Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

An atlas of genetic scores to predict multi-omic traits.

The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.

The effectiveness of pharmacological and lifestyle interventions to reduce the risk of diabetes and hyperglycaemia following gestational diabetes: A systematic review and meta-analysis.

AIMS: To synthesize the available evidence to better understand the effectiveness of interventions to prevent or delay hyperglycaemia and Type 2 diabetes mellitus (T2DM) postnatally in women with current or previous gestational diabetes mellitus (GDM). METHODS: We searched five databases up to December 2020 for primary peer-reviewed articles reporting postpartum glycaemic outcomes in women with (previous) GDM following pharmacological or lifestyle intervention. Outcomes were relative risk of T2DM or continuous measures of glycaemia, change or at follow-up. A minimum of two studies evaluating the same intervention-outcome combination were needed to conduct meta-analyses, otherwise studies were described narratively. Meta-regression was used to evaluate whether associations varied by additional variables. We assessed risk of bias using the Critical Appraisal Skills Programme checklist. PROSPERO record CRD42018102380. RESULTS: We included 31 studies in the review with a total sample size of 8624 participants, and 26 studies in meta-analyses. Two-thirds of studies followed up participants at 1 year or less. Pharmacological interventions were associated with reduced risk of T2DM (0.80 [95% CI 0.64-1.00], n = 6 studies), as were lifestyle interventions albeit with a smaller effect size (0.88 [95% CI 0.76-1.01], n = 12 studies). Dietary and physical activity interventions were associated with a small reduction in fasting plasma glucose, particularly in longer interventions, but inconsistent effects were seen for other continuous outcomes. CONCLUSIONS: Although possibly due to chance, interventions to reduce hyperglycaemia after GDM may be effective. Future research should improve understanding of how interventions affect glucose control and how to optimise interventions for this population.

Genomic atlas of the human plasma proteome.

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

Correction: Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

[This corrects the article DOI: 10.1371/journal.pbio.3000572.].

The influence of rare variants in circulating metabolic biomarkers.

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.

Mendelian Randomization Study of ACLY and Cardiovascular Disease.

BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).

Association between hypertensive disorders of pregnancy and later risk of cardiovascular outcomes.

BACKGROUND: Hypertensive disorders of pregnancy are common pregnancy complications that are associated with greater cardiovascular disease risk for mothers. However, risk of cardiovascular disease subtypes associated with gestational hypertension or pre-eclampsia is unclear. The present study aims to compare the risk of cardiovascular disease outcomes for women with and without a history of gestational hypertension and pre-eclampsia using national hospital admissions data. METHODS: This was a retrospective cohort study of national medical records from all National Health Service hospitals in England. Women who had one or more singleton live births in England between 1997 and 2015 were included in the analysis. Risk of total cardiovascular disease and 19 pre-specified cardiovascular disease subtypes, including stroke, coronary heart disease, cardiomyopathy and peripheral arterial disease, was calculated separately for women with a history of gestational hypertension and pre-eclampsia compared to normotensive pregnancies. RESULTS: Amongst 2,359,386 first live births, there were 85,277 and 74,542 hospital admissions with a diagnosis of gestational hypertension and pre-eclampsia, respectively. During 18 years (16,309,386 person-years) of follow-up, the number and incidence of total CVD for normotensive women, women with prior gestational hypertension and women with prior pre-eclampsia were n = 8668, 57.1 (95% CI: 55.9-58.3) per 100,000 person-years; n = 521, 85.8 (78.6-93.5) per 100,000 person-years; and n = 518, 99.3 (90.9-108.2) per 100,000 person-years, respectively. Adjusted HRs (aHR) for total CVD were aHR (95% CI) = 1.45 (1.33-1.59) for women with prior gestational hypertension and aHR = 1.62 (1.48-1.78) for women with prior pre-eclampsia. Gestational hypertension was strongly associated with dilated cardiomyopathy, aHR = 2.85 (1.67-4.86), and unstable angina, aHR = 1.92 (1.33-2.77). Pre-eclampsia was strongly associated with hypertrophic cardiomyopathy, aHR = 3.27 (1.49-7.19), and acute myocardial infarction, aHR = 2.46 (1.72-3.53). Associations were broadly homogenous across cardiovascular disease subtypes and increased with a greater number of affected pregnancies. CONCLUSIONS: Women with either previous gestational hypertension or pre-eclampsia are at greater risk of a range of cardiovascular outcomes. These women may benefit from clinical risk assessment or early interventions to mitigate their greater risk of various cardiovascular outcomes.

Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis.

AIMS: Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement. METHODS AND RESULTS: Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function. CONCLUSIONS: Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.

A Systematic Review of the Association Between Vegan Diets and Risk of Cardiovascular Disease.

BACKGROUND: Plant-based diets are gaining attention globally due to their environmental benefits and perceived health-protective role. A vegan diet may have cardiovascular benefits; however, evidence remains conflicting and insufficiently assessed. OBJECTIVES: We evaluated the utility of the vegan diet in cardiovascular disease (CVD) prevention. METHODS: We conducted a systematic review of studies evaluating the association between vegan diets and cardiovascular outcomes. We searched 5 databases (Ovid MEDLINE, EMBASE, Web of Science, Scopus, and OpenGrey) through 31 October 2020. Four investigators independently screened the full texts for inclusion, assessed quality, and extracted data from published reports. RESULTS: Out of the 5729 identified records, 7 were included, comprising over 73,000 participants, of whom at least 7661 were vegans. Three studies, with at least 73,426 individuals (including at least 7380 vegans), examined risks of primary cardiovascular events (total CVD, coronary heart disease, acute myocardial infarction, total stroke, hemorrhagic stroke, and ischemic stroke) in individuals who followed a vegan diet compared to those who did not. None of the studies reported a significantly increased or decreased risk of any cardiovascular outcome. One study suggested that vegans were at greater risk of ischemic stroke compared to individuals who consumed animal products (HR, 1.54; 95% CI, 0.95-2.48). Yet in another study, vegans showed lower common carotid artery intima-media thickness (0.56 ± 0.1 mm vs. 0.74 ± 0.1 mm in controls; P < 0.001), and in 3 studies of recurrent CVD events, vegans had 0-52% lower rates. Furthermore, endothelial function did not differ between vegans and nonvegans. Using the Grading of Recommendations Assessment, Development and Evaluation approach, evidence was deemed to be of low to very low strength/quality. CONCLUSIONS: Among the Western populations studied, evidence weakly demonstrates associations between vegan diets and risk of CVDs, with the direction of associations varying with the specific CVD outcome tested. However, more high-quality research on this topic is needed. This study was registered at PROSPERO as CRD42019146835.

Reproductive outcomes in women and men using complementary and alternative medicine treatment and not receiving artificial reproductive technology: a systematic review.

PURPOSE: Infertility is a global problem, but only a minority of couples access assisted reproductive technologies due to financial and sociocultural barriers. Complementary and alternative medicine are seen as another option. We aimed to determine the impact of complementary and alternative medicine on conception, miscarriage and live birth rates in couples not receiving assisted reproductive technology treatments. METHODS: The electronic databases EMBASE, PubMed, Web of Science and the Allied and Complementary Medicine Database were systematically searched before March 24th 2020. Reference lists of eligible studies were searched for relevant studies. Eligible studies included trials and observational studies that assessed a complementary or alternative medicine and conception, miscarriage or live births in men or women not undergoing fertility treatment. Data were extracted by two independent reviewers using a pre-designed data collection form. The study protocol was published in the PROSPERO database (CRD42018086980). RESULTS: Twenty randomized controlled trials were identified, including 2748 individuals. Most studies did not demonstrate any effect of a complementary or alternative medicine on pregnancy, live birth or miscarriage rates. Limited evidence was found for a positive effect of herbal therapies taken by women on conception rates. There was substantial diversity in quality across the studies. CONCLUSION: There is limited evidence of the effectiveness of complementary and alternative medicine on improving the chances of conception and live births, or increasing miscarriage risk. Owing to the generally sub-optimal quality and heterogeneous nature of the evidence, rigorous studies are needed to determine the impact of complementary and alternative medicine on fertility.

Safety of Men With Small and Medium Abdominal Aortic Aneurysms Under Surveillance in the NAAASP.

BACKGROUND: Population screening for abdominal aortic aneurysm (AAA) has commenced in several countries, and has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have an AAA <5.5 cm in diameter, the referral threshold for treatment, and are entered into an ultrasound surveillance program. This study aimed to determine the risk of ruptured AAA (rAAA) in men under surveillance. METHODS: Men in the National Health Service AAA Screening Programme who initially had a small (3-4.4 cm) or medium (4.5-5.4 cm) AAA were followed up. The screening program's database collected data on ultrasound AAA diameter measurements, dates of referral, and loss to follow-up. Local screening programs recorded adverse outcomes, including rAAA and death. Rupture and mortality rates were calculated by initial and final known AAA diameter. RESULTS: A total of 18 652 men were included (50 103 person-years of surveillance). Thirty-one men had rAAA during surveillance, of whom 29 died. Some 952 men died of other causes during surveillance, mainly cardiovascular complications (26.3%) and cancer (31.2%). The overall mortality rate was 1.96% per annum, similar for men with small and medium AAAs. The rAAA risk was 0.03% per annum (95% CI, 0.02%-0.05%) for men with small AAAs and 0.28% (0.17%-0.44%) for medium AAAs. The rAAA risk for men with AAAs just below the referral threshold (5.0-5.4 cm) was 0.40% (0.22%-0.73%). CONCLUSIONS: The risk of rAAA under surveillance is <0.5% per annum, even just below the present referral threshold of 5.5 cm, and only 0.4% of men under surveillance are estimated to rupture before referral. It can be concluded that men with small and medium screen-detected AAAs are safe provided they are enrolled in an intensive surveillance program, and that there is no evidence that the current referral threshold of 5.5 cm should be changed.

Mid- and Long-Term Health Risks in Living Kidney Donors: A Systematic Review and Meta-analysis.

Background: Long-term health risks for adults who donate kidneys are unclear. Purpose: To summarize evidence about mid- and long-term health risks associated with living kidney donation in adults. Data Sources: PubMed, Embase, Scopus, and PsycINFO without language restriction from April 1964 to July 2017. Study Selection: Observational studies with at least 1 year of follow-up that compared health outcomes in adult living kidney donors versus nondonor populations. Data Extraction: Two investigators independently extracted study data and assessed study quality. Data Synthesis: 52 studies, comprising 118 426 living kidney donors and 117 656 nondonors, were included. Average follow-up was 1 to 24 years. No evidence suggested higher risk for all-cause mortality, cardiovascular disease, hypertension, type 2 diabetes, or adverse psychosocial health outcomes in living kidney donors than in nondonor populations. Donors had higher diastolic blood pressure, lower estimated glomerular filtration rates, and higher risk for end-stage renal disease (ESRD) (relative risk [RR], 8.83 [95% CI, 1.02 to 20.93]) and preeclampsia in female donors (RR, 2.12 [CI, 1.06 to 4.27]). Despite the increased RR, donors had low absolute risk for ESRD (incidence rate, 0.5 event [CI, 0.1 to 4.9 events] per 1000 person-years) and preeclampsia (incidence rate, 5.9 events [CI, 2.9 to 8.9 events] per 100 pregnancies). Limitation: Generalizability was limited by selected control populations, few studies reported pregnancy-related outcomes, and few studies were from low- and middle-income countries. Conclusion: Although living kidney donation is associated with higher RRs for ESRD and preeclampsia, the absolute risk for these outcomes remains low. Compared with nondonor populations, living kidney donors have no increased risk for other major chronic diseases, such as type 2 diabetes, or for adverse psychosocial outcomes. Primary Funding Source: National Health Service Blood and Transplant and National Institute for Health Research. (PROSPERO: CRD42017072284).

Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease.

Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.

Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk.

Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events. Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.

Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis.

IMPORTANCE: Between 40% and 50% of women in Western countries use complementary therapies to manage menopausal symptoms. OBJECTIVE: To determine the association of plant-based therapies with menopausal symptoms, including hot flashes, night sweats, and vaginal dryness. DATA SOURCES: The electronic databases Ovid MEDLINE, EMBASE, and Cochrane Central were systematically searched to identify eligible studies published before March 27, 2016. Reference lists of the included studies were searched for further identification of relevant studies. STUDY SELECTION: Randomized clinical trials that assessed plant-based therapies and the presence of hot flashes, night sweats, and vaginal dryness. DATA EXTRACTION: Data were extracted by 2 independent reviewers using a predesigned data collection form. MAIN OUTCOMES AND MEASURES: Hot flashes, night sweats, and vaginal dryness. RESULTS: In total, 62 studies were identified, including 6653 individual women. Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, -1.31 [95% CI, -2.02 to -0.61]) and vaginal dryness score (pooled mean difference of changes, -0.31 [95% CI, -0.52 to -0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, -2.14 [95% CI, -5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, -0.79 [-1.35 to -0.23]) and vaginal dryness score (pooled mean difference of changes, -0.26 [-0.48 to -0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality. CONCLUSIONS AND RELEVANCE: This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats. However, because of general suboptimal quality and the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of plant-based and natural therapies with menopausal health.

Changes in association between previous therapeutic abortion and preterm birth in Scotland, 1980 to 2008: a historical cohort study.

BACKGROUND: Numerous studies have demonstrated that therapeutic termination of pregnancy (abortion) is associated with an increased risk of subsequent preterm birth. However, the literature is inconsistent, and methods of abortion have changed dramatically over the last 30 years. We hypothesized that the association between previous abortion and the risk of preterm first birth changed in Scotland between 1 January 1980 and 31 December 2008. METHODS AND FINDINGS: We studied linked Scottish national databases of births and perinatal deaths. We analysed the risk of preterm birth in relation to the number of previous abortions in 732,719 first births (≥24 wk), adjusting for maternal characteristics. The risk (adjusted odds ratio [95% CI]) of preterm birth was modelled using logistic regression, and associations were expressed for a one-unit increase in the number of previous abortions. Previous abortion was associated with an increased risk of preterm birth (1.12 [1.09-1.16]). When analysed by year of delivery, the association was strongest in 1980-1983 (1.32 [1.21-1.43]), progressively declined between 1984 and 1999, and was no longer apparent in 2000-2003 (0.98 [0.91-1.05]) or 2004-2008 (1.02 [0.95-1.09]). A statistical test for interaction between previous abortion and year was highly statistically significant (p<0.001). Analysis of data for abortions among nulliparous women in Scotland 1992-2008 demonstrated that the proportion that were surgical without use of cervical pre-treatment decreased from 31% to 0.4%, and that the proportion of medical abortions increased from 18% to 68%. CONCLUSIONS: Previous abortion was a risk factor for spontaneous preterm birth in Scotland in the 1980s and 1990s, but the association progressively weakened and disappeared altogether by 2000. These changes were paralleled by increasing use of medical abortion and cervical pre-treatment prior to surgical abortion. Although it is plausible that the two trends were related, we could not test this directly as the data on the method of prior abortions were not linked to individuals in the cohort. However, we speculate that modernising abortion methods may be an effective long-term strategy to reduce global rates of preterm birth.

Maternal Cardiovascular Disease After Pre-Eclampsia and Gestational Hypertension: A Narrative Review.

Previous literature has highlighted that women who have a pregnancy affected by gestational hypertension or preeclampsia are at higher risk of cardiovascular disease (CVD) in later life. However, CVD is a composite of multiple outcomes, including coronary heart disease, heart failure, and stroke, and the risk of both CVD and hypertensive disorders of pregnancy varies by the population studied. We conducted a narrative review of the risk of cardiovascular outcomes for women with prior gestational hypertension and pre-eclampsia. Previous literature is summarized by country and ethnicity, with a higher risk of CVD and coronary heart disease observed after gestational hypertension and a higher risk of CVD, coronary heart disease and heart failure observed after pre-eclampsia in most of the populations studied. Only one study was identified in a low- or middle-income country, and the majority of studies were conducted in white or mixed ethnicity populations. We discuss potential interventions to mitigate cardiovascular risk for these women in different settings and highlight the need for a greater understanding of the epidemiology of CVD risk after gestational hypertension and pre-eclampsia outside of high-income, white populations.