The Relationship between Mitochondrial Genome Mutations in Monocytes and the Development of Obesity and Coronary Heart Disease.

BACKGROUND: Metabolic disorders, including obesity, are often accompanied by an increased risk of cardiovascular complications. Monocytes are the common link between obesity and cardiovascular diseases (CVDs). The bias of innate cellular immunity towards pro-inflammatory activation stimulates the development of diseases associated with chronic inflammation, in particular metabolic disorders, including obesity, as well as CVDs. Disorders in the functional state of monocytes and activation of inflammation may be associated with mitochondrial dysfunction. Mutations accumulating in mitochondrial DNA with age may lead to mitochondrial dysfunction and may be considered a potential marker for developing chronic inflammatory diseases. METHODS: The present study aimed to study the relationship between mitochondrial heteroplasmy in CD14+ monocytes and cardiovascular risk factors in 22 patients with obesity and coronary heart disease (CHD) by comparing them to 22 healthy subjects. RESULTS: It was found that single-nucleotide variations (SNV) A11467G have a negative correlation with total cholesterol (r = -0.82, p < 0.05), low density lipoproteins (LDL) (r = -0.82, p < 0.05), with age (r = -0.57, p < 0.05) and with mean carotid intima-media thickness (cIMT) (r = -0.43, p < 0.05) and a positive correlation with HDL level (r = 0.71, p < 0.05). SNV 576insC positively correlated with body mass index (BMI) (r = 0.60, p < 0.001) and LDL level (r = 0.43, p < 0.05). SNV A1811G positively correlated with mean cIMT (r = 0.60, p < 0.05). CONCLUSIONS: It was revealed that some variants of mitochondrial DNA (mtDNA) heteroplasmy are associated with CVD risk factors. The results demonstrate the potential for using these molecular genetic markers to develop personalized CVD and metabolic disorder treatments.

Genetically Predicted Apolipoprotein E Levels with the Risk of Panvascular Diseases: A Mendelian Randomization Study.

The aim of this study was to comprehensively assess the causal relationship between the overall genetic effect of circulating ApoE levels and panvascular lesions using newer genome-wide association data and two-sample bidirectional Mendelian randomization (MR) analysis. Two-way MR using single-nucleotide polymorphisms of circulating ApoE as instrumental variables was performed using the highest-priority Genome-wide association study (GWAS) data, with factor-adjusted and data-corrected statistics, to estimate causal associations between circulating ApoE levels and 10 pan-vascular diseases in > 500,000 UK Biobank participants, > 400,000 participants of Finnish ancestry, and numerous participants in a consortium of predominantly European ancestry. Meta-analysis was conducted to assess positive results. After correcting for statistical results, elevated circulating ApoE levels were shown to have a significant protective effect against Cerebral ischemia (CI) [IVW odds ratio (OR) 0.888, 95% Confidence Interval (CI): 0.823-0.958, p = 2.3 × 10-3], Coronary heart disease [IVW OR 0.950,95% CI: 0.924-0.976, p = 2.0 × 10-4] had a significant protective effect and potentially suggestive protective causality against Angina pectoris [IVW odds ratio (OR) 0.961, 95%CI: 0.931-0.991, p = 1.1 × 10-2]. There was a potential causal effect for increased risk of Heart failure (HF) [IVW ratio (OR) 1.040, 95%CI: 1.006-1.060, p = 1.8 × 10-2]. (Bonferroni threshold p < 0.0026, PFDR < 0.05) Reverse MR analysis did not reveal significant evidence of a causal effect of PVD on changes in circulating ApoE levels. Meta-analysis increases reliability of results. Elevated circulating ApoE levels were particularly associated with an increased risk of heart failure. Elevated ApoE levels reduce the risk of cerebral ischemia, coronary heart disease, and angina pectoris, reflecting a protective effect. The possible pathophysiological role of circulating ApoE levels in the development of panvascular disease is emphasized.

Novel polymorphisms in CYP4A22 associated with susceptibility to coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) has become a worldwide public health problem. Genetic factors are considered important risk factors for CHD. The aim of this study was to explore the correlation between CYP4A22 gene polymorphism and CHD susceptibility in the Chinese Han population. METHODS: We used SNPStats online software to complete the association analysis among 962 volunteers. False-positive report probability analysis was used to confirm whether a positive result is noteworthy. Haploview software and SNPStats were used for haplotype analysis and linkage disequilibrium. Multi-factor dimensionality reduction was applied to evaluate the interaction between candidate SNPs. RESULTS: In overall and some stratified analyses (male, age ≤ 60 years or CHD patients complicated with hypertension), CYP4A22-rs12564525 (overall, OR = 0.83, p-value is 0.042) and CYP4A22-rs2056900 (overall, OR = 1.22, p-value is 0.032) were associated with the risk of CHD. CYP4A22-4926581 was associated with increased CHD risk only in some stratified analyses. FPRP indicated that all positive results in our study are noteworthy findings. In addition, MDR showed that the single-locus model composed of rs2056900 is the best model for predicting susceptibility to CHD. CONCLUSION: There are significant associations between susceptibility to CHD and CYP4A22 rs12564525, and rs2056900.

Telomere length as biomarker of nutritional therapy for prevention of type 2 diabetes mellitus development in patients with coronary heart disease: CORDIOPREV randomised controlled trial.

BACKGROUND: Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years. METHODS: The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements. FINDINGS: 1002 patients (59.5 ± 8.7 years and 82.5% men) were enrolled into Mediterranean diet (n = 502) or a low-fat diet (n = 500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL < percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group. CONCLUSION: Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease. TRIAL REGISTRATION: Clinicaltrials.gov number NCT00924937.

Association of adiponectin and its receptor gene polymorphisms with the risk of coronary heart disease in northern Guangxi.

OBJECTIVE: To investigate the association of circulating adiponectin (APN) level and single nucleotide polymorphisms (rs1501299 and rs266729) of the APN gene in the coronary heart disease (CHD) population of Northern Guangxi Province. METHODS: Two hundred and sixty-three CHD patients and 235 healthy controls from our hospital from August 2018 to October 2020 were included in this study. ELISA was used to determine the serum APN concentration. PCR-RFLP and direct DNA sequencing were used to analyze the genotypes of APN gene rs1501299 G/T and rs266729 C/G single-nucleotide loci, their distribution differences between the two groups were compared and their correlation with APN concentration was analyzed. RESULTS: The serum APN concentration in the CHD group was significantly lower than the control group (14.40(1.42-52.26) µg/mL vs. 29.40 (3.18-90.31) µg/mL, P < 0.001). There were statistically significant differences in the rs266729 genotype of APN single nucleotide locus between the two groups (P < 0.001). The dominant model and recessive model of rs266729 genotype showed that mutant homozygous GG genotype carriers significantly increased the risk of CHD in comparison with C allele carriers (CG + CC) (OR = 2.156, 95 %CI: 1.004-4.631, P = 0.049), and this effect was still significant after adjusting gender and age (OR = 2.695, 95 %CI 1.110-6.540, P = 0.028). In both the dominant and recessive models for rs1501299, ORs before and after adjustment for age and sex revealed no significant association with CHD, with ORs of 0.765 (95 % CI: 0.537-1.091, P = 0.139) and 0.718 (95 % CI: 0.466-1.106, P = 0.133) in the Dominant model, and ORs of 0.960 (95 % CI: 0.442-2.087, P = 0.918) and 0.613 (95 % CI: 0.239-1.570, P = 0.308) in the Recessive model, respectively. No statistically significant differences in APN concentrations across genotypes in both groups (P > 0.05), with chi-square values of 1.633 (control group) and 0.823 (CHD group) for rs1501299, and 1.354 (control group) and 0.618 (CHD group) for rs266729. CONCLUSIONS: APN gene of rs266729 C/G single-nucleotide loci gene mutation can significantly increase the risk of CHD. There was no significant correlation between rs1501299 G/T single-nucleotide loci and CHD in Northern Guangxi populations.

Role of low-density lipoprotein in mediating the effect of air pollution on coronary heart disease: a two-step multivariate Mendelian randomization study.

OBJECTIVE: Air pollution is affecting the health of millions of people all over the world. The causal correlations of PM2.5, PM10, and nitrogen dioxide (NOx), as the main fine particulate matter, and coronary heart disease (CHD) are yet to be explored. Low-density lipoprotein (LDL) has been a principal factor in the pathogenesis of CHD. It is an interesting issue to consider whether LDL mediates the effect of air pollutants in CHD pathogenesis. MATERIALS AND METHODS: A genome-wide association study (GWAS) on the European population, followed up from 2010 to 2018, involving over 400,000 participants, was based on a land-use regression model. The annual mean concentrations of major air pollutant particles, PM2.5 (n=423,796), PM10 (n=423,796), and NOx (n=456,380), were recorded. The large GWAS database of CHD covered over ten million SNPs with independent single nucleotide polymorphisms (SNPs). LDL database collected major biochemical blood parameters from over 400,000 patients (n=440,546). Taken together, we conducted independent two-sample Mendelian randomization (MR) analyses for the causality between air pollutants (PM2.5, PM10, and NOx) and CHD. Multivariate MR analysis was conducted using causal relationships to determine the direct effects of exposure on outcome. The fixed-effect inverse variance weighted (IVW2) method was mainly employed to assess this relationship, with a confidence interval of 95% for the odds ratio (OR). Also, MR-Egger, weighted median, maximum likelihood ratio method, and random-effects inverse variance-weighted (IVW1) method were adopted as supplementary methods. RESULTS: Two-sample MR results based on the IVW2 method suggested positive correlations between PM2.5 and CHD [OR 1.875 (1.279-2.748), p=0.001], PM10 and CHD [OR 2.586 (1.479-4.523), p=0.001], and NOx and CHD [OR 2.991 (2.021-4.427), p=4.37E-08]. The direct effect and mediating proportion were calculated using multivariable Mendelian randomization (MVMR). Lastly, the mediating proportions of LDL in the regulatory roles of PM2.5, PM10, and NOx in CHD were 2.82%, 4.73%, and 9.54%, respectively. CONCLUSIONS: PM2.5, PM10, and NOx share direct causal associations with CHD, and LDL performs a mediating role in this pathogenic process. Early prevention against air pollution (such as increasing green areas and reducing large-scale industrial dust emissions) and early lipid-lowering treatment can effectively prevent the occurrence of CHD.

Breakfast skipping and traits of cardiometabolic health: A mendelian randomization study.

BACKGROUND: Breakfast skipping has been linked to poor cardiometabolic health in observational studies, but the causality remains unknown. Herein, we used Mendelian randomization (MR) approach to elucidate the potential causal effects of breakfast skipping on cardiometabolic traits. METHODS: Genetic association estimates for breakfast skipping, cardiometabolic diseases, and cardiometabolic risk factors were extracted from the UK Biobank and several large genome-wide association studies. Two-sample MR analyses were performed primarily using the inverse variance weighted method, followed by sensitivity analysis to test the reliability of results. RESULTS: MR results indicated no causal relationship between breakfast shipping with coronary heart disease (odds ratio [OR]: 1.079, 95 % confidence interval [CI]: 0.817-1.426; p = 0.591), stroke (OR: 0.877, 95 % CI: 0.680-1.131; p = 0.311), and type 2 diabetes mellitus (OR: 1.114, 95 % CI: 0.631-1.970; p = 0.709). However, genetically predicted breakfast skipping was significantly associated with increased body mass index (ß: 0.250, standard error [SE]: 0.079; p = 0.001), waist-to-hip ratio (ß: 0.177, SE: 0.076; p = 0.019), and low-density lipoprotein cholesterol (ß: 0.260, SE: 0.115; p = 0.024). We found no evidence of association of genetic liability to breakfast skipping with blood pressure, glycemic traits, and other blood lipids. Sensitivity analysis supported the above results. CONCLUSION: Our study suggested that breakfast skipping is causally linked to weight gain and higher serum low-density lipoprotein cholesterol, which may mediate the increased risk of cardiometabolic diseases reported in epidemiological studies.

Association of GAL-8 promoter methylation levels with coronary plaque inflammation.

BACKGROUND AND AIMS: Coronary heart disease (CHD) is a condition that carries a high risk of mortality and is associated with aging. CHD is characterized by the chronic inflammatory response of the coronary intima. Recent studies have shown that the methylation level of blood mononuclear cell DNA is closely associated with adverse events in CHD, but the roles and mechanisms of DNA methylation in CHD remain elusive. METHODS AND RESULTS: In this study, the DNA methylation status within the epigenome of human coronary tissue in the sudden coronary death (SCD) group and control (CON) group of coronary heart disease was analyzed using the Illumina® Infinium Methylation EPIC BeadChip (850 K chip), resulting in the identification of a total of 2553 differentially methylated genes (DMGs). The differentially methylated genes were then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and significant differential DNA methylation was found. Among the differentially hypomethylated genes were GAL-8, LTF, and RFPL3, while the highly methylated genes were TMEM9B, ANK3, and C6orF48. These genes were mainly enriched in 10 significantly enriched pathways, such as cell adhesion junctions, among which the differentially methylated gene GAL-8 was involved in inflammatory pathway signaling. For functional analysis of GAL-8, we first examined the differences in GAL-8 promoter methylation levels among different subgroups of human coronary tissue in the CON, CHD, and SCD groups using pyrophosphate sequencing. The results revealed reduced GAL-8 promoter methylation levels in the SCD group, while the difference between the CHD and CON groups was not statistically significant (P > 0.05). The reduced GAL-8 promoter methylation level was associated with upregulated GAL-8 expression, which led to increased expression of the inflammatory markers TNF-α, IL-1ß, MCP-1, MIP-2, MMP-2, and MMP-9. This enhanced inflammatory response contributed to the accumulation of foam cells, thickening of the intima of human coronary arteries, and increased luminal stenosis, which promoted the occurrence of sudden coronary death. Next, we found that GAL-8 promoter methylation levels in PBMC were consistent with human coronary tissue. The unstable angina group (UAP) had significantly lower GAL-8 promoter methylation levels than stable angina (SAP) and healthy controls (CON) (P < 0.05), and there was a significant correlation between reduced GAL-8 promoter methylation levels and risk factors for coronary heart disease. These findings highlight the association between decreased GAL-8 promoter methylation and the presence of coronary heart disease risk factors. ROC curve analysis suggests that methylation of the GAL 8 promoter region is an independent risk factor for CHD. In conclusion, our study confirmed differential expression of GAL-8, LTF, MUC4D, TMEM9B, MYOM2, and ANK3 genes due to DNA methylation in the SCD group. We also established the consistency of GAL-8 promoter methylation alterations between human coronary tissue and patient peripheral blood monocytes. The decreased methylation level of the GAL-8 promoter may be related to the increased expression of GAL-8 and the coronary risk factors. CONCLUSIONS: Accordingly, we hypothesized that reduced levels of GAL-8 promoter methylation may be an independent risk factor for adverse events in coronary heart disease.

Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis.

BACKGROUND: Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate. OBJECTIVES: The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle. METHODS: Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed. RESULTS: The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis. CONCLUSIONS: We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.

The causal effect of Helicobacter pylori infection on coronary heart disease is mediated by the body mass index: a Mendelian randomization study.

The association between Helicobacter pylori (H. pylori) infection and coronary heart disease (CHD) remains controversial, with an unclear causal link. This study employed bidirectional Mendelian randomization (MR) method, using H. pylori infection as the exposure, to investigate its causal relationship with CHD diagnosis, prognosis, and potential pathogenesis. H. pylori infection exhibited a causal association with body mass index (BMI) (ß = 0.022; 95% CI 0.008-0.036; p = 0.001). Conversely, there was no discernible connection between H. pylori infection and the diagnosis of CHD (OR = 0.991; 95% CI 0.904-1.078; p = 0.842; IEU database; OR = 1.049; 95% CI 0.980-1.118; p = 0.178; FinnGen database) or CHD prognosis (OR = 0.999; 95% CI 0.997-1.001; p = 0.391; IEU database; OR = 1.022; 95% CI 0.922-1.123; p = 0.663; FinnGen database). Reverse MR analysis showed no causal effect of CHD on H. pylori infection. Our findings further support that H. pylori infection exerts a causal effect on CHD incidence, mediated by BMI. Consequently, eradicating or preventing H. pylori infection may provide an indirect clinical benefit for patients with CHD.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

A linear weighted combination of polygenic scores for a broad range of traits improves prediction of coronary heart disease.

Polygenic scores (PGS) for coronary heart disease (CHD) are constructed using GWAS summary statistics for CHD. However, pleiotropy is pervasive in biology and disease-associated variants often share etiologic pathways with multiple traits. Therefore, incorporating GWAS summary statistics of additional traits could improve the performance of PGS for CHD. Using lasso regression models, we developed two multi-PGS for CHD: 1) multiPGSCHD, utilizing GWAS summary statistics for CHD, its risk factors, and other ASCVD as training data and the UK Biobank for tuning, and 2) extendedPGSCHD, using existing PGS for a broader range of traits in the PGS Catalog as training data and the Atherosclerosis Risk in Communities Study (ARIC) cohort for tuning. We evaluated the performance of multiPGSCHD and extendedPGSCHD in the Mayo Clinic Biobank, an independent cohort of 43,578 adults of European ancestry which included 4,479 CHD cases and 39,099 controls. In the Mayo Clinic Biobank, a 1 SD increase in multiPGSCHD and extendedPGSCHD was associated with a 1.66-fold (95% CI: 1.60-1.71) and 1.70-fold (95% CI: 1.64-1.76) increased odds of CHD, respectively, in models that included age, sex, and 10 PCs, whereas an already published PGS for CHD (CHD_PRSCS) increased the odds by 1.50 (95% CI: 1.45-1.56). In the highest deciles of extendedPGSCHD, multiPGSCHD, and CHD_PRSCS, 18.4%, 17.5%, and 16.3% of patients had CHD, respectively.

Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses.

BACKGROUND: Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. METHODS: Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. FINDINGS: Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95-1·01), stroke (1·01, [0·97-1·05]), or all-cause mortality (0·99, 0·95-1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations. INTERPRETATION: Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status. FUNDING: British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Exploring apolipoprotein C-III: pathophysiological and pharmacological relevance.

The availability of pharmacological approaches able to effectively reduce circulating LDL cholesterol (LDL-C) has led to a substantial reduction in the risk of atherosclerosis-related cardiovascular disease (CVD). However, a residual cardiovascular (CV) risk persists in treated individuals with optimal levels of LDL-C. Additional risk factors beyond LDL-C are involved, and among these, elevated levels of triglycerides (TGs) and TG-rich lipoproteins are causally associated with an increased CV risk. Apolipoprotein C-III (apoC-III) is a key regulator of TG metabolism and hence circulating levels through several mechanisms including the inhibition of lipoprotein lipase activity and alterations in the affinity of apoC-III-containing lipoproteins for both the hepatic receptors involved in their removal and extracellular matrix in the arterial wall. Genetic studies have clarified the role of apoC-III in humans, establishing a causal link with CVD and showing that loss-of-function mutations in the APOC3 gene are associated with reduced TG levels and reduced risk of coronary heart disease. Currently available hypolipidaemic drugs can reduce TG levels, although to a limited extent. Substantial reductions in TG levels can be obtained with new drugs that target specifically apoC-III; these include two antisense oligonucleotides, one small interfering RNA and an antibody.

Application of Mendelian randomization in the discovery of risk factors for coronary heart disease from 2009 to 2023: A bibliometric review.

Coronary heart disease (CHD) is a life-threatening condition that poses a significant risk to individuals. Mendelian randomization (MR) is an emerging epidemiological research method that offers substantial advantages in identifying risk factors for diseases. Currently, there are ongoing CHD-related MR studies. To gain comprehensive insights into the focal areas and trends of CHD-related MR research, this study utilizes bibliometrics to conduct an in-depth analysis of CHD-related MR articles published in the core database of Web of Science (WOS) from 2009 to 2023. A search was performed to identify CHD-related MR articles published between 2009 and 2023 in WOS. The data, including publication countries, research institutions, journals, citations, and keywords, were analyzed using the Bibliometrix R-4.0 software package. A total of 111 articles published in 71 journals were included in the analysis. The journal with the highest impact factor (IF) was the New England Journal of Medicine. The articles were distributed across 24 categories within the 71 journals, with the highest number of publications falling under Cardiac & Cardiovascular Systems, Medicine, General & Internal, and Genetics & Heredity. Among the articles, 57 were published in Q1 journals, 42 in Q2 journals, 9 in Q3 journals, and 2 in Q4 journals. The most frequently published journals on CHD-related MR were Frontiers in Cardiovascular Medicine, Frontiers in Genetics, and the Journal of the American College of Cardiology. A total of 963 authors participated in the 111 articles, with the majority affiliated with institutions in the United Kingdom, the US, and China. The national cooperation network revealed close collaborations between the UK and the US, as well as between the UK and China. The publication of the 111 articles involved 453 research institutions, with Oxford University, Bristol University, and Cambridge University being the most frequently involved institutions. Out of the 111 articles, only 62 were directly related to CHD and MR, with CHD being the outcome factor in 61 of them. These 61 articles investigated 47 exposure factors across eight categories. Among these factors, 10 had been studied in more than 2 articles. The findings concerning the impact of serum uric acid and omega-6 fatty acids on CHD risk were not entirely consistent. Research in MR related to CHD has been gradually gaining recognition, with an increase in both its academic credibility and collaborative efforts within this field. Indeed, MR has facilitated the identification of risk factors associated with CHD. However, the relationship between these disease risk factors and CHD requires further investigation for clarification. Future MR studies on CHD could prioritize the elucidation and validation of contentious disease risk factors, thereby paving the way for a more comprehensive exploration of additional factors contributing to the onset of CHD.

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.

Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5 days (n = 54,180). Relative mean LTL at baseline (5-6 years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity > 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8 years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant (P = .171).

The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins.

BACKGROUND: The relationship between genetically-driven liver fat and coronary heart disease (CHD) remains unclear. ApoB-containing lipoproteins are known causal factors for CHD and may explain this relationship. METHODS AND RESULTS: We conducted a genome-wide association study (GWAS) in the UK Biobank to identify genetic variants associated with liver fat. We then investigated the effects that these genetic variants had on both apoB-containing lipoproteins and CHD. Using Mendelian Randomization (MR) analyses, we examined if the relationship between genetically-driven liver fat and CHD could be attributed to its effect on apoB-containing lipoproteins. We found 25 independent liver-fat associated single-nucleotide polymorphisms (SNPs) with differing effects on lipoprotein metabolism. The SNPs were classified into three groups/clusters. The first cluster (N = 3 SNPs) displayed lipoprotein-raising effects. The second cluster (N = 12 SNPs) displayed neutral effects on lipoproteins and the third cluster (N = 10 SNPs) displayed lipoprotein-lowering effects. For every 1% higher liver fat, the first cluster showed an increased risk of CHD (OR = 1.157 [95% CI: 1.108-1.208]). The second cluster showed a non-significant effect on CHD (OR = 0.988 [95% CI: 0.965-1.012], whereas the third cluster showed a protective effect of increased liver fat on CHD (OR = 0.942 [95% CI: 0.897-0.989]). When adjusting for apoB, the risk for CHD became null. CONCLUSIONS: Here, we identify 25 liver-fat associated SNPs. We find that SNPs that increase, decrease or have neutral effects on apoB-containing lipoproteins show increased, decreased or neutral effects on CHD, respectively. Therefore, the relationship between genetically-driven liver fat and CHD is mediated by the causal effect of apoB.

CYP4V2 rs56413992 C > T was associated with the risk of coronary heart disease in the Chinese Han population: a case-control study.

PURPOSE: The research aimed to detect the association between single nucleotide polymorphisms (SNPs) in CYP4V2 gene and coronary heart disease (CHD) risk. METHODS: This case-control study included 487 CHD subjects and 487 healthy individuals. Logistic regression was performed to analyze the connection between five SNPs in CYP4V2 (rs1398007, rs13146272, rs3736455, rs1053094, and rs56413992) and CHD risk, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the connection. RESULTS: As a result, we found that rs56413992 T allele (OR = 1.36, 95% CI = 1.09-1.70, p = 0.007) and CT genotype (OR = 1.40, 95% CI = 1.06-1.83, p = 0.017) were significantly associated with an increased risk of CHD in the overall analysis. Precisely, rs56413992 was linked to an elevated risk of CHD in people aged > 60, males, smokers and drinkers. The study also indicated that rs1398007 was linked to an increased CHD risk in drinkers. In addition, rs1053094 was correlated with a decreased risk of CHD complicated with diabetes mellitus (DM), and rs1398007 was correlated with a decreased risk of CHD complicated with hypertension (HTN). CONCLUSION: This study was the first to experimentally demonstrate that CYP4V2 rs56413992 was associated with the risk of CHD, which will provide a certain reference for revealing the pathogenesis of CHD.

Marcadores genéticos y séricos relacionados con una rápida progresión clínica de la arteriosclerosis coronaria / Serum and genetic markers related to rapid clinical progression of coronary artery disease

Introducción y objetivos: La progresión de la enfermedad coronaria una vez se hace evidente a la clínica tiene una gran variabilidad interindividual. El objetivo es determinar marcadores séricos y genéticos en pacientes con rápida progresión clínica (RPC) de la enfermedad coronaria frente a pacientes con estabilidad clínica mantenida (ECM). Métodos: Estudio retrospectivo de casos (RPC) y controles (ECM) (1:2). Se consideró RPC a los pacientes que precisaron al menos 2 revascularizaciones por progresión de la ateroesclerosis en los 10 años posteriores a una primera angioplastia y ECM a aquellos sin eventos durante el mismo periodo tras la primera angioplastia. Una vez seleccionados, se determinaron los valores séricos, la expresión de ácido ribonucleico mensajero (ARNm) y polimorfismos genéticos de interleucina 6, proteína C reactiva y factor de necrosis tumoral alfa (TNFα) como marcadores de inflamación y proproteína convertasa subtilisina/kexina tipo 9 (PCSK9), receptor de lipoproteínas de baja densidad, proteína 2 de unión a elementos reguladores de esteroles y apolipoproteína B como marcadores aterogénicos. Resultados: Se incluyó a 180 pacientes (58 en RPC y 122 en ECM). Las características basales demográficas, del perfil de riesgo clásico y de la extensión de la enfermedad coronaria fueron comparables. El grupo de RPC presentó valores séricos más altos de interleucina 6 y PCSK9 y mayor expresión de ARNm de TNF. Los alelos de Interleucina-6 rs180075C, de TNF rs3093664 non-G y de PCSK9 rs2483205 T confieren riesgo de RPC (p<0,05 en todos los casos). Un 51,7% de los pacientes del grupo RPC presentaron los tres alelos de riesgo frente al 18% de los pacientes del grupo en ECM (p<0,001). Conclusiones: Se propone la existencia de marcadores genotípicos y fenotípicos asociados con la RPC de enfermedad coronaria y que podrían servir para individualizar la intensidad y el tipo de tratamiento.(AU)

Introduction and objectives: Patients with clinically evident coronary artery disease differ in their rate of progression, which impacts prognosis. We aimed to characterize serum and genetic markers in patients with rapid clinical progression (RCP) of coronary artery disease vs those with long standing stable (LSS) disease. Methods: Retrospective study of cases (RCP) and controls (LSS) (1:2). Patients requiring ≥ 2 revascularizations due to atherosclerotic progression in the 10 years after a first angioplasty were considered to be RCP and those without events during the same period after the first angioplasty were considered to have LSS disease. After patient selection, we analyzed serum values, mRNA expression and genetic polymorphisms of inflammatory markers, including interleukin-6, C-reactive protein, and tumor necrosis factor (TNF)-a, and atherogenic markers consisted of proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, sterol regulatory element binding transcription factor 2, and apolipoprotein-B. Results: The study included 180 patients (58 RCP and 122 LSS). Demographic characteristics, classic risk factors and the extent of coronary disease were similar in the 2 groups. Patients with RCP showed higher serum levels of interleukin-6 and PCSK9 and higher TNF mRNA expression. Interleukin-6 rs180075C, TNF rs3093664 non-G and PCSK9 rs2483205 T alleles conferred a risk of RCP (P<.05 in all cases). Among patients with RCP, 51.7% had all 3 risk alleles vs 18% of those with LSS (P<.001). Conclusions: We suggest the existence of specific phenotypic and genotypic markers associated with RCP of coronary artery disease that could help to individualize the type and intensity of treatment.(AU)

Association between systolic blood pressure and low-density lipoprotein cholesterol with coronary heart disease according to age.

BACKGROUND: The impact of elevated systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) at different stages of life is unclear. We aimed to investigate whether genetically mediated SBP/LDL-C is associated with the risk of CHD throughout life. METHODS AND FINDINGS: We conducted a three-sample Mendelian randomization analysis using data from the UK Biobank including 136,648 participants for LDL-C, 135,431 participants for SBP, and 24,052 cases for CHD to assess the effect of duration of exposure to the risk factors on risk of CHD. Analyses were stratified by age at enrolment. In univariable analyses, there was a consistent association between exposure to higher LDL-C and SBP with increased odds of incident CHD in individuals aged ≤55 years, ≤60 years, and ≤65 years (p-value for heterogeneity = 1.00 for LDL-C and 0.67 for SBP, respectively). In multivariable Mendelian randomization analyses, exposure to elevated LDL-C/SBP early in life (age ≤55 years) was associated with a higher risk of CHD independent of later life levels (age >55 years) (odds ratio 1.68, 95% CI 1.20-2.34 per 1 mmol/L LDL-C, and odds ratio 1.33, 95% CI 1.18-1.51 per 10 mmHg SBP). CONCLUSIONS: Genetically predicted SBP and LDL-C increase the risk of CHD independent of age. Elevated SBP and LDL-C in early to middle life is associated with increased CHD risk independent of later-life SBP and LDL-C levels. These findings support the importance of lifelong risk factor control in young individuals, whose risk of CHD accumulates throughout life.