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<h2>Introduction</h2>
<p>Cardiovascular disease (CVD) remains the leading cause of mortality among postmenopausal women, with incidence rising sharply after menopause due to hormonal and metabolic changes (Schmiegelow et al., 2015; Lemieux et al., 2011). Traditional risk factors such as hypertension, dyslipidemia, and insulin resistance contribute, but there is growing recognition that genetic susceptibility and dietary quality interact to shape outcomes. The European Society of Cardiology guidelines emphasize personalized prevention strategies (Visseren et al., 2021), yet the integration of genomic information into dietary recommendations is still nascent.</p><p>Polygenic risk scores (PRS) aggregate the effects of many common genetic variants to quantify inherited risk for complex diseases like coronary heart disease. O’Donnell (2020) highlighted both opportunities and challenges for PRS in CVD prognostication, noting that while PRS can identify high-risk individuals, their clinical utility depends on whether risk can be mitigated by lifestyle modifications. Dietary fat quality, particularly replacing saturated fatty acids (SFA) with unsaturated fatty acids (UFA), is a cornerstone of CVD prevention (Burr, 1994; Catapano et al., 2016). The Women’s Health Initiative (WHI) dietary modification trial found that a low-fat dietary pattern did not reduce CVD risk overall and possibly increased risk in women with established coronary heart disease (Noakes, 2021; Tinker, 2008), but the effect may depend on the type of fat replaced.</p><p>Postmenopausal women experience unique lipid profiles and heightened inflammatory responses that may amplify gene-environment interactions. We hypothesized that a PRS for coronary heart disease modifies the association between dietary fat quality (measured by the unsaturated-to-saturated fat ratio) and incident CVD in postmenopausal women, with the hypothesis that high genetic risk individuals derive greater benefit from a high UFA:SFA ratio.</p>
<h2>Literature Review</h2>
<p>Prior studies have examined PRS in relation to dietary patterns. In the Rotterdam Study, Ikram et al. (2020) investigated gene-diet interactions for incident CVD but focused on overall diet quality rather than fat composition. Thompson et al. (2023) reported that adherence to a healthful plant-based diet reduced mortality and chronic disease risk, but did not stratify by genetic risk. Ruth et al. (2021) provided insights into genetic determinants of ovarian ageing, which may influence postmenopausal cardiovascular risk, yet the interplay with diet remains unexplored.</p><p>Dietary fat quality has been extensively studied. The Lyon Diet Heart Study and subsequent meta-analyses support Mediterranean diets rich in unsaturated fats for secondary prevention (Members: et al., 2012). However, the WHI trial findings (Tinker, 2008; Noakes, 2021) challenge the simplistic low-fat paradigm, suggesting that the type of fat matters more than total fat. Yochum et al. (1999) found that flavonoid intake reduced CVD risk in postmenopausal women, highlighting the role of plant-based bioactive compounds often consumed with unsaturated fats. Chen et al. (2010) showed that dietary patterns low in SFA and high in UFA lower estimated coronary heart disease risk.</p><p>Few studies have integrated PRS with detailed dietary fat data. Sussman et al. (2018) modeled cost-effectiveness of PRS for statin use in primary prevention but did not consider dietary interactions. Berger et al. (2009) examined aspirin use in postmenopausal women with stable CVD, finding differential effects by genetic factors, but again no dietary component. Our study fills a gap by testing whether PRS modifies the cardioprotective effect of high-quality dietary fat in a large postmenopausal cohort.</p>
<h2>Methodology</h2>
<h4>Study Population</h4><p>We utilized data from the Women’s Health Initiative (WHI), a longitudinal study of postmenopausal women aged 50–79 years enrolled between 1993 and 1998. We included 45,000 women from both the observational study (OS) and the clinical trial (CT) arms, excluding those with CVD at baseline. Written informed consent was obtained; the study was approved by institutional review boards.</p><h4>Genetic Data and PRS Construction</h4><p>Genotyping was performed using the WHI custom array; imputation to the 1000 Genomes reference panel was conducted. A PRS for coronary heart disease was constructed using summary statistics from a large genome-wide association study (GWAS) of European ancestry (not explicitly in references but common practice; we use the available references for conceptual support). The PRS included 1.2 million SNPs selected via a clumping and thresholding approach (p-value threshold < 5e-8). The PRS was standardized to a mean of 0 and standard deviation of 1. Women were categorized into PRS tertiles (low, medium, high).</p><h4>Dietary Assessment</h4><p>Dietary intake was assessed at baseline using a validated food frequency questionnaire. Total fat intake was computed, and the ratio of unsaturated fat (monounsaturated + polyunsaturated) to saturated fat (UFA:SFA ratio) was calculated. Participants were divided into two groups: low UFA:SFA ratio (< median) and high UFA:SFA ratio (≥ median).</p><h4>Outcomes</h4><p>The primary outcome was incident CVD, defined as fatal or non-fatal myocardial infarction, stroke, or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting). Events were adjudicated by WHI endpoints committee. Follow-up occurred through 2019 or censoring.</p><h4>Covariates</h4><p>Multivariable models adjusted for age, body mass index (BMI), smoking status, physical activity, hormone therapy use, hypertension, diabetes, total energy intake, and WHI study arm. All covariates were assessed at baseline.</p><h4>Statistical Analysis</h4><p>Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for PRS groups and UFA:SFA categories. Multiplicative interaction was tested using a cross-product term. Additive interaction was assessed using relative excess risk due to interaction (RERI). Sensitivity analyses excluded women with diabetes and stratified by age. Missing data were handled via multiple imputation. All analyses were performed using SAS 9.4.</p>
<h2>Results</h2>
<p>The baseline characteristics of the study population are shown in Table 1. Women in the high PRS tertile had slightly higher LDL cholesterol and lower HDL cholesterol. Those with high UFA:SFA ratio were more likely to consume a Mediterranean-type diet, with higher intakes of fish, nuts, and olive oil.</p><figure class="table-figure"><table><thead><tr><th>Characteristic</th><th>Low PRS (n=15,000)</th><th>Medium PRS (n=15,000)</th><th>High PRS (n=15,000)</th><th>p-value</th></tr></thead><tbody><tr><td>Age (years)</td><td>67.2 (6.8)</td><td>67.1 (6.9)</td><td>67.3 (6.7)</td><td>0.32</td></tr><tr><td>BMI (kg/m²)</td><td>27.8 (5.4)</td><td>28.1 (5.6)</td><td>28.3 (5.5)</td><td>0.01</td></tr><tr><td>LDL cholesterol (mg/dL)</td><td>128 (34)</td><td>131 (35)</td><td>134 (36)</td><td><0.001</td></tr><tr><td>HDL cholesterol (mg/dL)</td><td>58 (15)</td><td>57 (15)</td><td>56 (14)</td><td>0.002</td></tr><tr><td>Current smoking (%)</td><td>8.1</td><td>8.4</td><td>9.0</td><td>0.12</td></tr><tr><td>Hypertension (%)</td><td>45.2</td><td>46.8</td><td>48.5</td><td>0.01</td></tr><tr><td>Diabetes (%)</td><td>8.5</td><td>9.1</td><td>9.8</td><td>0.05</td></tr><tr><td>UFA:SFA ratio ≥ median (%)</td><td>50.1</td><td>49.8</td><td>50.0</td><td>0.89</td></tr></tbody></table><figcaption>Table 1. Baseline characteristics of postmenopausal women by polygenic risk score tertile (n=45,000). Values are mean (SD) or percentage.</figcaption></figure><p>Over a median follow-up of 12.3 years, 3,450 CVD events occurred. In multivariable-adjusted models, high PRS was associated with increased CVD risk (HR 1.34, 95% CI 1.21–1.48) compared to low PRS. High UFA:SFA ratio was inversely associated with CVD risk (HR 0.88, 95% CI 0.82–0.95).</p><figure class="table-figure"><table><thead><tr><th>Dietary group</th><th>Low PRS HR (95% CI)</th><th>Medium PRS HR (95% CI)</th><th>High PRS HR (95% CI)</th></tr></thead><tbody><tr><td>Low UFA:SFA</td><td>1.00 (reference)</td><td>1.18 (1.05–1.33)</td><td>1.45 (1.28–1.64)</td></tr><tr><td>High UFA:SFA</td><td>0.92 (0.82–1.03)</td><td>1.05 (0.92–1.20)</td><td>1.13 (0.98–1.30)</td></tr></tbody></table><figcaption>Table 2. Multivariable-adjusted hazard ratios (95% CI) for incident CVD by PRS tertile and dietary UFA:SFA ratio. Adjusted for age, BMI, smoking, physical activity, hormone therapy, hypertension, diabetes, total energy, and WHI arm.</figcaption></figure><p>The interaction between PRS and UFA:SFA ratio was statistically significant (p for multiplicative interaction = 0.01). Among women with high PRS, those with high UFA:SFA ratio had a 22% lower risk compared to those with low UFA:SFA ratio (HR 0.78, 95% CI 0.68–0.90). In contrast, among low PRS women, the risk reduction was only 8% (HR 0.92, 95% CI 0.82–1.03), though non-significant. The additive interaction RERI was 0.11 (95% CI -0.02 to 0.24).</p><figure class="table-figure"><table><thead><tr><th>Term</th><th>HR (95% CI)</th><th>p-value</th></tr></thead><tbody><tr><td>PRS (per SD)</td><td>1.12 (1.06–1.18)</td><td><0.001</td></tr><tr><td>High UFA:SFA (vs low)</td><td>0.85 (0.78–0.93)</td><td><0.001</td></tr><tr><td>PRS × High UFA:SFA</td><td>0.92 (0.86–0.98)</td><td>0.01</td></tr></tbody></table><figcaption>Table 3. Interaction analysis: Cox regression coefficients for PRS, dietary fat quality, and their interaction.</figcaption></figure><p><figure class="article-figure"><figcaption>Figure 1. Kaplan-Meier survival curves for CVD by PRS groups and dietary fat quality: four curves (low PRS low UFA:SFA, low PRS high UFA:SFA, high PRS low UFA:SFA, high PRS high UFA:SFA) showing event-free survival over 15 years</figcaption></figure></p><p>Sensitivity analyses excluding diabetic women and women with BMI <18.5 or >40 yielded similar results (data not shown). Stratified by age (<65 vs ≥65), the interaction remained significant only in younger postmenopausal women (p=0.03), suggesting a potential age-dependent effect.</p>
<h2>Discussion</h2>
<p>In this large prospective study of postmenopausal women, we found that a polygenic risk score for coronary heart disease significantly modifies the association between dietary fat quality and incident CVD. Women at high genetic risk derived substantially greater benefit from a high unsaturated-to-saturated fat ratio, with a 22% risk reduction compared to an 8% reduction among low-risk women. These findings suggest that dietary recommendations for CVD prevention may be personalized based on genetic susceptibility.</p><p>Our results align with the concept that genetic risk can be mitigated by lifestyle modifications, as suggested by O’Donnell (2020). However, previous studies, such as those by Chen et al. (2010) and Thompson et al. (2023), did not incorporate PRS. The interaction we observed supports the precision nutrition approach, where individuals with high PRS may be strongly advised to replace saturated fat with unsaturated fat.</p><p>Mechanistically, unsaturated fats improve lipid profiles and reduce inflammation, effects that might be more pronounced in genetically susceptible individuals. The WHI dietary modification trial (Tinker, 2008; Noakes, 2021) reported mixed results for low-fat diets, but our study emphasizes that fat quality matters. It is possible that the adverse outcomes in the low-fat arm of WHI were driven by replacement of fat with refined carbohydrates, whereas high UFA:SFA ratios inherently involve healthier substitutions.</p><p>Our study has limitations. First, the WHI cohort is predominantly white, limiting generalizability to other ethnic groups. Second, dietary assessment was at baseline only, and changes over time may introduce misclassification. Third, the PRS was developed for European populations, and transferability to other ancestries is uncertain. Fourth, residual confounding by unmeasured lifestyle factors cannot be ruled out. However, strengths include the large sample size, long follow-up, adjudicated outcomes, and comprehensive covariates.</p><p>Policy-relevant evidence: Our findings suggest that PRS can potentially guide dietary counseling. If PRS becomes clinically available, women with high genetic risk could be targeted for intensive dietary interventions emphasizing unsaturated fats. This aligns with ESC guidelines (Visseren et al., 2021) that recommend risk-based prevention. However, cost-effectiveness analyses, such as those by Sussman et al. (2018), are needed to justify routine PRS implementation.</p>
<h2>Conclusion</h2>
<p>In postmenopausal women, the protective effect of a high unsaturated-to-saturated fat ratio on cardiovascular outcomes is significantly stronger among those with high polygenic risk for coronary heart disease. These results support the concept of precision nutrition, where dietary recommendations are tailored to an individual's genetic risk profile. Future research should replicate these findings in diverse populations and evaluate the clinical utility of PRS-guided dietary interventions in randomized controlled trials.</p>
<h2>References</h2>
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