Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Lipoprotein(a) and cardiovascular disease.

One in five people are at high risk for atherosclerotic cardiovascular disease and aortic valve stenosis due to high lipoprotein(a). Lipoprotein(a) concentrations are lowest in people from east Asia, Europe, and southeast Asia, intermediate in people from south Asia, the Middle East, and Latin America, and highest in people from Africa. Concentrations are more than 90% genetically determined and 17% higher in post-menopausal women than in men. Individuals at a higher cardiovascular risk should have lipoprotein(a) concentrations measured once in their lifetime to inform those with high concentrations to adhere to a healthy lifestyle and receive medication to lower other cardiovascular risk factors. With no approved drugs to lower lipoprotein(a) concentrations, it is promising that at least five drugs in development lower concentrations by 65-98%, with three currently being tested in large cardiovascular endpoint trials. This Review covers historical perspectives, physiology and pathophysiology, genetic evidence of causality, epidemiology, role in familial hypercholesterolaemia and diabetes, management, screening, diagnosis, measurement, prevention, and future lipoprotein(a)-lowering drugs.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Remnant Cholesterol, Not LDL Cholesterol, Explains Peripheral Artery Disease Risk Conferred by apoB: A Cohort Study.

BACKGROUND: Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction. METHODS: apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010). RESULTS: In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. CONCLUSIONS: PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.

Susceptible Young Adults and Development of Chronic Obstructive Pulmonary Disease Later in Life.

Rationale: Chronic obstructive pulmonary disease (COPD) has its origin in early life, and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposes a predisease state termed "pre-COPD." Objectives: We tested the hypothesis that susceptible young adults identified with chronic bronchitis and subtle lung function impairment will develop COPD later in life. Methods: We followed random individuals without COPD ages 20-50 years from two population-based cohorts from different smoking eras-the Copenhagen General Population Study from 2003 (N = 5,497) and the Copenhagen City Heart Study from 1976-1978 (N = 2,609)-for 10 and 25 years, for the development of COPD (FEV1/FVC <0.70) and COPD GOLD Stages 2-4 (additionally, FEV1 <80% predicted). Measurements and Main Results: After 10 years, 28% developed COPD and 13% developed COPD GOLD Stages 2-4 in individuals susceptible to COPD, compared with 8% and 1% in those without any susceptibility to COPD. Correspondingly, after 25 years, 22% versus 13% developed COPD and 20% versus 8% developed COPD GOLD Stages 2-4. More than half of incident COPD cases developed from a susceptible state. Compared with those without susceptibility to COPD, multivariable-adjusted odds ratios in those susceptible to COPD were 3.42 (95% confidence interval: 2.78-4.21) for COPD and 10.1 (6.77-15.2) for COPD GOLD Stages 2-4 after 10 years and were 1.54 (1.23-1.93) and 2.12 (1.64-2.73) after 25 years. The ability of a COPD risk score-consisting of the state of susceptibility to COPD with smoking and asthma as risk factors-to predict COPD later in life was high. Conclusions: Our study suggests the existence of a predisease state of COPD, which can be used for early identification of susceptible individuals at risk for COPD later in life.

Lung Function Trajectories in Mild COVID-19 With 2-year Follow-up.

BACKGROUND: The long-term pulmonary sequelae of mild coronavirus disease 2019 (COVID-19) remains unknown. In this study, we aimed to characterize lung function trajectories in individuals with mild COVID-19 from preinfection to 2 years postinfection. METHODS: We reinvited participants 2 years after infection from our matched cohort study of the Copenhagen General Population who had initially been examined 5.4 months after infection. We repeated lung tests and questionnaires. Linear mixed models were used to estimate dynamics in lung volumes in individuals with COVID-19 patients versus uninfected controls over two intervals: from pre-infection to 6 months postinfection and 6 months postinfection to 2 years postinfection. RESULTS: 52 individuals (48.6%) attended the 2-year examination at median 1.9 years (interquartile range, 1.8-2.4) after COVID-19, all with mild infection. Individuals with COVID-19 had an adjusted excess decline in forced expiratory volume in 1 second (FEV1) of 13.0 mL per year (95% confidence interval [CI], -23.5 to -2.5; P = .02) from before infection to 6 months after infection compared to uninfected controls. From 6 to 24 months after infection, they had an excess decline of 7.5 mL per year (95% CI, -25.6-9.6; P = .40). A similar pattern was observed for forced vital capacity (FVC). Participants had a mean increase in diffusing capacity for carbon monoxide (DLco) of 3.33 (SD 7.97) between the 6- and 24-month examination. CONCLUSIONS: Our results indicate that mild COVID-19 infection affects lung function at the time of infection with limited recovery 2 years after infection.

Hyperglycaemia, diabetes and risk of fragility fractures: observational and Mendelian randomisation studies.

AIMS/HYPOTHESIS: Fragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality. METHODS: In total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA1c concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses. RESULTS: Higher fasting and non-fasting glucose and HbA1c concentrations were associated with higher risk of any fragility fracture (p<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 [1.11, 1.79], p=0.004), with similar results for fasting glucose and HbA1c in two-sample MR analyses (ORs 1.50 [1.03, 2.18], p=0.03; and 2.79 [1.12, 6.93], p=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41), p=0.06; 1.36 (0.89, 2.09), p=0.15; and 2.47 (0.95, 6.43), p=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither. CONCLUSIONS/INTERPRETATION: Hyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population.

Low smoking exposure and development and prognosis of COPD over four decades: a population-based cohort study.

BACKGROUND: A diagnosis of COPD is mainly considered in individuals with >10 pack-years of smoking. We tested the hypothesis that low smoking exposure, below the critical threshold of 10 pack-years, increases risk of COPD and leads to poor prognosis. METHODS: We followed non-obstructed adult smokers from the Copenhagen City Heart Study for COPD, defined as a forced expiratory volume in 1 s (FEV1)/forced vital capacity <0.70 and FEV1 <80% predicted, and for related clinical outcomes. First, we followed individuals for 5 years according to baseline smoking for risk of developing COPD, and thereafter for up to four decades for severe exacerbations and death. RESULTS: In 6098 non-obstructed smokers, 1781 (29%) developed COPD after 5 years of follow-up: 23% of individuals with <10 pack-years of smoking at baseline, 26% of those with 10-19.9 pack-years, 30% of those with 20-39.9 pack-years and 39% of those with ≥40 pack-years. During four decades of follow-up, we recorded 620 exacerbations and 5573 deaths. Compared to individuals without COPD with <10 pack­years of smoking, multivariable adjusted hazard ratios (HRs) for exacerbations were 1.94 (95% CI 1.36-2.76) in those without COPD and ≥10 pack-years, 2.83 (95% CI 1.72-4.66) in those with COPD and <10 pack-years, 4.34 (95% CI 2.93-6.43) in those with COPD and 10-19.9 pack-years, 4.39 (95% CI 2.98-6.46) in those with COPD and 20-39.9 pack-years and 4.98 (95% CI 3.11-7.97) in those with COPD and ≥40 pack-years. Corresponding HRs for all-cause mortality were 1.20 (95% CI 1.10-1.32), 1.31 (95% CI 1.13-1.53), 1.59 (95% CI 1.40-1.79), 1.81 (95% CI 1.62-2.03) and 1.81 (95% CI 1.55-2.10). CONCLUSION: Low smoking exposure below the critical threshold of 10 pack-years increases risk of COPD in middle-aged adults within 5 years, and these individuals have increased risk of severe exacerbation and early death over four decades.

Alpha-1 antitrypsin deficiency associated with increased risks of skin cancer, leukemia, and hepatic cancer: A nationwide cohort study.

BACKGROUND: α1-Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression. We tested the hypothesis that individuals with α1-antitrypsin deficiency have increased susceptibility to cancer in the Danish population. METHODS: In a nationwide nested study, we identified 2702 individuals with α1-antitrypsin deficiency and 26,750 control subjects without α1-antitrypsin deficiency matched on age, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow-up of 62 years. RESULTS: Individuals with α1-antitrypsin deficiency versus control subjects had an increased hazard of skin cancer (2.18, 95%CI: 1.81-2.63), leukemia (1.76, 1.12-2.79), liver cancer (3.91, 2.23-6.85), and cancer overall (1.25, 1.13-1.38). Corresponding hazard ratios when the entire Danish population was used as control group were 3.02 (2.55-3.58), 1.83 (1.19-2.81), 4.46 (2.74-7.28), and 1.45 (1.31-1.59). When the analysis was stratified according to comorbidities, the hazard for skin cancer was higher in those with chronic obstructive pulmonary disease (COPD) (3.59, 2.60-4.95) and skin disease (2.93, 2.19-3.92) but remained elevated in those without any of these diseases. Hazards for skin cancer in individuals with α1-antitrypsin deficiency were similar when stratified by liver cirrhosis and ischemic heart disease (ps for interaction: ≥0.76). Hazards for liver cancer in individuals with α1-antitrypsin deficiency versus control subjects were similar when stratified according to liver cirrhosis, COPD, skin disease, and ischemic heart disease (ps for interaction: ≥0.13). CONCLUSION: Individuals with α1-antitrypsin deficiency have increased risks of skin cancer, leukemia, and liver cancer in the Danish population.

Worldwide Increasing Use of Nonfasting Rather Than Fasting Lipid Profiles.

BACKGROUND: Historically, lipids and lipoproteins were measured in the fasting state for cardiovascular risk prediction; however, since 2009 use of nonfasting lipid profiles has increased substantially worldwide. For patients, nonfasting lipid profiles are convenient and avoid any risk of hypoglycemia. For laboratories, blood sampling in the morning and extra visits for patients who have not fasted are avoided. For patients, clinicians, hospitals, and society, nonfasting sampling allows same-day visits with first blood sampling followed by a short wait for test results before clinical consultation. Therefore, nonfasting compared to fasting lipid profiles will save money and time and may improve patient compliance with cardiovascular prevention programs. CONTENT: We report on the progression of endorsement and implementation of nonfasting lipid profiles for cardiovascular risk prediction worldwide and summarize the recommendations from major medical societies and health authorities in different countries. We also describe practical advantages and disadvantages for using nonfasting lipid profiles. Further, we include a description of why fasting has been the standard historically, the barriers against implementation of nonfasting lipid profiles, and finally we suggest the optimal content of a nonfasting lipid profile. SUMMARY: Lipid, lipoprotein, and apolipoprotein concentrations vary minimally in response to normal food intake and nonfasting lipid profiles are equal or superior to fasting profiles for cardiovascular risk prediction. Major guidelines and consensus statements in Europe, the United States, Canada, Brazil, Japan, India, and Australia now endorse use of nonfasting lipid profiles in some or all patients; however, there are still gaps in endorsement and implementation of nonfasting lipid profiles worldwide.

Adiponectin and Risk of Psoriasis: Observational and Mendelian Randomization Studies in up to 900 000 Individuals.

BACKGROUND: Psoriasis is a chronic inflammatory skin disorder often associated with obesity. Adiponectin, an anti-inflammatory protein-hormone secreted by adipose tissue, may be a link between obesity and psoriasis. We hypothesized that low plasma adiponectin is associated with an increased risk of psoriasis in observational and causal genetic studies. METHODS: In observational analyses, we used information on plasma adiponectin and psoriasis in 30 045 individuals from the Copenhagen General Population Study (CGPS). In one-sample Mendelian randomization analyses, we used genetic information on adiponectin and psoriasis in 107 308 individuals from the CGPS. In two-sample Mendelian randomization analyses, we used genetic information on adiponectin from the ADIPOGen consortium and genetic information on psoriasis in 373 338 and 462 933 individuals from the FinnGen study and UK Biobank (UKB). RESULTS: In observational analyses, a 1-unit log-transformed higher plasma adiponectin was associated with a hazard ratio (HR) for psoriasis of 0.67 (95% confidence interval: 0.48-0.94) in an age- and sex-adjusted model but not in a multivariable adjusted model including obesity measures with a HR of 0.95 (0.66-1.35). In genetic one-sample Mendelian randomization analysis, a 1-unit log-transformed higher plasma adiponectin was not associated with a causal risk ratio for psoriasis of 1.33 (0.77-2.32) in the CGPS. In two-sample Mendelian randomization analyses, a 1-unit log-transformed higher plasma adiponectin was not associated with causal risk ratios for psoriasis of 0.96 (0.81-1.14) in FinnGen and 1.00 (1.00-1.01) in UKB. CONCLUSIONS: Low plasma adiponectin is associated with increased risk of psoriasis in age- and sex-adjusted observational analyses; however, this was not the case after adjustment for obesity measures or in causal genetic analyses.

Small Dense Low-Density Lipoprotein Cholesterol and Ischemic Stroke.

OBJECTIVE: For decades, it has been suggested that small dense low-density lipoprotein (sdLDL) may be particularly atherogenic. High levels of sdLDL are associated with an increased risk of ischemic heart disease; however, the association of sdLDL with ischemic stroke has not been explored in a large prospective study on the general population. We tested the hypothesis that high sdLDL cholesterol levels are associated with an increased risk of ischemic stroke. METHODS: This prospective study included 38,319 individuals from the Copenhagen General Population Study with fresh sample measurements of sdLDL cholesterol. Median follow-up time was 3.1 years. We observed 302 and 74 ischemic and hemorrhagic strokes from baseline in 2013 to 2017 to the end of follow-up in 2018. For comparison, we included estimates for large buoyant LDL cholesterol and total LDL cholesterol. RESULTS: Higher levels of sdLDL cholesterol were log-linearly associated with increased risk of ischemic stroke. Compared with individuals with sdLDL cholesterol in the lowest tertile (≤0.60 mmol/l; ≤23 mg/dl) the multivariable adjusted hazard ratio for ischemic stroke was 1.79 (95% confidence interval = 1.31-2.43) for the highest tertile (≥0.86 mmol/l; ≥33 mg/dl). Multivariable adjusted hazard ratios for ischemic stroke per 1 mmol/l (38.7 mg/dl) higher levels were 1.69 (1.28-2.22) for sdLDL cholesterol, 0.95 (0.78-1.16) for large buoyant LDL cholesterol, and 1.08 (0.93-1.25) for total LDL cholesterol. Hazard ratios were similar when further adjusting for body mass index (BMI) and diabetes mellitus in the biological pathway in combination with related lipids and lipoproteins. INTERPRETATION: Higher sdLDL cholesterol levels were robustly associated with increased risk of ischemic stroke. ANN NEUROL 2023;93:952-964.

Contributions of elevated CRP, hyperglycaemia, and type 2 diabetes to cardiovascular risk in the general population: observational and Mendelian randomization studies.

OBJECTIVE: To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related. RESEARCH DESIGN AND METHODS: Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC. RESULTS: Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (ß-coefficient: 0.02 (0.02, 0.03), p = 3 × 10- 20); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)). CONCLUSIONS: Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.

Remnant cholesterol and low-grade inflammation jointly in atherosclerotic cardiovascular disease: implications for clinical trials.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death despite the development of effective treatments. Recently, elevated remnant cholesterol and low-grade inflammation have emerged as factors explaining part of the residual ASCVD risk. Interestingly, the coexistence of both high remnant cholesterol and low-grade inflammation can further increase the risk of ASCVD. The aim of this review is to describe the role of elevated remnant cholesterol and low-grade inflammation, separately and combined, in ASCVD. RECENT FINDINGS: Results from recently published studies, including observational and genetic Mendelian randomization studies, support a causal relationship between elevated remnant cholesterol and low-grade inflammation on risk of ASCVD in both primary and secondary prevention settings. In addition, current evidence from observational studies suggests that the coexistence of elevated remnant cholesterol and low-grade inflammation further increases the risk of ASCVD. SUMMARY: Recent observational studies suggest that high remnant cholesterol combined with low-grade inflammation may confer a particular high risk for ASCVD. Attention on the dual threat from high remnant cholesterol and low-grade inflammation is necessary, and further research in this field is warranted. The effect of remnant cholesterol-lowering drugs and anti-inflammatory drugs on ASCVD risk alone and combined remains to be elucidated. VIDEO ABSTRACT: http://links.lww.com/COCN/A20.

Measuring lipoprotein(a) for cardiovascular disease prevention - in whom and when?

PURPOSE OF REVIEW: The aim of this study is to summarize major cardiovascular guideline recommendations on lipoprotein(a) and highlighting recent findings that emphasize how measuring lipoprotein(a) once in all adults is meaningful regardless of age, sex, comorbidities, or ethnicity. RECENT FINDINGS: Many international guidelines now recommend once in a lifetime measurement of lipoprotein(a) in all adult individuals to facilitate accurate risk prediction. Lipoprotein(a)-lowering therapy to reduce cardiovascular disease is on the horizon, with results from the first phase 3 trial expected in 2025. SUMMARY: Elevated lipoprotein(a) is an independent causal risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis and measuring lipoprotein(a) once in all individuals regardless of age, sex, comorbidities, or ethnicity is meaningful to aid in risk stratification.

Novel Therapies for Lipoprotein(a): Update in Cardiovascular Risk Estimation and Treatment.

PURPOSE OF REVIEW: Lipoprotein(a) is an important causal risk factor for cardiovascular disease but currently no available medication effectively reduces lipoprotein(a). This review discusses recent findings regarding lipoprotein(a) as a causal risk factor and therapeutic target in cardiovascular disease, it reviews current clinical recommendations, and summarizes new lipoprotein(a) lowering drugs. RECENT FINDINGS: Epidemiological and genetic studies have established lipoprotein(a) as a causal risk factor for cardiovascular disease and mortality. Guidelines worldwide now recommend lipoprotein(a) to be measured once in a lifetime, to offer patients with high lipoprotein(a) lifestyle advise and initiate other cardiovascular medications. Clinical trials including antisense oligonucleotides, small interfering RNAs, and an oral lipoprotein(a) inhibitor have shown great effect on lowering lipoprotein(a) with reductions up to 106%, without any major adverse effects. Recent clinical phase 1 and 2 trials show encouraging results and ongoing phase 3 trials will hopefully result in the introduction of specific lipoprotein(a) lowering drugs to lower the risk of cardiovascular disease.

Elevated plasma triglycerides increase the risk of psoriasis: a cohort and Mendelian randomization study.

BACKGROUND: It is increasingly clear that triglyceride-rich lipoproteins are proinflammatory and cause low-grade systemic inflammation. However, it is currently unknown whether elevated plasma triglycerides are causally related to the development of psoriasis, a skin disorder driven by chronic inflammation. OBJECTIVES: To determine if elevated plasma triglycerides are associated with increased risk of psoriasis in observational and Mendelian randomization analysis. METHODS: Consecutive individuals from the Copenhagen General Population Study were included. We used plasma triglycerides (n = 108 043) and a weighted triglyceride allele score (n = 92 579) on nine known triglyceride-altering genetic variants. Genetic results were replicated in 337 159 individuals from the UK Biobank. Psoriasis was defined using the International Classification of Diseases, version 10 (ICD-10) code for hospital contact in the main analyses, and prescription of topical antipsoriatics for mild psoriasis in the sensitivity analysis. RESULTS: During a follow-up of median (range) 9.3 (0.1-15.1) years from 2003 to 2015 through 2018, 855 (1%) individuals were diagnosed with psoriasis by ICD-10 in the observational analysis and 772 (1%) in the Mendelian randomization analysis. In the observational analysis, the multivariable adjusted hazard ratio for psoriasis by ICD-10 was 1.26 [95% confidence interval (CI) 1.15-1.39] per doubling in plasma triglycerides with a corresponding causal odds ratio of incident psoriasis of 2.10 (95% CI 1.30-3.38). Causality was confirmed from data from the UK Biobank. Results were similar but slightly attenuated when we used topical antipsoriatic prescriptions for mild psoriasis. CONCLUSIONS: Elevated plasma triglycerides are associated with an increased risk of psoriasis in observational and Mendelian randomization analysis.

Psoriasis is a common skin condition, characterized by inflammation in the body (the body's response to an unwanted agent). People with psoriasis often have higher lipid levels in their blood compared with people without psoriasis. Some studies have shown that triglyceride-rich lipoprotein (a certain type of lipid) is irritative to the body and can cause inflammation. However, it is unclear whether high levels of triglycerides in the blood can cause them to penetrate into the skin and trigger the onset of psoriasis. We aimed to test this question in 100,000 people from a Danish population without previously diagnosed psoriasis. Specifically, we measured plasma triglycerides at initial examination and at the same time assessed the same people for genetic variants that impact on the concentration of plasma triglycerides. Importantly, genetic variants are inherited by chance, meaning that we could look specifically at whether a change in triglycerides was the mechanism that causes psoriasis. Next, we observed these people for about 10 years and noted any new occurrence of psoriasis during follow-up. We found that the risk of developing psoriasis was higher both as a function of plasma triglyceride concentration and the genetic variants that increase plasma triglyceride concentration. Overall, our study findings suggest that high levels of triglycerides in the blood could be a causal risk factor for the development of psoriasis.

Epigenetic Regulation of F2RL3 Associates With Myocardial Infarction and Platelet Function.

BACKGROUND: DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. METHODS: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. RESULTS: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2-2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. CONCLUSIONS: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner.

Elevated remnant cholesterol, plasma triglycerides, and cardiovascular and non-cardiovascular mortality.

AIMS: Cholesterol carried in triglyceride-rich lipoproteins, also called remnant cholesterol, is being increasingly acknowledged as an important causal risk factor for atherosclerosis. Elevated remnant cholesterol, marked by elevated plasma triglycerides, is associated causally with an increased risk of atherosclerotic cardiovascular disease. The association with cause-specific mortality is, however, unclear. The aim of this study was to test the hypothesis that elevated remnant cholesterol and plasma triglycerides are associated with increased mortality from cardiovascular disease, cancer, and other causes. METHODS AND RESULTS: Using a contemporary population-based cohort, 87 192 individuals from the Copenhagen General Population Study aged 20-69 years at baseline in 2003-2015 were included. During up to 13 years of follow-up, 687 individuals died from cardiovascular disease, 1594 from cancer, and 856 from other causes, according to the National Danish Causes of Death Registry. In individuals with remnant cholesterol ≥1.0 mmol/L (≥39 mg/dL; 22% of the population) compared with those with levels <0.5 mmol/L (<19 mg/dL), multivariable-adjusted mortality hazard ratios were 2.2 (95% confidence interval 1.3-3.5) for cardiovascular disease, 1.0 (0.7-1.3) for cancer, and 2.1 (1.4-3.3) for other causes. Exploratory analysis of the cause of death subcategories showed corresponding hazard ratios of 4.4 (1.6-11) for ischemic heart disease, 8.4 (2.0-34) for infectious diseases, and 9.1 (1.9-43) for endocrinological diseases. Results for plasma triglycerides >2 vs. <1 mmol/L (>177 vs. <89 mg/dL) were similar. CONCLUSION: Remnant cholesterol of ≥1 mmol/L (39 mg/dL), present in 22% of the population, and plasma triglycerides of ≥2 mmol/L (177 mg/dL), present in 28% of the population, were associated with two-fold mortality from cardiovascular and other causes, but not from cancer. This novel finding should be confirmed in other cohorts.

Lipoprotein(a) is linked to atherothrombosis and aortic valve stenosis independent of C-reactive protein.

AIMS: Recent evidence suggest that the lipoprotein(a)-associated risk of atherosclerotic cardiovascular disease (ASCVD) may be observed only in individuals with low-grade systemic inflammation. It was hypothesized that high lipoprotein(a) is a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis irrespective of C-reactive protein levels. METHODS AND RESULTS: A total of 68 090 individuals from the Copenhagen General Population Study, a prospective cohort study, were included. During a median follow-up of 8.1 years, 5104 individuals developed ASCVD, 2432 myocardial infarction, and 1220 aortic valve stenosis. The risk of ASCVD, myocardial infarction, and aortic valve stenosis increased with higher values of both lipoprotein(a) and C-reactive protein. For individuals with lipoprotein(a) in the 91st-100th percentiles (≥70 mg/dl, ≥147 nmol/l) vs. the 1st-33rd percentiles (≤6 mg/dl, ≤9 nmol/l), the multivariable-adjusted hazard ratio for ASCVD was 1.61 (95% confidence interval 1.43-1.81) for those with C-reactive protein <2 mg/l and 1.57 (1.36-1.82) for those with C-reactive protein ≥2 mg/l (P for interaction = 0.87). The corresponding values were 2.08 (1.76-2.45) and 1.65 (1.34-2.04) for myocardial infarction, and 2.01 (1.59-2.55) and 1.73 (1.31-2.27) for aortic valve stenosis, respectively (P for interaction = 0.15 and = 0.18). The highest absolute 10-year risks were found in men aged 70-79 years with lipoprotein(a) levels in the 91st-100th percentiles and C-reactive protein ≥2 mg/l, with 34% for ASCVD, 19% for myocardial infarction, and 13% for aortic valve stenosis. The corresponding values in women were 20%, 10%, and 8%, respectively. CONCLUSION: High lipoprotein(a) was a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis independent of C-reactive protein levels.