Identification of potential causal metabolites associated with atopic dermatitis.

Atopic dermatitis is a chronically recurrent dermatologic disease affected by complex pathophysiology with limited therapeutic options. To identify promising biomarkers for atopic dermatitis, we conducted a Mendelian randomization (MR) study to systematically screen blood metabolome for potential causal mediators of atopic dermatitis and further predict target-mediated side effects. We selected 128 unique blood metabolites from three European-descent metabolome genome-wide association studies (GWASs) with a total of 147 827 participants. Atopic dermatitis dataset originated from a large-scale GWAS including 10 788 cases and 30 047 controls of European ancestry. MR analyses were performed to estimate the associations of blood metabolites with atopic dermatitis. We then applied a phenome-wide MR analysis to ascertain potential on-target side effects of metabolite intervention. Three metabolites were identified as potential causal mediators for atopic dermatitis, including docosahexaenoic acid (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.81-0.94; P = 3.45 × 10-4), arachidonate (OR, 0.30; 95% CI, 0.17-0.53; P = 4.09 × 10-5) and 1-arachidonoylglycerophosphoethanolamine (1-arachidonoyl-GPE) (OR, 0.25; 95% CI, 0.12-0.53; P = 2.58 × 10-4). In the phenome-wide MR analysis, docosahexaenoic acid and arachidonate were also identified to have beneficial or detrimental effects on multiple diseases beyond atopic dermatitis, respectively. No adverse side effects were found for 1-arachidonoyl-GPE. In this systematic MR study, docosahexaenoic acid, arachidonate and 1-arachidonoyl-GPE were identified as potential causal and beneficial mediators in the development of atopic dermatitis. Side-effect profiles were characterized to help inform drug target prioritization, and 1-arachidonoyl-GPE was a promising target for prevention and treatment of atopic dermatitis with no predicted adverse side effects.

Genetically Determined Plasma Hepatocyte Growth Factor Levels Are Associated With the Risk and Prognosis of Ischemic Stroke.

BACKGROUND: Observational studies suggest that hepatocyte growth factor (HGF) is associated with the risk and prognosis of ischemic stroke, but the causality of these associations remains unclear. Therefore, we conducted Mendelian randomization (MR) analyses to explore the associations of genetically determined plasma HGF levels with the risk and prognosis of ischemic stroke. METHODS: A total of 13 single-nucleotide polymorphisms associated with plasma HGF were selected as genetic instruments based on the data from a genome-wide association study with 21 758 European participants. Summary data about the risk of ischemic stroke were obtained from the MEGASTROKE (Multiancestry Genome-Wide Association Study of Stroke) Consortium with 34 217 ischemic stroke cases and 406 111 controls of European ancestry, and summary data about the prognosis of ischemic stroke were obtained from the GISCOME study (Genetics of Ischaemic Stroke Functional Outcome) with 6165 European patients with ischemic stroke. We conducted an inverse-variance weighted Mendelian randomization analysis followed by a series of sensitivity analyses to evaluate the associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke. RESULTS: The primary analyses showed that genetically determined high HGF was associated with an increased risk of ischemic stroke (odds ratio per SD increase, 1.11 [95% CI, 1.04-1.19]; P=1.10×10-3) and poor prognosis of ischemic stroke (odds ratio per SD increase, 2.43 [95% CI, 1.76-3.52]; P=6.35×10-8). In the secondary analysis, genetically determined plasma HGF was associated with a high risk of large atherosclerotic stroke (odds ratio per SD increase, 1.39 [95% CI, 1.18-1.63]; P=5.08×10-5) but not small vessel stroke and cardioembolic stroke. Mendelian randomization-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different Mendelian randomization methods further confirmed these findings. CONCLUSIONS: We found positive associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke, suggesting that HGF might be implicated in the occurrence and development of ischemic stroke.

High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment.

BACKGROUND: BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke). METHODS: We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI. RESULTS: In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, APOE ɛ4 carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; P=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (P value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, P=0.001; integrated discrimination index: 1.02%, P=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score. CONCLUSIONS: Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.

Association of Crohn's disease and ulcerative colitis with the risk of neurological diseases: a large-scale Mendelian randomization study.

Observational studies suggested increased risks of Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to assess the causality for the associations of CD and UC with the risks of AD, PD, and MS through a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms associated with CD (17,897 cases and 33,977 controls) and UC (13,768 cases and 33,977 controls) were identified as genetic instruments based on a European-descent genome-wide association study (GWAS) released by the International Inflammatory Bowel Disease Genetics Consortium. Summary statistics for AD (combined: 25,881 cases and 256,837 controls), PD (combined: 35,836 cases and 665,686 controls), and MS (combined: 48,477 cases and 285,515 controls) were obtained from the largest GWASs and FinnGen study of European ancestry, respectively. MR estimates were generated using the inverse-variance weighted method in the main analysis with a series of sensitivity analyses. MR analyses were conducted per outcome database and were subsequently meta-analyzed to generate combined estimates. Genetically predicted UC was significantly associated with increased risks of AD (combined: OR, 1.03; 95% CI, 1.01-1.05; P = 1.80 × 10-3) and MS (combined: OR, 1.37; 95% CI, 1.23-1.53; P = 1.18 × 10-8), while there was no association between genetically predicted UC and the risk of PD. In contrast, no significant associations were observed for genetically predicted CD with AD, PD, and MS. MR-Egger regression showed no directional pleiotropy for the identified associations, and sensitivity analyses with different MR methods further confirmed these findings. This study suggested significant adverse effects of UC on AD and MS, highlighting that UC patients should receive early intervention with optimal adjunctive medical therapy to reduce the risks of AD and MS.

The bidirectional association between frailty index and cardiovascular disease: A Mendelian randomization study.

BACKGROUND AND AIM: Observational studies have suggested a relationship between frailty and cardiovascular disease (CVD), but the causality is still uncertain. We used bidirectional Mendelian randomization (MR) design to investigate the potential causal associations between frailty and four main CVDs, including hypertension, myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Independent single-nucleotide polymorphisms for frailty index (FI) and CVDs (hypertension, MI, HF, and AF) were selected as genetic instruments based on European-descent genome-wide association studies (GWASs). Summary-level data for outcomes on FI (n = 175,226), hypertension (n = 463,010), MI (n = 171,875), HF (n = 977323), and AF (n = 1,030,836) was derived from five large-scale GWASs of European ancestry. We used the inverse-variance weighted (IVW) method to examine the bidirectional associations between FI and CVDs in the main analyses. In the IVW MR analyses, genetically determined high FI was significantly associated with increased risks of hypertension (odds ratio [OR] per 1-SD increase: 1.07 [95 % confidence interval, 1.05-1.08]), MI (OR per 1-SD increase: 1.74 [1.21-2.51]), HF (OR per 1-SD increase: 1.28 [1.10-1.48]), and AF (OR per 1-SD increase: 1.20 [1.08-1.33]). In addition, genetically determined hypertension (beta: 1.406 [1.225-1.587]), MI (beta: 0.045 [0.023-0.067]), HF (beta: 0.105 [0.066-0.143]) and AF (beta: 0.021 [0.012-0.031]) were significantly associated with high FI. These findings were robustly supported by a series of sensitivity analyses with different MR models. CONCLUSIONS: We found potential bidirectional causal associations between elevated FI and increased risks of CVD, suggesting mutual risk factors between frailty and CVD.

Osteoprotegerin and Ischemic Stroke Prognosis: A Prospective Multicenter Study and Mendelian Randomization Analysis.

BACKGROUND: Osteoprotegerin was implicated in vascular injury and inflammatory responses, but its prognostic value in ischemic stroke remained unclear. We aimed to prospectively investigate the association between plasma osteoprotegerin and ischemic stroke prognosis combined with a Mendelian randomization analysis. METHODS: Our prospective study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline. We measured baseline plasma osteoprotegerin levels for 3490 ischemic stroke patients recruited between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was a composite outcome of death and major disability at 3 months after ischemic stroke. RESULTS: After adjustment for age, sex, admission National Institutes of Health Stroke Scale score, and other important covariates, elevated osteoprotegerin levels were associated with increased risks of primary outcome (odds ratio, 1.40 [95% CI, 1.05-1.88]), death (hazard ratio, 2.05 [95% CI, 1.04-4.08]), and composite outcome of death and vascular events (hazard ratio, 2.00 [95% CI, 1.15-3.48]) when 2 extreme quartiles were compared. Each 1-SD higher log-osteoprotegerin was associated with a 18% (95% CI, 6%-32%) increased risk of primary outcome, 69% (95% CI, 31%-118%) increased risk of death, and 53% (95% CI, 24%-89%) increased risk of composite outcome of death and vascular events, respectively. Multiple-adjusted spline regression model showed a linear association of osteoprotegerin with primary outcome (P for linearity <0.001). Adding osteoprotegerin to conventional risk factors did not significantly improve discriminatory power (C statistics, 0.817 versus 0.818; P=0.232) but did slightly improve the risk reclassification of primary outcome (net reclassification improvement: 13.68%, P<0.001; integrated discrimination improvement: 0.23%, P=0.039). In Mendelian randomization analysis, genetically determined high plasma osteoprotegerin was associated with increased risk of primary outcome (odds ratio, 5.74 [95% CI, 1.12-29.44]; P=0.036). CONCLUSIONS: Elevated plasma osteoprotegerin was associated with poor prognosis of ischemic stroke, and genetically determined high plasma osteoprotegerin was associated with an increased risk of primary outcome in Mendelian randomization analysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01840072.

High Serum Brain-Derived Neurotrophic Factor Is Associated With Decreased Risks of Poor Prognosis After Ischemic Stroke.

BACKGROUND: BDNF (brain-derived neurotrophic factor) has been implicated in cardiovascular homeostasis and ischemic stroke pathogenesis. We aimed to prospectively investigate the associations between serum BDNF levels and the prognosis of ischemic stroke in a multicenter cohort study. METHODS: This prospective study follows the STROBE reporting guideline. Serum BDNF concentrations were measured in 3319 ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was the composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Multivariate logistic regression or Cox proportional hazards regression analysis was used to assess the associations between serum BDNF levels and adverse clinical outcomes. RESULTS: During the 3-month follow-up period, 827 (24.92%) patients experienced a primary outcome, including 734 major disabilities and 93 deaths. After adjusting for age, sex, and other important prognostic factors, elevated serum BDNF levels were associated with decreased risks of primary outcome (odds ratio, 0.73 [95% CI, 0.58-0.93]), major disability (odds ratio, 0.78 [95% CI, 0.62-0.99]), death (hazard ratio, 0.55 [95% CI, 0.32-0.97]), and the composite outcome of death and vascular events (hazard ratio, 0.61 [95% CI, 0.40-0.93]) when 2 extreme tertiles were compared. Multivariable-adjusted spline regression analyses showed a linear association between serum BDNF levels and the primary outcome (P value for linearity=0.005). The addition of BDNF to conventional risk factors slightly improved reclassification for the primary outcome (net reclassification improvement: 19.33%; P<0.001; integrated discrimination index: 0.24%; P=0.011). CONCLUSIONS: Elevated serum BDNF concentrations were independently associated with decreased risks of adverse outcomes after ischemic stroke, suggesting that serum BDNF may be a potential biomarker for prognosis after ischemic stroke. Further studies are warranted to investigate the potential therapeutic benefit of BDNF for ischemic stroke.

Association between human blood metabolome and the risk of breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women with limited treatment options. To identify promising drug targets for breast cancer, we conducted a systematical Mendelian randomization (MR) study to screen blood metabolome for potential causal mediators of breast cancer and further predict target-mediated side effects. METHODS: We selected 112 unique blood metabolites from 3 large-scale European ancestry-based genome-wide association studies (GWASs) with a total of 147,827 participants. Breast cancer data were obtained from a GWAS in the Breast Cancer Association Consortium (BCAC), involving 122,977 cases and 105,974 controls of European ancestry. We conducted MR analyses to systematically assess the associations of blood metabolites with breast cancer, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions. RESULTS: Two blood metabolites were identified as the potential causal mediators for breast cancer, including high-density lipoprotein cholesterol (HDL-C) (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.06-1.12; P = 9.67 × 10-10) and acetate (OR, 1.24; 95% CI, 1.13-1.37; P = 1.35 × 10-5). In the phenome-wide MR analysis, lowering HDL-C might have deleterious effects on the risk of the circulatory system and foreign body injury, while lowering acetate had deleterious effects on mental disorders disease. CONCLUSIONS: The present systematic MR analysis revealed that HDL-C and acetate may be the causal mediators in the risk of developing breast cancer. Side-effect profiles were characterized to help inform drug target prioritization for breast cancer prevention. HDL-C and acetate might be promising drug targets for preventing breast cancer, but they should be applied under weighting advantages and disadvantages.

Association between Human Blood Metabolome and the Risk of Alzheimer's Disease.

OBJECTIVE: Alzheimer's disease (AD) is the most common degenerative neurological disorder with limited therapeutic options. Therefore, it is particularly important to explore the potential biomarkers implicated in the occurrence and progression of AD prior to clinical testing. METHODS: We selected 119 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with 147,827 European participants. Summary data about AD were obtained from a GWAS meta-analysis with 63,926 European individuals from the International Genomics of Alzheimer's Project. MR analyses were performed to assess the associations of blood metabolites with AD, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions. RESULTS: Four metabolites were identified as causal mediators for AD, including epiandrosterone sulfate (odds ratio [OR] per SD increase: 0.60; 95% confidence interval [CI]: 0.51-0.71; p = 6.14 × 10-9 ), 5alpha-androstan-3beta-17beta-diol disulfate (OR per SD increase: 0.69; 95% CI: 0.57-0.84; p = 1.98 × 10-4 ), sphingomyelin (OR per SD increase: 2.53; 95% CI: 1.78-3.59; p = 2.10 × 10-7 ), and glutamine (OR per SD increase: 0.83; 95% CI: 0.77-0.89; p = 2.09 × 10-6 ). Phenome-wide MR analysis showed that epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate and sphingomyelin mediated the risk of multiple diseases, and glutamine had beneficial effects on the risk of 4 diseases. INTERPRETATION: Genetically predicted increased epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate, and glutamine might be associated with a decreased risk of AD, while sphingomyelin was associated with an increased risk. Side-effect profiles were characterized to help inform drug target prioritization, and glutamine might be a promising target for the prevention and treatment of AD with no predicted detrimental side effects. ANN NEUROL 2022;92:756-767.

Plasma homeostatic chemokines CCL19 and CCL21 and the prognosis of ischemic stroke in two Chinese prospective cohorts.

BACKGROUND: The homeostatic chemokines CCL19 and CCL21 are involved in carotid plaque vulnerability and post-ischemic neuroinflammatory responses. This study aimed to examine the prognostic values of CCL19 and CCL21 in ischemic stroke. METHODS: Plasma CCL19 and CCL21 were measured in 4483 ischemic stroke patients from two independent cohorts of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) and IIPAIS (Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke), and participants were followed up at 3 months after stroke. The primary outcome was the composite outcome of death or major disability. The associations of CCL19 and CCL21 levels with the primary outcome were examined. RESULTS: In CATIS, multivariable-adjusted odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 compared with the lowest quartiles were 2.06 and 2.62, respectively. In IIPAIS, odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 were 2.81 and 2.78 compared with the lowest quartiles, respectively. In the pooled analysis of the two cohorts, odds ratios of the primary outcome associated with the highest quartiles of CCL19 and CCL21 were 2.24 and 2.66, respectively. Similar findings were observed in the analysis with major disability, death, and the composite outcome of death or cardiovascular events as the secondary study outcomes. Adding CCL19 and CCL21 to conventional risk factors significantly improved risk reclassification and discrimination for adverse outcomes. CONCLUSIONS: Both CCL19 and CCL21 levels were independently associated with adverse outcomes within 3 months after ischemic stroke and should be further investigated for risk stratification and potential therapeutic targets of ischemic stroke.

Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study.

BACKGROUND: Experimental studies suggested that intercellular adhesion molecule 4 (ICAM-4) might be implicated in ischemic stroke, but the population-based evidence on the relationship between ICAM-4 and ischemic stroke were limited. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and its subtypes. METHODS: A total of 11 single-nucleotide polymorphisms associated with ICAM-4 were selected as instrumental variables based on the genome-wide association studies (GWAS) with 3,301 European individuals. Summary-level data about ischemic stroke and its subtypes were obtained from the Multi-ancestry GWAS launched by the International Stroke Genetics Consortium. We used the inverse-variance weighted method followed by a series of sensitivity analyses to evaluate the associations of genetically determined ICAM-4 with the risks of ischemic stroke and its subtypes. RESULTS: Genetically determined higher ICAM-4 levels were significantly associated with increased risks of ischemic stroke (in the IVW method fitted to multiplicative random effects model: odds ratio [OR] per standard deviation [SD] increase, 1.04; 95% confidence interval [CI], 1.01-1.07; P = 0.006; in the IVW analysis with fixed effects model: OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.003) and cardioembolic stroke (in multiplicative random effects model: OR per SD increase, 1.08; 95% CI, 1.02-1.14; P = 0.004; in fixed effects model: OR per SD increase, 1.08; 95% CI, 1.03-1.13; P = 0.003). There was no association of ICAM-4 with the risks of large artery stroke and small vessel stroke. MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different MR methods further confirmed these findings. CONCLUSIONS: We found positive associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and cardioembolic stroke. Future studies are needed to explore the detailed mechanism and investigate the targeting effect of ICAM-4 on ischemic stroke.

Association between myeloperoxidase and the risks of ischemic stroke, heart failure, and atrial fibrillation: A Mendelian randomization study.

BACKGROUND AND AIMS: The causality between myeloperoxidase (MPO) and cardiovascular disease still remains unclear. We performed a two-sample Mendelian randomization (MR) study to estimate the potential causal effect of MPO on the risks of ischemic stroke, ischemic stroke subtypes, heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Seventeen independent single-nucleotide polymorphisms associated with MPO levels were identified as instrumental variables from a European-descent genome-wide association study. Summary-level data on ischemic stroke originated from the Multiancestry Genome-wide Association Study of Stroke Consortium with 440 328 European individuals. We used the inverse-variance weighted method to assess the potential causality of plasma MPO with ischemic stroke and its subtypes in the main analysis. Genetically determined higher plasma MPO concentration was significantly associated with increased risks of ischemic stroke (odds ratio [OR] per standard deviation [SD] increase, 1.05; 95% confidence interval [CI], 1.02-1.09; P = 0.002) and cardioembolic stroke (CES) (OR per SD increase, 1.10; 95% CI, 1.03-1.18; P = 0.005), but was not associated with risks of large artery stroke or small vessel stroke. In the secondary analysis, MPO was associated with a high risk of HF (OR per SD increase, 1.05; 95% CI, 1.02-1.07; P = 0.001) and AF (OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.004). MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses further confirmed these findings. CONCLUSION: High plasma MPO levels were potentially associated with increased risks of ischemic stroke, CES, HF, and AF, suggesting that MPO plays an important role in the development of cardiovascular disease.

Associations of genetically proxied inhibition of HMG-CoA reductase, NPC1L1, and PCSK9 with breast cancer and prostate cancer.

BACKGROUND: Preclinical and epidemiological studies indicate a potential chemopreventive role of low-density lipoprotein cholesterol (LDL-C) -lowering drugs in the risks of breast cancer and prostate cancer, but the causality remains unclear. We aimed to evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Niemann-Pick C1-Like 1 (NPC1L1), and proprotein convertase subtilisin/kexin type 9 (PCSK9) with risks of breast cancer and prostate cancer using a two-sample Mendelian randomization (MR) method. METHODS: Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with LDL-C in a genome-wide association study (GWAS) meta-analysis from the Global Lipids Genetics Consortium (GLGC; up to 188,577 European individuals) were used to proxy inhibition of HMG-CoA reductase, NPC1L1, and PCSK9. Summary statistics with outcomes were obtained from a GWAS meta-analysis of the Breast Cancer Association Consortium (BCAC; 228,951 European females) and a Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL; 140,254 European males) consortium. SNPs were combined into multiallelic models and MR estimates representing lifelong inhibition of targets were generated using the inverse-variance weighted method. RESULTS: Genetically proxied inhibition of HMG-CoA reductase (OR: 0.84; 95% CI 0.74-0.95; P = 0.005) and NPC1L1 (OR: 0.72; 95% CI 0.58-0.90; P = 0.005) equivalent to a 1-mmol/L (38.7 mg/dL) reduction in LDL-C was associated with reduced breast cancer risk. There were no significant associations of genetically proxied inhibition of PCSK9 with breast cancer. In contrast, genetically proxied inhibition of PCSK9 (OR: 0.81; 95% CI 0.73-0.90; P < 0.001) but not HMG-CoA reductase and NPC1L1 was negatively associated with prostate cancer. In the secondary analysis, genetically proxied inhibition of HMG-CoA reductase (OR: 0.82; 95% CI 0.71-0.95; P = 0.008) and NPC1L1 (OR: 0.66; 95% CI 0.50-0.86; P = 0.002) was associated with estrogen receptor-positive breast cancer, whereas there was no association of HMG-CoA reductase and NPC1L1 with estrogen receptor-negative breast cancer. CONCLUSIONS: Genetically proxied inhibition of HMG-CoA reductase and NPC1L1 was significantly associated with lower odds of breast cancer, while genetically proxied inhibition of PCSK9 was associated with reduced risk of prostate cancer. Further randomized controlled trials are needed to confirm the respective roles of these LDL-C-lowering drugs in breast cancer and prostate cancer.

Association of serum growth differentiation factor-15 levels with the risks of death and vascular events in patients with ischemic stroke: The role of diabetes.

BACKGROUND AND AIMS: Researchers have not determined whether the association between growth differentiation factor-15 (GDF-15) levels and stroke outcomes is modified by the diabetes status. We aimed to evaluate the prognostic value of GDF-15 among patients with ischemic stroke stratified by diabetes. METHODS AND RESULTS: A total of 3001 patients with ischemic stroke were selected from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and included in this study. The primary outcome was a composite outcome of death and vascular events at 3 months after acute ischemic stroke. An elevated GDF-15 level was significantly associated with the primary outcome in patients with diabetes but not in those without diabetes (pinteraction = 0.038). The multivariate-adjusted hazard ratio (95% confidence intervals) for the primary outcome was 3.33 (1.07-10.35) when 2 extreme tertiles were compared, and a linear association between GDF-15 levels and the primary outcome was observed in patients with diabetes (p for linearity = 0.046). The addition of serum GDF-15 to conventional risk factors improved the risk prediction for the primary outcome in patients with diabetes (net reclassification improvement: 31.98%, p = 0.043; integrated discrimination index: 0.85%, p = 0.034) but not in those without diabetes. CONCLUSIONS: A modifying effect of the diabetes status on the association between serum GDF-15 levels and ischemic stroke prognosis was observed. Elevated serum GDF-15 levels were associated with the primary outcome within 3 months after ischemic stroke in patients with diabetes, suggesting that GDF-15 may be an important prognostic factor for ischemic stroke in patients with diabetes.

Contribution of metabolic risk factors and lifestyle behaviors to cardiovascular disease: A mendelian randomization study.

BACKGROUND AND AIMS: Etiologic associations between some modifiable factors (metabolic risk factors and lifestyle behaviors) and cardiovascular disease (CVD) remain unclear. To identify targets for CVD prevention, we evaluated the causal associations of these factors with coronary artery disease (CAD) and ischemic stroke using a two-sample Mendelian randomization (MR) method. METHODS AND RESULTS: Previously published genome-wide association studies (GWASs) for blood pressure (BP), glucose, lipids, overweight, smoking, alcohol intake, sedentariness, and education were used to identify instruments for 15 modifiable factors. We extracted effects of the genetic variants used as instruments for the exposures on coronary artery disease (CAD) and ischemic stroke from large GWASs (N = 60 801 cases/123 504 controls for CAD and N = 40 585 cases/406 111 controls for ischemic stroke). Genetically predicted hypertension (CAD: OR, 5.19 [95% CI, 4.21-6.41]; ischemic stroke: OR, 4.92 [4.12-5.86]), systolic BP (CAD: OR, 1.03 [1.03-1.04]; ischemic stroke: OR, 1.03 [1.03-1.03]), diastolic BP (CAD: OR, 1.05 [1.05-1.06]; ischemic stroke: OR, 1.05 [1.04-1.05]), type 2 diabetes (CAD: OR, 1.11 [1.08-1.15]; ischemic stroke: OR, 1.07 [1.04-1.10]), smoking initiation (CAD: OR, 1.26 [1.18-1.35]; ischemic stroke: OR, 1.24 [1.16-1.33]), educational attainment (CAD: OR, 0.62 [0.58-0.66]; ischemic stroke: OR, 0.68 [0.63-0.72]), low-density lipoprotein cholesterol (CAD: OR, 1.55 [1.41-1.71]), high-density lipoprotein cholesterol (CAD: OR, 0.82 [0.74-0.91]), triglycerides (CAD: OR, 1.29 [1.14-1.45]), body mass index (CAD: OR, 1.25 [1.19-1.32]), and alcohol dependence (OR, 1.04 [1.03-1.06]) were causally related to CVD. CONCLUSION: This systematic MR study identified 11 modifiable factors as causal risk factors for CVD, indicating that these factors are important targets for preventing CVD.

Increased Serum Complement C3 Levels Are Associated With Adverse Clinical Outcomes After Ischemic Stroke.

BACKGROUND AND PURPOSE: Complement C3 has been implicated in inflammation and ischemia/reperfusion injury, but its impact on the prognosis of ischemic stroke remains unclear. Aim of this study was to prospectively investigate the association between serum complement C3 and adverse clinical outcomes after ischemic stroke. METHODS: We measured serum complement C3 levels for 3474 patients with ischemic stroke in 26 participating hospitals and collected data of clinical outcomes at 3 months after ischemic stroke. The primary outcome was composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset and secondary outcomes included major disability, death, and vascular events. RESULTS: During 3 months of follow-up, 866 participants (25.4%) developed primary outcome. After multivariate adjustment, elevated serum complement C3 levels were associated with increased risk of primary outcome (odds ratio, 1.30 [95% CI, 1.02-1.65]; Ptrend=0.038) when 2 extreme tertiles were compared. Each SD increase of log-transformed complement C3 was associated with 13% (95% CI, 2%-25%) increased risk of primary outcome. Multivariable-adjusted spline regression model showed a linear relationship between serum complement C3 and the risk of primary outcome (Plinearity=0.022). Addition of serum complement C3 to conventional risk factors significantly improved the risk prediction of primary outcome (net reclassification index: 8.87%, P=0.028; integrated discrimination index: 0.19%, P=0.029). CONCLUSIONS: High serum complement C3 levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that serum complement C3 may be a valuable prognostic biomarker for ischemic stroke.

Causal associations of serum matrix metalloproteinase-8 level with ischaemic stroke and ischaemic stroke subtypes: a Mendelian randomization study.

BACKGROUND AND PURPOSE: Elevated serum matrix metalloproteinase-8 (MMP-8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two-sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP-8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease. METHODS: Ten independent single-nucleotide polymorphisms related to serum MMP-8 concentrations were identified as instrumental variables from a genome-wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome-wide Association Study of Stroke consortium with 446,696 European individuals. The inverse-variance weighted method was applied to assess the causal associations of serum MMP-8 with ischaemic stroke and its subtypes in the main analysis. RESULTS: No significant causal association was observed for MMP-8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 - unit higher log-transformed serum MMP-8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12-1.39; p < 0.001). In secondary analysis, a similar adverse impact was reported for MMP-8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01-1.10; p = 0.017). Sensitivity analyses further confirmed the relationship between serum MMP-8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias. CONCLUSIONS: High serum MMP-8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP-8 on the vascular system requires further investigation.

Association between serum netrin-1 and prognosis of ischemic stroke: The role of lipid component levels.

BACKGROUND AND AIMS: High serum netrin-1 levels decrease the risk of ischemic stroke and are negatively associated with outcomes after ischemic stroke. However, it remains unclear whether the association between netrin-1 and ischemic stroke prognosis is modified by lipid component levels. METHODS AND RESULTS: We measured baseline serum netrin-1 levels in 3065 ischemic stroke patients from China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 3 months after ischemic stroke. Total cholesterol (TC) levels could modify the association between netrin-1 and prognosis of ischemic stroke (Pinteraction = 0.040). After multivariate adjustment, the odds ratios of the primary outcome associated with the highest quartile of netrin-1 were 0.39 (95%CI, 0.17-0.90; Ptrend = 0.004) for the patients with high TC levels and 0.82 (95%CI, 0.61-1.11; Ptrend = 0.149) for those with normal TC levels. Adding netrin-1 to conventional risk factors improved risk prediction for the primary outcome in the patients with high TC levels (net reclassification improvement: 26.8%, P = 0.015; integrated discrimination index: 1.6%, P = 0.028) but not in those with normal TC levels. CONCLUSIONS: Elevated netrin-1 is associated with improved prognosis at 3 months after ischemic stroke in the patients with high TC levels but not in those with normal TC levels. Further prospective studies from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

Association of Cardiac Biomarkers in Combination With Cognitive Impairment After Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment is a severe and common clinical complication that constitutes a substantial global health burden. We aimed to evaluate the association of 3 cardiac biomarkers in combination with poststroke cognitive impairment and their prognostic significance. METHODS AND RESULTS: This prospective study included 566 patients with ischemic stroke. Cardiac biomarkers, including sST2 (soluble suppression of tumorigenicity-2 receptor), GDF-15 (growth differentiation factor-15), and NT-proBNP (N-terminal pro-B-type natriuretic peptide), were measured. Cognitive impairment was defined as a Mini-Mental State Examination score of <27 or a Montreal Cognitive Assessment score of <25 at 3 months after ischemic stroke. Odds of cognitive impairment 3 months after ischemic stroke increased with the number of elevated cardiac biomarkers (sST2, GDF-15, and NT-proBNP; Ptrend<0.001). The multivariable adjusted odds ratios (95% CIs) of cognitive impairment defined by the Mini-Mental State Examination and Montreal Cognitive Assessment were 2.45 (1.48-4.07) and 1.86 (1.10-3.14) for the participants with ≥2 elevated cardiac biomarkers, respectively, compared with those without any elevated cardiac biomarker. Additionally, higher cardiac biomarker scores were associated with an increased risk of cognitive impairment (Ptrend<0.05). Simultaneously adding all 3 cardiac biomarkers to the basic model with traditional risk factors significantly improved the risk prediction of Mini-Mental State Examination-defined cognitive impairment (net reclassification improvement=34.99%, P<0.001; integrated discrimination index=2.67%, P<0.001). Similar findings were observed using the Montreal Cognitive Assessment scores. CONCLUSIONS: An increased number of elevated novel cardiac biomarkers were associated with an increased odds of poststroke cognitive impairment, suggesting that a combination of these cardiac biomarkers may improve the risk prediction of cognitive impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Antiphospholipid Antibodies Modify the Prognostic Value of Baseline Platelet Count for Clinical Outcomes After Ischemic Stroke.

BACKGROUND: Antiphospholipid antibodies (aPLs) have been reported to be involved in platelet-mediated thrombosis and inflammation, but the impact on the prognosis of ischemic stroke remains unclear. We aimed to examine whether the association between baseline platelet count (PLT) and long-term clinical outcomes within 2 years after ischemic stroke onset is modulated by aPLs. METHODS AND RESULTS: A total of 2938 patients with ischemic stroke were included in this prospective cohort study. Cox proportional hazards regression models were used to assess the association between the baseline PLT stratified by aPLs status and 2-year clinical outcomes after stroke onset, and an interaction effect between PLT and aPLs on clinical outcomes was tested by likelihood ratio test. There was a significant interaction effect of aPLs and PLT on recurrent stroke (Pinteraction=0.002) and cardiovascular events (Pinteraction=0.001) within 2 years after stroke onset. After multivariate adjustment, high PLT was associated with increased risks of recurrent stroke (hazard ratio [HR], 2.78 [95% CI, 1.03-7.45]; Ptrend=0.039) and cardiovascular events (HR, 2.58 [95% CI, 1.12-5.90]; Ptrend=0.024) when 2 extreme tertiles were compared among patients with aPL positive, but not among those with aPL negative. CONCLUSIONS: The aPLs had a modifying effect on the association between PLT and clinical outcomes within 2 years after ischemic stroke onset. Increased PLT was associated with recurrent stroke and cardiovascular events after ischemic stroke onset among patients with aPL positive, but not in those with aPL negative.