6.1)29 (13.4)
G6PD 5, n (%)
Normal77 (89.5)109 (83.2)186 (85.7)
Deficiency9 (10.5)22 (16.8)31 (14.3)
1 TC, total cholesterol; 2 Low-density lipoprotein cholesterol; 3 HDL-C, high-density lipoprotein cholesterol; 4 TG, triglycerides; 5 G6PD—glucose-6-phosphate dehydrogenase. Note: CVD categories above are defined as per the Section 2; some patients had multiple CVD manifestations but are categorized under their primary presentation in this table (hence category counts sum to 217).
Table 2. Cardiovascular disease in 217 FH patients according to G6PD status.
Table 2. Cardiovascular disease in 217 FH patients according to G6PD status.
Cardiovascular DiseaseFH Subjects with G6PD Deficiency
(n = 31)		FH Subjects Without G6PD Deficiency
(n = 186)		p-Value
Sex, n (%) 0.192
Male9 (29.0)77 (41.4)
Female22 (71.0)109 (58.6)
Age, years (mean ± SD)57.9 ± 15.844.5 ± 19.10.004
Smoking, n (%) 0.301
Never smokers17 (54.8)131 (70.4)
Current or former smokers14 (45.2)55 (29.6)
Body mass index, n (%) 0.480
<25 kg/m222 (70.9)105 (56.4)
25–29.95 (16.1)73 (39.2)
≥304 (12.9)8 (4.3)
Lipid profile (mg/dL)
Total cholesterol407.7 ± 109.2357.3 ± 78.60.055
HDL cholesterol50.4 ± 11.250.5 ± 14.00.889
Non-HDL cholesterol378.8 ± 95.5306.4 ± 77.90.002
LDL cholesterol356.0 ± 95.9282.9 ± 76.60.002
Triglycerides113.8 ± 36.1117.4 ± 70.70.714
Cardiovascular disease, n (%) <0.0001
No7 (22.6)112 (60.2)
Yes24 (77.4)74 (39.8)
Table 3. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CI) for cardiovascular disease in 217 study participants.
Table 3. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CI) for cardiovascular disease in 217 study participants.
CovariatesUnadjusted OR
(95% CI)		Adjusted OR
(95% CI)
Sex
FemalesRef.Ref.
Males2.22 (1.27–3.86) **2.91 (1.44–5.88) **
Age #1.05 (1.03–1.07) **1.04 (1.02–1.07) **
Body mass index
<25 kg/m2Ref.Ref.
25–29.93.35 (1.86–6.05) **2.12 (1.06–4.25) *
≥306.29 (1.62–24.4) **1.57 (0.36–6.94)
High blood pressure
NoRef.Ref.
Yes2.21 (1.26–3.87) **2.31 (1.17–4.55) *
Smoking
NoRef.Ref.
Yes3.69 (2.02–6.75) **2.71 (1.33–5.53) *
G6PD deficiency
NoRef.Ref.
Yes5.19 (2.13–12.66) **3.57 (1.30–9.83) *
* p < 0.05; ** p < 0.001; Glucose-6-phosphate dehydrogenase; # the odds ratios for age correspond to a one-year increase.
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Errigo, A.; Dore, M.P.; Merola, E.; Pes, G.M. Glucose-6-Phosphate Dehydrogenase Deficiency and Cardiovascular Risk in Familial Hypercholesterolemia: A Retrospective Cohort Study. Lipidology 2025, 2, 22. https://doi.org/10.3390/lipidology2040022

AMA Style

Errigo A, Dore MP, Merola E, Pes GM. Glucose-6-Phosphate Dehydrogenase Deficiency and Cardiovascular Risk in Familial Hypercholesterolemia: A Retrospective Cohort Study. Lipidology. 2025; 2(4):22. https://doi.org/10.3390/lipidology2040022

Chicago/Turabian Style

Errigo, Alessandra, Maria Pina Dore, Elettra Merola, and Giovanni Mario Pes. 2025. "Glucose-6-Phosphate Dehydrogenase Deficiency and Cardiovascular Risk in Familial Hypercholesterolemia: A Retrospective Cohort Study" Lipidology 2, no. 4: 22. https://doi.org/10.3390/lipidology2040022

APA Style

Errigo, A., Dore, M. P., Merola, E., & Pes, G. M. (2025). Glucose-6-Phosphate Dehydrogenase Deficiency and Cardiovascular Risk in Familial Hypercholesterolemia: A Retrospective Cohort Study. Lipidology, 2(4), 22. https://doi.org/10.3390/lipidology2040022

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