apoB/apoA-I Ratio and Lp(a) Associations With Aortic Valve Stenosis Incidence: Insights From the EPIC-Norfolk Prospective Population Study.

Background Apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio and lipoprotein(a) (Lp[a]) are associated with aortic valve stenosis (AVS) disease progression. Clinical characteristics such as age, sex, and presence of concomitant coronary artery disease may strongly modify these associations; however, these effects have not been well defined in longitudinal studies. We set out to assess these associations between apoB/apoA-I ratio, Lp(a), and AVS incidence in a large population study. Methods and Results We analyzed data from 17 745 participants (mean age, 59.2±9.1 years; men, 44.9%) in the EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk Prospective Population Study) population study in whom apoB/apoA-I and Lp(a) levels were measured. Participants were identified as having incident AVS if they were hospitalized or died with AVS as an underlying cause. After a median follow-up of 19.8 years (17.9-21.0 years) there were 403 (2.2%) incident cases of AVS. The hazard ratio for AVS risk was 1.30 (95% CI, 1.19-1.41; P50 mg/dL) remained an independent risk factor for AVS after adjustment for age, sex, low-density lipoprotein cholesterol, and concomitant coronary artery disease (hazard ratio, 1.70; 95% CI, 1.33-2.19 [P<0.001]). Conclusions In this population study, apoB/apoA-I ratio was associated with risk of AVS incidence, especially in younger and female participants and those without concomitant coronary artery disease. Lp(a) was an independent risk factor for AVS incidence. Interventional trials are needed to investigate whether modulating apoB/apoA-I or lowering Lp(a) can prevent or slow down AVS

C-Reactive Protein Identifies Low-Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer-Norfolk Prospective Population Study.

BACKGROUND: Conflicting data exist about the cardiovascular risk of metabolically healthy obese persons. The prognostic value of C-reactive protein (CRP) in this intriguing group is unknown. We assessed the association between CRP levels and the risk of coronary heart disease (CHD) in metabolically healthy persons with abdominal obesity. METHODS AND RESULTS: In the European Prospective Investigation of Cancer-Norfolk prospective cohort, CRP levels and information on metabolic syndrome criteria were available for 7279 participants, of whom 825 (11%) developed CHD during a follow-up period of 10.9±1.8 years. There was a trend toward a higher multivariable-adjusted hazard ratio for CHD in metabolically healthy obese participants with CRP levels >2 mg/L compared with <2 mg/L (hazard ratio 1.59, 95% CI 0.97-2.62, P=0.066). Metabolically unhealthy obese participants had significantly higher CHD risk compared with metabolically healthy obese participants with CRP levels <2 mg/L (hazard ratio 1.88, 95% CI 1.20-2.94, P=0.006). Most important, we found that the risk of CHD among metabolically healthy obese persons with CRP levels <2 mg/L was comparable to that of metabolically healthy nonobese persons (hazard ratio 0.91, 95% CI 0.60-1.39, P=0.674). CONCLUSIONS: Among metabolically healthy obese persons, low CRP levels were associated with a CHD risk comparable to that of metabolically healthy nonobese persons. CRP appears to be an easy and widely available method for identifying a low-risk subpopulation among metabolically healthy obese persons.EPIC‐Norfolk is supported by program grants from the Medical Research Council UK and Cancer Research UK. The CRP measurements in the full cohort were supported by a grant from the Medical Research Council to the Medical Research Council Epidemiology Unit, Cambridge, United Kingdom (MRC G0701863). The funding sources had no role in the study design, the conduct of the analysis, or the decision to submit the manuscript for publication

Understanding Gene-Lifestyle Interaction in Obesity: The Role of Mediation versus Moderation

BACKGROUND: Obesity results from complex interactions between genetic susceptibility to weight gain and poor eating and lifestyle behaviors. The approach that has been traditionally used in genetics to investigate gene-environment/lifestyle interaction in obesity is based on the concept of moderation or effect modification. Another approach called mediation analysis can be used to investigate gene-environment interaction in obesity. The objective of this review article is to explain the differences between the concepts of moderation and mediation and summarize the studies that have used mediation analysis to support the role of eating or lifestyle behaviors as putative mediators of genetic susceptibility to obesity. SUMMARY: Moderation is used to determine whether the effect of an exposure (genes associated with obesity) on an outcome (obesity phenotype) differs in magnitude and/or direction across the spectrum of environmental exposure. Mediation analysis is used to assess the extent to which the effect of the exposure on the outcome is explained by a given set of hypothesized mediators with the aim of understanding how the exposure could lead to the outcome. In comparison with moderation, relatively few studies used mediation analyses to investigate gene-environment interaction in obesity. Most studies found evidence that traits related to appetite or eating behaviors partly mediated genetic susceptibility to obesity in either children or adults. KEY MESSAGES: Moderation and mediation represent two complementary approaches to investigate gene-environment interaction in obesity and address different research questions pertaining to the cause-effect relationship between genetic susceptibility to obesity and various obesity outcomes. More studies relying on mediation are needed to better understand the role of eating and lifestyle habits in mediating genetic susceptibility to obesity

Lipoprotein(a) has no major impact on calcification activity in patients with mild to moderate aortic valve stenosis

OBJECTIVE: To assess whether patients with aortic valve stenosis (AS) with elevated lipoprotein(a) (Lp(a)) are characterised by increased valvular calcification activity compared with those with low Lp(a). METHODS: We performed (18)F-sodium fluoride ((18)F-NaF) positron emission tomography/CT in patients with mild to moderate AS (peak aortic jet velocity between 2 and 4 m/s) and high versus low Lp(a) (>50 mg/dL vs <50 mg/dL, respectively). Subjects were matched according to age, gender, peak aortic jet velocity and valve morphology. We used a target to background ratio with the most diseased segment approach to compare (18)F-NaF uptake. RESULTS: 52 individuals (26 matched pairs) were included in the analysis. The mean age was 66.4±5.5 years, 44 (84.6%) were men, and the mean aortic valve velocity was 2.80±0.49 m/s. The median Lp(a) was 79 (64–117) mg/dL and 7 (5–11) mg/dL in the high and low Lp(a) groups, respectively. Systolic blood pressure and low-density-lipoprotein cholesterol (corrected for Lp(a)) were significantly higher in the low Lp(a) group (141±12 mm Hg vs 128±12 mm Hg, 2.5±1.1 mmol/L vs 1.9±0.8 mmol/L). We found no difference in valvular (18)F-NaF uptake between the high and low Lp(a) groups (3.02±1.26 vs 3.05±0.96, p=0.902). Linear regression analysis showed valvular calcium score to be the only significant determinant of valvular (18)F-NaF uptake (β=0.63; 95% CI 0.38 to 0.88 per 1000 Agatston unit increase, p<0.001). Lp(a) was not associated with (18)F-NaF uptake (β=0.17; 95% CI −0.44 to 0.88, p=0.305 for the high Lp(a) group). CONCLUSION: Among patients with mild to moderate AS, calcification activity is predominantly determined by established calcium burden. The results do not support our hypothesis that Lp(a) is associated with valvular (18)F-NaF uptake

Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease-Free Survival, and Mortality Risk: A Mendelian Randomization Analysis.

IMPORTANCE: Elevated lipoprotein(a) (Lp[a]) levels are associated with atherosclerotic cardiovascular diseases. The association between high Lp(a) levels and human longevity phenotypes is, however, controversial. OBJECTIVE: To examine whether genetically determined Lp(a) levels are associated with parental life span and chronic disease-free survival (health span) and the association between Lp(a) levels and long-term, all-cause mortality risk. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, cross-sectional mendelian randomization (UK Biobank [2006-2010] and LifeGen Consortium) and prospective analyses (European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk [1993-1997, with patients followed up to 2016]) were conducted using individual-level data on 139 362 participants. The association between a weighted genetic risk score of 26 independent single-nucleotide polymorphisms at the LPA locus on parental life span using individual participant data from the UK Biobank, as well as with summary statistics of a genome-wide association study of more than 1 million life spans (UK Biobank and LifeGen), were examined. The association between these single-nucleotide polymorphisms and the age at the end of the health span was tested using summary statistics of a previous genome-wide association study in the UK Biobank. The association between Lp(a) levels and all-cause mortality in the EPIC-Norfolk study was also investigated. Data were analyzed from December 2018 to December 2019. EXPOSURES: Genetically determined and measured Lp(a) levels. MAIN OUTCOMES AND MEASURES: Parental life span, health span, and all-cause mortality. RESULTS: In 139 362 white British participants (mean [SD] age, 62.8 [3.9] years; 52% women) from the UK Biobank, increases in the genetic risk score (weighted for a 50-mg/dL increase in Lp[a] levels) were inversely associated with a high parental life span (odds ratio, 0.92; 95% CI, 0.89-0.94; P = 2.7 × 10-8). Using the Egger-mendelian randomization method, a negative association between LPA single-nucleotide polymorphisms and parental life span (mean [SD] Egger-mendelian randomization slope, -0.0019 [0.0002]; P = 2.22 × 10-18) and health span (-0.0019 [0.0003]; P = 3.00 × 10-13) was noted. In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064]). CONCLUSIONS AND RELEVANCE: The results of this study suggest a potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality. The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels

Sex-Specific Associations of Genetically Predicted Circulating Lp(a) (Lipoprotein(a)) and Hepatic LPA Gene Expression Levels With Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses.

BACKGROUND: Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. METHODS: To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically predicted Lp(a) levels (using 27 single nucleotide polymorphisms at the LPA locus) and hepatic LPA expression (using 80 single nucleotide polymorphisms at the LPA locus associated with LPA mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS, and CAVS using individual participant data from the UK Biobank: 408 403 participants of European ancestry (37 102, 4283, and 2574 with prevalent CAD, IS, and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS, and CAVS was also investigated in European Prospective Investigation into Cancer and Nutrition-Norfolk: 18 721 participants (3964, 846, and 424 with incident CAD, IS, and CAVS, respectively). RESULTS: Genetically predicted plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically predicted plasma Lp(a) levels were associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically predicted LPA expression levels were associated with prevalent CAD and CAVS in men and women but not with IS. CONCLUSIONS: Genetically predicted blood Lp(a) and hepatic LPA gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials

Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans. METHODS AND RESULTS: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351). CONCLUSIONS: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS

Human biting mosquitoes and implications for West Nile virus transmission

West Nile virus (WNV), primarily vectored by mosquitoes of the genus Culex, is the most important mosquito-borne pathogen in North America, having infected thousands of humans and countless wildlife since its arrival in the USA in 1999. In locations with dedicated mosquito control programs, surveillance methods often rely on frequent testing of mosquitoes collected in a network of gravid traps (GTs) and CO2-baited light traps (LTs). Traps specifically targeting oviposition-seeking (e.g. GTs) and host-seeking (e.g. LTs) mosquitoes are vulnerable to trap bias, and captured specimens are often damaged, making morphological identification difficult. This study leverages an alternative mosquito collection method, the human landing catch (HLC), as a means to compare sampling of potential WNV vectors to traditional trapping methods. Human collectors exposed one limb for 15 min at crepuscular periods (5:00–8:30 am and 6:00–9:30 pm daily, the time when Culex species are most actively host-seeking) at each of 55 study sites in suburban Chicago, Illinois, for two summers (2018 and 2019). A total of 223 human-seeking mosquitoes were caught by HLC, of which 46 (20.6%) were mosquitoes of genus Culex. Of these 46 collected Culex specimens, 34 (73.9%) were Cx. salinarius, a potential WNV vector species not thought to be highly abundant in upper Midwest USA. Per trapping effort, GTs and LTs collected > 7.5-fold the number of individual Culex specimens than HLC efforts. The less commonly used HLC method provides important insight into the complement of human-biting mosquitoes in a region with consistent WNV epidemics. This study underscores the value of the HLC collection method as a complementary tool for surveillance to aid in WNV vector species characterization. However, given the added risk to the collector, novel mitigation methods or alternative approaches must be explored to incorporate HLC collections safely and strategically into control programs.https://doi.org/10.1186/s13071-022-05603-