Increased Risk Of Atherosclerosis Research Articles

Genetic Polymorphisms and Genetic Risk Scores Contribute to the Risk of Coronary Artery Disease (CAD) in a North Indian Population.

Coronary artery disease (CAD) is the leading cause of death in India. Many genetic polymorphisms play a role in regulating oxidative stress, blood pressure and lipid metabolism, contributing to the pathophysiology of CAD. This study examined the association between ten polymorphisms and CAD in the Jat Sikh population from Northern India, also considering polygenic risk scores. This study included 177 CAD cases and 175 healthy controls. The genetic information of GSTM1 (rs366631), GSTT1 (rs17856199), ACE (rs4646994), AGT M235T (rs699), AGT T174M (rs4762), AGTR1 A1166C (rs5186), APOA5 (rs3135506), APOC3 (rs5128), APOE (rs7412) and APOE (rs429358) and clinical information was collated. Statistical analyses were performed using SPSS version 27.0 and SNPstats. Significant independent associations were found for GST*M1, GST*T1, ACE, AGT M235T, AGT T174M, AGTR1 A1166C and APOA5 polymorphisms and CAD risk (all p < 0.05). The AGT CT haplotype was significantly associated with a higher CAD risk, even after controlling for covariates (adjusted OR = 3.93, 95% CI [2.39-6.48], p < 0.0001). The APOA5/C3 CC haplotype was also significantly associated with CAD (adjusted OR = 1.86, 95% CI [1.14-3.03], p < 0.05). A higher polygenic risk score was associated with increased CAD risk (adjusted OR = 1.98, 95% CI [1.68-2.34], p < 0.001). Seven polymorphisms were independently associated with an increase in the risk of CAD in this North Indian population. A considerable risk association of AGT, APOA5/C3 haplotypes and higher genetic risk scores is documented, which may have implications for clinical and public health applications.

Investigating the Added Value of Beck's Depression Inventory in Atherosclerosis Prediction: Lessons from Paracelsus 10,000.

Background: Depression is the most common mental illness worldwide and generates an enormous health and economic burden. Furthermore, it is known to be associated with an elevated risk of arteriosclerotic cardiovascular diseases (ASCVD), particularly stroke. However, it is not a factor reflected in many ASCVD risk models, including SCORE2. Thus, we analysed the relationship between depression, ASCVD and SCORE2 in our cohort. Methods: We analysed 9350 subjects from the Paracelsus 10,000 cohort, who underwent both a carotid artery ultrasound and completed a Beck Depression Inventory (BDI) screening. Patients were categorised binomially based on the BDI score. Atherosclerotic carotid plaque or absence was dichotomised for logistic regression modelling. Odds ratios and adjusted relative risks were calculated using Stata. Results: Subjects with an elevated BDI (≥14) had higher odds for carotid plaques compared to subjects with normal BDI, especially after adjusting for classical risk factors included in SCORE2 (1.21; 95%CI 1.03-1.43, p = 0.023). The adjusted relative risk for plaques was also increased (1.09; 95%CI 1.01-1.18, p = 0.021). Subgroup analysis showed an increased odds of plaques with increases in depressive symptoms, particularly in women and patients ≤55 yrs. Conclusions: In our cohort, the BDI score is associated with subclinical atherosclerosis beyond classical risk factors. Thus, depression might be an independent risk factor which may improve risk stratification if considered in ASCVD risk prediction models, such as SCORE2. Furthermore, reminding clinicians to take mental health into consideration to identify individuals at increased atherosclerosis risk may provide added opportunities to address measures which can reduce the risk of ASCVD.

LDLR variant classification for improved cardiovascular risk prediction in familial hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles. MethodsParticipants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model. ResultsOut of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97–5.0) to 12.0 (95%CI 5.5–24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively. ConclusionsThis study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods.

Evaluation of Polygenic Risk Scores for Prediction of Coronary Artery Disease in a Greek Case-Control Study.

Coronary artery disease (CAD) stands as the most predominant type of cardiovascular disease (CVD). Polygenic risk scores (PRSs) have become essential tools for quantifying genetic susceptibility, and researchers endeavor to improve their predictive precision. The aim of the present work is to assess the performance and the relative contribution of PRSs developed for CVD or CAD within a Greek population. The sample under study comprised 924 Greek individuals (390 cases with CAD and 534 controls) from the THISEAS study. Nine PRSs drawn from the PGS catalog were replicated and tested for CAD risk prediction. PRSs computations were performed in the R language, and snpStats was used to process genotypic data. Descriptive characteristics of the study were analyzed using the statistical software IBM SPSS Statistics v21.0. The effectiveness of each PRS was assessed using the PRS R2 metric provided by PRSice2. Among nine PRSs, PGS000747 greatly increased the predictive value of primary CAD risk factors by 21.6% (p-value = 2.63 × 10-25). PGS000012 was associated with a modest increase in CAD risk by 2.2% (p-value = 9.58 × 10-4). The remarkable risk discrimination capability of PGS000747 stands out as the most noteworthy outcome of our study.

Lifestyle factors, genetic susceptibility to obesity and their interactions on coronary artery disease risk: A cohort study in the UK Biobank

ObjectiveWe aimed to evaluate potential modifying effects of genetic susceptibility to obesity on the association of lifestyle factors with coronary artery disease (CAD) risk. MethodsA total of 328,606 participants (54% women) were included using data from the UK Biobank. We evaluated the risk of developing CAD associated with obesity-related polygenic scores (PGSs) and healthy lifestyle scores (HLSs). HLSs were constructed using six lifestyle factors. Obesity PGSs were created using genetic variants identified by genome-wide association studies, including 941 variants for body mass index (BMI) and 457 for waist-to-hip ratio (WHR). Both HLSs and PGSs were categorized into three groups. ResultsDuring a 9-year median follow-up, 14,541 participants developed CAD. An unhealthy lifestyle was significantly associated with an increased CAD risk (hazard ratio [HR] = 2.24, 95% confidence interval [CI] = 2.09–2.40). High BMI and WHR PGSs were each significantly associated with an increased CAD risk (HRBMI = 1.23, 1.17–1.29; HRWHR = 1.15, 1.09–1.21). Lifestyle factors explained 41% (95% CI = 38%–45%) of CAD, while genetic variants for BMI explained only 10% (7%–14%). Risks of CAD were increased with poorer HLS independent of obesity-related PGSs. Individuals with the most unhealthy lifestyle and highest BMI PGS had the highest risk of CAD risk (HR = 2.59, 95% CI = 2.26–2.97), compared with participants with the healthiest lifestyle and lowest BMI PGS. ConclusionsWhile the observational nature of the study precludes the establishment of causality, our study provides supports for a causal association between obesity and CAD risk and the importance of lifestyle modification in the prevention of CAD.

Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality

Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive. To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations. This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023. Genetically predicted apoB, LDL-C, and TG. The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality. This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age. In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.

Association of flavonoid intake with coronary artery disease risk in the older population based on the National Health and Nutrition Examination Survey.

We investigated the association between flavonoid intake and coronary artery disease (CAD) risk in older adults. Data were extracted from the National Health and Nutrition Examination Survey (age ≥ 70 years; 2007-2010 and 2017-2018; n = 2 417). The total flavonoid and flavonoid subclass intake was calculated using validated food frequency questionnaires. The association between flavonoid intake and CAD risk was examined using generalized linear models with restricted cubic spline models. After multivariate adjustment, anthocyanin intake was positively associated with CAD risk; no significant associations were observed between other flavonoid subcategories and endpoint outcomes. Anthocyanins exhibited a non-linear association with CAD risk, and threshold effect analysis showed an inflection point of 15.8 mg/day for anthocyanins. Per unit increase in anthocyanins, the odds of CAD on the left of the inflection point decreased by 2%, while the odds on the right increased by 35.8%. Excessive flavonoid intake may increase CAD risk in the older population.

Association of air pollution exposure and increased coronary artery disease risk: the modifying effect of genetic susceptibility

BackgroundBoth genetic factors and air pollution are risk factors for coronary artery disease (CAD), but their combined effects on CAD are uncertain. The study aimed to comprehensively investigate their separate, combined and interaction effects on the onset of CAD.MethodsWe utilized data from the UK Biobank with a recruitment of 487,507 participants who were free of CAD at baseline from 2006 to 2010. We explored the separate, combined effect or interaction association among genetic factors, air pollution and CAD with the polygenic risk score (PRS) and Cox proportional hazard models.ResultsThe hazard ratios (HRs) [95% confidence interval (CI)] of CAD for 10-µg/m3 increases in PM2.5, NO2 and NOx concentrations were 1.25 (1.09, 1.44), 1.03 (1.01, 1.05) and 1.01 (1.00, 1.02), respectively. Participants with high PRS and air pollution exposure had a higher risk of CAD than those with the low genetic risk and low air pollution exposure, and the HRs (95% CI) of CAD in the PM2.5, PM10, NO2 and NOx high joint exposure groups were 1.56 (1.48, 1.64), 1.55(1.48, 1.63), 1.57 (1.49, 1.65), and 1.57 (1.49, 1.65), respectively. Air pollution and genetic factors exerted significant additive effects on the development of CAD (relative excess risk due to the interaction [RERI]: 0.12 (0.05, 0.19) for PM2.5, 0.17 (0.10, 0.24) for PM10, 0.14 (0.07, 0.21) for NO2, and 0.17 (0.10, 0.24) for NOx; attributable proportion due to the interaction [AP]: 0.09 (0.04, 0.14) for PM2.5, 0.12 (0.07, 0.18) for PM10, 0.11 (0.06, 0.16) for NO2, and 0.13 (0.08, 0.18) for NOx).ConclusionExposure to air pollution was significantly related to an increased CAD risk, which could be further strengthened by CAD gene susceptibility. Additionally, there were positive additive interactions between genetic factors and air pollution on the onset of CAD. This can provide a more comprehensive, precise and individualized scientific basis for the risk assessment, prevention and control of CAD.

Factors associated with secondary coronary artery disease in rheumatoid arthritis patients: A systematic review and meta-analysis based on observational studies.

The main objective of this systematic review was to investigate the factors influencing the development of coronary artery disease (CAD) in patients with rheumatoid arthritis (RA). PubMed, Embase, Web of Science, Wan Fang Date, CBM, CNKI, and VIP databases were systematically searched to select the relevant literature. The quality of the incorporated studies was assessed with reference to the Newcastle-Ottawa Scale. Stata16 was adopted to summarise the odds ratios, risk ratios, hazard ratios, and 95% confidence intervals for meta-analysis. A total of 29 studies were included in this analysis, wherein the average age of RA patients was 50.5-81years and the proportion of women was 44.4%-92%. The present meta-analysis suggested that increased CAD risk in RA patients was associated with age, male gender, smoking, glucocorticoids, Health Assessment Questionnaire scores, hyperlipidaemia, hypertension, diabetes, and C-reactive protein concentration. The present systematic review revealed the influencing factors of secondary CAD in RA patients, some of which could reduce the risk of secondary CAD through effective interventions, such as smoking cessation, exercise, and medications. However, the effects of age, RA severity, and different medication subgroups on CAD risk stratification warrant further investigation.

Does gestational diabetes mellitus increase the risk of cardiovascular disease? A Mendelian randomization study.

In recent years, epidemiological studies have revealed the relationship between gestational diabetes mellitus (GDM) and cardiovascular disease (CVD). In this study, we utilized Mendelian randomization (MR) to investigate the potential causal impact of GDM on cardiovascular disease for the first time. We retrieved summary statistics from published genome-wide association studies. MR was first performed using significant SNPs extracted from the eighth data release of the FinnGen study. Next, a replication analysis for coronary artery disease (CAD) was conducted in another European ancestry population to validate our findings. Finally, mediation analysis was carried out to assess potential mediation effects. Our data analysis revealed that genetically predicted GDM was significantly associated with increased CAD risk (OR 1.10, 95% CI 1.02-1.18, p 0.006). Replication analysis confirmed a significant genetic association between GDM and CAD (OR 1.07, 95% CI 1.02-1.12, p 0.003) in another European ancestry population. Mediation analysis indicated no significant mediation effect by type 2 diabetes mellitus (T2DM)on the GDM-CAD relationship (mediation effect β [95% CI]: 0.005 [-0.003, -0.017]). Women with a prior history of GDM face an elevated risk of future CAD. This increased risk of CAD cannot be solely attributed to the subsequent onset of diabetes. Regular CAD risk assessment and primary prevention strategies are of paramount importance for women with a history of GDM.

Abstract 17580: "Healthy Smile for a Healthy Heart": A National Study on the Correlation Between Periodontal Diseases and Coronary Artery Disease

Introduction: Chronic inflammatory periodontal disease (CIPD) is a common disease of the supporting tissues of the teeth that manifest as swelling, bleeding, pain, and clinical attachment loss (CAL) upon periodontal examination. CIPD has been associated with a chronic inflammatory state, also a known risk factor for coronary artery disease (CAD). Hypothesis: There is a possible correlation between CIPD and CAD. Methods: We utilized the 2013-2014 National Health and Nutrition Examination Survey database. We included participants aged 30 years and above who reported having gum disease and had undergone a periodontal examination. CAL measured in millimeters, was reported at six different locations around 28 teeth. To obtain national estimates, we conducted complex survey sample analyses, accounting for weights, clustering, and strata. Furthermore, we adjusted for well-known CAD risk factors in multivariate analyses. Results: Our study included 184,010,722 participants; 7.3% had CAD (n=13,461,796), and 17.1% reported CIPD (n=31,425,382). Baseline Characteristics are presented in Table 1. The unadjusted rate of CAD was higher in patients with CIPD than those without CIPD [10.3% (n=3,238,995) vs 6.7% (n=10,222,801), p=0.018]. Similarly, average CAL was higher in patients with CAD (2.04 vs 1.62 mm, p&lt;0.001). After adjusting for confounders listed in Table 1, CIPD was a significant predictor of CAD (OR 1.744, 95% CI 1.088-2.796, p=0.012). The average CAL of all the teeth also predicted CAD (OR 1.195, 95% CI 1.025-1.394, p=0.026). Conclusions: Our data suggest that patients with reported CIPD had a 1.7 times higher risk of developing CAD. Similarly, each 1 mm increase in CAL leads to a 20% increased CAD risk (OR 1.2). Further prospective studies are needed to confirm these findings and to explore whether treatment of CIPD mitigates the increased CAD risk. These findings underscore the significance of optimizing dental health in patients with CAD.

Abstract 18381: Long-Term Coronary Artery Disease Risk in Female Adults With Surgically-Induced Menopause : A Systematic Review

Introduction: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in female adults. Prior studies have suggested an association between surgically-induced menopause (SIM) and long-term CAD risk. Yet, the pathophysiology and clinical significance of this relationship remains unclear. As SIM causes a premature cessation of potentially cardioprotective hormones, this review aimed to further investigate if SIM is a risk factor for CAD. Methods: SCOPUS, Web of Science, Cochrane Library, OVID/Embase, SciELO, and LILACS were searched from inception to April 2023 for observational studies reporting the effects of hysterectomy, oophorectomy, and/or salpingectomy prior to age fifty on long-term CAD risk. Results: Among 3056 identified records, nineteen studies were included with a combination of benign and malignant surgical indications. The studies reported on coronary heart disease (n=6), CAD (n=4), ischemic heart disease (n=3), and myocardial infarction (n=7). Sixteen articles with an average of 106,433 participants per study demonstrated a significantly increased risk of CAD following SIM (Table 1). In particular, hysterectomy with or without bilateral oophorectomy, and bilateral oophorectomy alone were found to have the most profound influence. Unilateral oophorectomy or hysterectomy with salpingo-oophorectomy did not appear to increase CAD risk. Average follow-up duration after SIM ranged from six to twenty-four years. Five studies adjusted for post-menopausal hormone replacement therapy use. Conclusions: SIM may elevate long-term CAD risk following hysterectomy and/or bilateral oophorectomy. Given that the majority of SIM are performed pre- or peri-menopausal for benign indications, understanding the associated cardiovascular risks is vital for informed decision-making, early detection, and prevention.

Circulating fatty acids, genetic risk, and incident coronary artery disease: A prospective, longitudinal cohort study.

The role of fatty acids (FAs) in primary prevention of coronary artery disease (CAD) is highly debated, and the modification effect by genetic risk profiles remains unclear. Here, we report the prospective associations of circulating FAs and genetic predisposition with CAD development in 101,367 U.K. Biobank participants. A total of 3719 CAD cases occurred during a mean follow-up of 11.5 years. Plasma monounsaturated FAs (MUFAs) were positively associated with risk of CAD, whereas the risk was significantly lower with higher n-3 polyunsaturated FAs (PUFAs) and more reductions in risk were detected among TT carriers of rs174547. Furthermore, increased plasma saturated FAs (SFAs) and linoleic acid were related to a significant increase in CAD risk among participants with high genetic risk (genetic risk score > 90%). These findings suggest that individuals with high genetic risk need to reduce plasma SFAs levels for CAD prevention. Supplementation of n-3 PUFAs for CAD prevention may consider individuals' genetic makeup.

Decisive Guidelines for Keeping the Heart Attacks on The Sidelines

A heart attack is usually a shocking event that compels the victim to modify his lifestyle considerably out of fear of death. Cardiovascular disorders have burdened developed and developing nations with increased mortality and morbidity rates. High cholesterol levels increase atherosclerosis risk, resulting in heart attacks, strokes, and chronic kidney disease. There are many ways to reduce the risk of heart disease, although one can't change some risk factors, such as family history, age, or gender. Cessation of tobacco use, reduction of salt in the diet, eating more fruits and vegetables, regular physical activity, avoiding alcohol, and stress management have been shown to reduce the risk of cardiovascular disease. Our small choices every day have a tremendous cumulative impact on cardiovascular health. Social determinants like poverty, housing insecurity, low education, and lack of insurance can adversely influence one's cardiovascular health. One must not fear fatality if one lives a happy, healthy, and peaceful life. A personalized approach that considers individual differences in genes, metabolism rate, presence of other diseases, and lifestyle is likely the most effective strategy in reducing the risk of precipitating heart attacks. A heart-friendly diet, regular physical activity, quitting alcohol, smoking cessation, and keeping blood pressure in the normal range are effective measures to prevent heart attacks. In light of the above, the authors have recommended valuable guidelines to laymen for keeping heart attacks on the sidelines in this fascinating and helpful article.

Genetic Predisposition, Sedentary Behavior and Incident Coronary Artery Disease: A Prospective Chinese Cohort Study.

Whether the association of sedentary behaviors with coronary artery disease (CAD) can be influenced by genetic susceptibility remains unclear. We aimed to investigate the joint and interplay effects between genetic risk and sedentary time (ST), and further explore the extent to which the risk for CAD can be counteracted by reducing ST in different genetic groups. This prospective cohort study included 39,164 Chinese adults without CAD history. Genetic susceptibility was quantified by a predefined polygenic risk score (PRS) with 540 genetic variants, and daily ST was assessed by questionnaire. We analyzed the modification effect of genetic risk on the association of ST with CAD using the Cox proportional hazards models. During a median follow-up of 11.60 years, 1156 CAD events were documented.Higher ST and PRS were separately related to elevated CAD risk. Significant additive interaction was also observed (relative excess risk due to interaction: 0.77; 95%CI: 0.27-1.28). Compared with participants with low genetic risk and low ST (<6 h/day), those with high genetic risk and high ST (≥10 h/day) had the highest CAD risk, with the hazard ratio (HR) and 95% confidence interval (95%CI) of 4.22 (2.65-6.71). When stratified by genetic risks, participants with high ST had gradient increment of CAD risks across low, intermediate, and high genetic risk groups, with the HR (95%CI) of 1.21 (0.61-2.40), 1.57 (1.14-2.16), and 2.15 (1.40-3.31), respectively. For the absolute risk reduction, individuals with high genetic risk achieved the greatest benefit from low ST (Ptrend = 0.024). Genetic susceptibility may synergistically interact with ST to increase CAD risk. Reducing ST could attenuate the CAD risk, especially among individuals with high genetic risk.

Egg consumption and risk of coronary artery disease, potential amplification by high genetic susceptibility: a prospective cohort study

BackgroundRemarkable heterogeneity has been observed among population-based studies on egg consumption and risk of coronary artery disease (CAD). Whether genetic susceptibility serves as a potential explanation for this inconsistency remains unknown. ObjectivesWe performed a prospective cohort study to investigate the association of egg consumption with incident CAD at different genetic susceptibilities. MethodsWe included 34,111 participants without CAD at baseline from the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China. Egg consumption was assessed with food frequency questionnaires. Genetic susceptibility was quantified by a predefined polygenic risk score (PRS) with 540 genetic variants. The hazard ratio (HR) and 95% confidence interval (95% CI) of incident CAD associated with egg consumption and PRS were estimated using the Cox proportional hazards models. ResultsOver a median 11.7 y of follow-up, 1,128 incident cases of CAD were recorded. Both higher egg consumption and increased PRS were related to higher risk of CAD. When stratified by genetic risk, each increment of 3 eggs/wk was associated with a 5% higher risk of CAD for participants at low to intermediate genetic risk (HR: 1.05; 95% CI: 1.01, 1.09), whereas risk increased to HR 1.10 (95% CI: 1.05, 1.16) for those at high genetic risk; a significant synergistic interaction was also indicated at both multiplicative (Pinteraction = 0.007) and additive (relative excess risk: 0.73; 95% CI: 0.24, 1.22) scales. When the joint effect was examined, in comparison with those at low to intermediate genetic risk and consuming <1 egg/wk, the HR (95% CI) was 2.95 (2.41, 3.62) for participants with high genetic risk and consumption of ≥10 eggs/wk, and the corresponding standardized 10-y CAD rates increased from 1.37% to 4.24%. ConclusionsGenetic predisposition may synergistically interact with egg consumption in relation to increased CAD risk. PRS-stratified recommendations on egg consumption may help formulate personalized nutrition policies.

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.

In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β=0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

A Correlative Study of Vitamin D Receptor Variants Fok1, Apa1, Bsm1, and Taq1 Polymorphism and Vitamin D Deficiency with Higher Risk Ratio of Coronary Artery Disease in Female Population

Abstract No studies are available on single nucleotide polymorphisms (SNPs) of the VDR gene in association with coronary artery disease (CAD) in women. The study aimed to investigate the association between SNPs in the VDR regions Fok I (rs10735810), Bsm I (rs1544410), Apa I (rs7975232), and Taq I (rs731236) and its associated risk of CAD in female patients. This prospective case-control study included 100 women diagnosed with CAD and age-matched healthy controls. The association between 1,25-dihydroxy vitamin D levels and VDR polymorph was assessed. In cases, the genotype ‘ff’ was reduced (14%) in co-dominant (OR, 0.13; CI, 0.03–0.65, p=0.0018) and recessive (OR, 0.11; CI, 0.02–0.54, p=0.0018) models. The ‘Ff’ genotype frequency in the over-dominant model was significantly higher (15%) in some cases (OR, 2.58; CI, 1.04–6.41, p=0.031). The frequency of genotype ‘Bb’ was increased (14%) in co-dominant (OR, 2.24; CI, 0.83–6.01, p=0.029) and over-dominant (OR, 2.65; CI, 1.01–6.94, p=0.035) cases. Women with CAD had a significantly lower frequency (14%) of the ‘bb’ genotype in both co-dominant (OR, 0.48; CI, 0.19–1.17, p=0.029) and recessive models (OR, 0.40; CI, 0.17–0.95, p=0.039). VDR genotypes such as Aa+aa, BB+Bb, Aa, Bb, FF+Ff, Tt+tt, aa, Ff, and tt were associated with an increased risk of CAD, and serum vitamin D levels were lower. Alleles ‘a’, ‘B’, and ‘t’ increase CAD risk in women. Subjects with genotypes (BB/Bb), (Tt/tt), and (FF) have a 2-fold, 2.6-fold, and 3-fold increased risk of low 25(OH)D3 levels. We found a statistically significant association between VDR polymorphisms and 25(OH)D3 levels for Taq I and Bsm I genotypes in females with CAD.

Inflammasomes and Atherosclerosis: a Mixed Picture.

The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.

Predisposition to atherosclerosis in children and adults with trisomy 21: biochemical and metabolomic studies.

Atherosclerosis, aprecursor to cardiovascular disease (CVD), is deeply intertwined with lipid metabolism. The metabolic process in the Down syndrome (DS) population remain less explored. Aim of the study: This study examines the lipid profiles of DS in comparison to their siblings (CG), aiming to uncover potential atherosclerotic and CVD risks. The study included 42 people with DS (mean age 14.17 years) and the CG - 20 individuals (mean age 15.92 years). Anthropometric measurements: BMI, BMI SDS, and TMI were calculated. Lipid profile (LP) and metabolomics were determined. LP: DS display significantly reduced HDL (DS vs. CG: 47±10 vs. 59 ±12 mg/dl; p=0.0001) and elevated LDL (104 ±25 vs. 90 ±22 mg/dl; p=0.0331). Triglycerides, APO A1, and APO B/APO A1 ratio corroborate with the elevated risk of CVD in DS. Despite no marked differences in: TCH and APO B, the DS group demonstrated aconcerning BMI trend. Of 31 identified metabolites, 12 showed statistical significance (acetate, choline, creatinine, formate, glutamine, histidine, lysine, proline, pyroglutamate, threonine, tyrosine, and xanthine). However, only 8 metabolites passed the FDR validation (acetate, creatinine, formate, glutamine, lysine, proline, pyroglutamate, xanthine). Down syndrome individuals show distinct cardiovascular risks, with decreased HDL and increased LDL levels. Combined with metabolomic disparities and higher BMI and TMI, this suggests an increased atherosclerosis risk compared to controls.