Identifying novel proteins for migraine by integrating proteomes from blood and CSF with genome-wide association data.

BACKGROUND: Proteome-wide Mendelian randomization studies have been increasingly utilized to identify potential drug targets for diseases. We aimed to identify potential therapeutic targets for migraine and its subtypes through the application of Mendelian randomization and co-localization analysis methods. METHODS: We utilized cis-protein quantitative trait loci data for 1378 plasma proteins available from two studies with 7213 individuals and 35,559 individuals, respectively. Summary data for migraine and its subtypes were obtained from a genetic study involving up to 1,339,303 individuals. Proteins that passed both the discovery and validation Mendelian randomization analysis, sensitivity analysis, heterogeneity test, and pleiotropy test, were associated with ≥2 outcomes, and received strong support from co-localization analysis (PP.H4.abf ≥0.80) and were classified as tier 1 proteins. RESULTS: We identified three tier 1 proteins (LRP11, ITIH1, and ADGRF5), whose genes have not been previously identified as causal genes for migraine in genetic studies. LRP11 was significantly associated with the risk of any migraine (OR [odds ratio] = 0.968, 95% CI [confidence interval] = 0.955-0.981, p = 1.27 × 10-6) and significantly/suggestively associated with three migraine subtypes. ITIH1 was significantly associated with the risk of any migraine (OR = 1.044, 95% CI = 1.024-1.065, p = 1.08 × 10-5) and migraine with visual disturbances. ADGRF5 was significantly associated with the risk of any migraine (OR = 0.964, 95% CI = 0.946-0.982, p = 8.74 × 10-5) and suggestively associated with migraine with aura. The effects of LRP11 and ADGRF5 were further replicated using cerebrospinal fluid protein data. Apart from ADGRF5, there was no evidence of potential adverse consequences when modulating the plasma levels. We also identified another four proteins (PLCG1, ARHGAP25, CHGA, and MANBA) with no potential adverse consequences when modulating the plasma levels, and their genes were not reported by previous genetic studies. CONCLUSIONS: We found compelling evidence for two proteins and suggestive evidence for four proteins that could be promising targets for migraine treatment without significant adverse consequences. The corresponding genes were not reported in previous genetic studies. Future studies are needed to confirm the causal role of these proteins and explore the underlying mechanisms.

Association between egg consumption and mortality risk in United States adults with established coronary heart disease or stroke: A cohort study using data from NHANES 1999-2018.

BACKGROUND: To investigate the relationship between egg consumption and mortality in individuals with pre-existing coronary heart disease or stroke. METHODS: This study utilized data from the National Health and Nutrition Examination Survey conducted between 1999 and 2018. Egg consumption was evaluated through 24 h dietary recalls at baseline. Mortality status was tracked until December 31, 2019. Survey-weighted Cox proportional hazards models were utilized. RESULTS: The study involved 3,975 participants aged 20 years or older with a median follow-up of 89.00 months. A total of 1,675 individuals died during follow-up. Compared to individuals who did not consume eggs, the consumption of 0-50 g/day (hazard ratio [HR] = 1.033, 95% confidence interval [CI] =0.878-1.214) was not found to have a significant association with all-cause mortality. However, consuming 50-100 g/day (HR = 1.281, 95% CI = 1.004-1.635) and >100 g/day (HR = 1.312, 95% CI =1.036-1.661) exhibited a significant association with an increased risk of all-cause mortality. We identified a non-liner relationship between egg consumption and cardiovascular mortality, where the risk was found to be lowest at an intake of about 50 g/day. For individuals consuming more than 50 g/day, each additional 50 g increment in egg consumption was significantly linked to an elevated risk of cardiovascular mortality (HR = 1.276, 95% CI = 1.009-1.614). CONCLUSION: In U.S. adults with pre-existing cardiovascular disease, a significant positive association was found between consuming over 50 g of eggs per day and the risk of mortality, highlighting the importance of moderate intake.

Association between migraine and venous thromboembolism: a Mendelian randomization and genetic correlation study.

Objective: Previous observational studies have reported an increased risk of venous thromboembolism (VTE) among individuals with migraine. This study aimed to investigate the causal effect of migraine on the development of VTE, as well as explore the genetic correlation between them. Methods: We conducted a two-sample Mendelian randomization (MR) study using publicly available summary statistics from large-scale genome-wide association studies for migraine and VTE. Linkage disequilibrium score regression analysis was performed to estimate the genetic correlation between migraine and VTE. Results: There were several shared risk variants (p-value < 5 × 10-8) between migraine and VTE. Linkage disequilibrium score regression analysis found a significant positive genetic correlation between migraine and VTE. The genetic correlations based on two migraine datasets were 0.208 (se = 0.031, p-value = 2.91 × 10-11) and 0.264 (se = 0.040, p-value = 4.82 × 10-11), respectively. Although main MR analysis showed that migraine was associated with an increased risk of VTE (odds ratio = 1.069, 95% confidence interval = 1.022-1.118, p-value = 0.004), the association attenuated to non-significance when using several other MR methods and using another set of genetic instruments. In addition, evidence of heterogeneity was found. Reverse MR analysis showed VTE was associated with increased risk of migraine with aura (odds ratio = 1.137, 95% confidence interval = 1.062-1.218, p-value = 2.47 × 10-4) with no evidence of pleiotropy and heterogeneity. Conclusion: We showed suggestive evidence indicating an association between migraine and increased risk of VTE. Additionally, we found robust evidence suggesting that VTE is associated with an increased risk of migraine. The positive genetic correlation indicates that migraine and VTE has shared genetic basis. Further investigations will be necessary to address potential sex-specific effects in the analysis.

Higher Circulating Vitamin D Levels Are Associated With Decreased Migraine Risk: A Mendelian Randomization Study.

Background: Evidence showed the supplementation of vitamin D might have beneficial effects for migraine patients. We aimed to investigate the causal effects of serum vitamin D levels on migraine risk using two-sample Mendelian randomization (MR) method. Methods: A total of 184 independent genetic instruments for serum vitamin D levels were selected from a study in 417,580 Europeans from UK biobank. Six variants from an independent study were obtained to perform replication analysis. Summary-level data for migraine were obtained from three studies with 48,975 migraine cases, 28,852 migraine cases and 10,536 migraine cases, respectively. Results: The estimated odds ratios (ORs) per standard deviation increase in circulating vitamin D levels based on the three migraine datasets were 0.948 (95% CI = 0.883-1.016, p = 0.133), 0.902 (95% confidence intervals [CI] = 0.825-0.986, p = 0.023), and 0.880 (95% CI = 0.786-0.984, p = 0.025), respectively. Using pooled migraine summary data with no sample overlap, MR analysis showed per standard deviation increase in circulating vitamin D levels was significantly associated with a decreased migraine risk (OR = 0.916, 95% CI = 0.859-0.977, p = 0.008). Multivariable MR analyses, sensitivity analyses and replication analysis confirmed the association. MR analyses showed similar estimates for migraine with aura and migraine without aura but with wider 95% CIs. Mediation analysis showed the effect of vitamin D on migraine risk via pathway of serum calcium was corresponding to an OR of 1.003 (95% CI = 1.001-1.005) and a proportion mediated of 3.42%. The reverse MR analysis showed migraine might not affect vitamin D levels. Conclusion: This two-sample MR study showed genetically determined increased circulating vitamin D levels are associated with decreased migraine risk. The effect seems consistent across different migraine subtypes. In addition, the role of serum calcium in mediating the association between vitamin D and migraine is negligible. Future large well-designed randomized trials are warranted to assess the effects of vitamin D supplementation for migraine patients, especially in those with vitamin D deficiency.

Circulating Insulin-Like Growth Factor 1 Levels and Migraine Risk: A Mendelian Randomization Study.

INTRODUCTION: Preclinical studies have indicated insulin-like growth factor 1 (IGF1) as a novel therapeutic target in the treatment of migraines. We aimed to investigate the causal effect of circulating IGF1 levels on migraine risk using the two-sample Mendelian randomization method. METHODS: A total of 431 independent variants from 363,228 unrelated individuals in the UK Biobank were used as genetic instruments for circulating IGF1 levels. Summary-level data for migraines were obtained from two independent studies with 10,536 and 28,852 migraine cases, respectively. RESULTS: Mendelian randomization using inverse-variance weighting showed that increased IGF1 levels were significantly associated with decreased risk of migraines in both outcome datasets (odds ratio 0.905, 95% confidence interval 0.842-0.972, p = 0.006; odds ratio 0.929, 95% confidence interval 0.882-0.979, p = 0.006). Although some other robust Mendelian randomization methods did not demonstrate a significant association, no unbalanced horizontal pleiotropy was found by Mendelian randomization-Egger regression (p values for horizontal pleiotropy 0.232 and 0.435). The effect was confirmed in additional analyses including multivariable Mendelian randomization analyses. CONCLUSION: This two-sample Mendelian randomization study showed that genetically determined increased IGF1 levels are causally associated with decreased migraine risk. Future randomized controlled trials are warranted to confirm the benefits of IGF1 administration on migraines.

Maternal Testosterone and Offspring Birth Weight: A Mendelian Randomization Study.

CONTEXT: Evidence has shown maternal androgen levels in both the general population and populations with hyperandrogenic disorders are inversely associated with offspring birth weight. CONTEXT: We aimed to investigate the causal effect of maternal testosterone levels in the general population on offspring birth weight and preterm delivery risk using a two-sample Mendelian randomization (MR) method. METHODS: We obtained independent genetic instruments from a sex-specific genome-wide association study with up to 230 454 females of European descent from the UK Biobank. Genetic instruments with consistent testosterone effects but no aggregate effect on sex hormone-binding globulin were used to perform the main analysis. Summary-level data of offspring birth weight adjusted for genotype were obtained from a study with 210 406 females of European descent. Summary-level data of preterm delivery were obtained from the FinnGen study (6736 cases and 116 219 controls). RESULTS: MR analysis showed that each SD (0.62 nmol/L) increase in testosterone levels could reduce the offspring birth weight by 37.26 g (95% CI, 19.59-54.94 g; P = 3.62 × 10-5). Each SD increase in testosterone levels was also associated with an increased risk of preterm delivery (odds ratio = 1.329; 95% CI, 1.161-1.520; P = 3.57 × 10-5). Similar results were found using different MR methods and multivariable MR analyses. CONCLUSION: This two-sample MR study showed genetically determined higher circulating testosterone levels in females from the general population were associated with low birth weight of offspring and increased risk of preterm delivery.

Higher Coffee Consumption Is Associated With Reduced Cerebral Gray Matter Volume: A Mendelian Randomization Study.

Background: Recently published two-sample Mendelian randomization (MR) studies showed that genetically predicted coffee consumption may be associated with increased risk of Alzheimer's disease and intracerebral hemorrhage but associated with a decreased risk of small vessel ischemic stroke. We aimed to investigate the effects of genetically predicted coffee consumption on magnetic resonance imaging (MRI) markers of cerebral small vessel disease and brain volume using the two-sample MR method. Methods: Twelve single nucleotide polymorphisms (SNPs) in up to 375,833 individuals were used as genetic instruments for cups consumed per day of coffee. Another four SNPs from an independent sample were used to perform the replication analysis. Three SNPs in up to 45,821 individuals were used as genetic instruments for high coffee consumption vs. low/no coffee consumption. Results: Mendelian randomization analysis showed that coffee consumption (cups/day) was inversely associated with gray matter volume (beta = -0.371, 95% CI = -0.596 to -0.147, p = 0.001). Replication analysis and multivariable analyses after adjusting for other risk factors confirmed the effect. High coffee consumption was also suggestively associated with decreased gray matter volume (beta = -0.061, 95% CI = -0.109 to -0.013, p = 0.013) compared with low/no coffee consumption. All analyses did not find an effect of coffee consumption on other outcomes including white matter hyperintensity volume, mean diffusivity, fractional anisotropy, brain microbleed, total brain volume, white matter volume, and hippocampus volume. Conclusion: This two-sample MR study showed that genetically predicted higher coffee consumption is causally associated with reduced gray matter volume of the brain.

Association of Interleukin-6 Signaling and C-Reactive Protein With Intracranial Aneurysm: A Mendelian Randomization and Genetic Correlation Study.

BACKGROUND AND OBJECTIVE: Evidence suggests that interleukin-6 (IL6) signaling is causally associated with aortic aneurysm independently of the effect of C-reactive protein (CRP). We aimed to explore the genetic overlap and associations between inflammation (IL6 signaling and CRP) and intracranial aneurysm (IA) risk. METHODS: Two-sample Mendelian randomization (MR) methods were used to assess the causal effects of soluble IL6 receptor (sIL6R) (n = 21,758) and CRP (n = 204,402) levels on IA (7,495 cases and 71,934 controls) risk using genome-wide association study summary data of European individuals. Cross-trait linkage disequilibrium score regression was used to estimate the genetic correlations of CRP (n = 400,094) with IA. RESULTS: MR analyses showed that circulating sIL6R and CRP levels were not associated with the risk of IA. The odds ratios based on the inverse variance-weighted method were 0.986 (0.950-1.023, p = 0.45) and 0.957 (0.846-1.084, p = 0.49) for sIL6R and CRP, respectively. MR analyses using data of ruptured and unruptured IA each showed no association. Linkage disequilibrium score regression showed that the genetic correlation between CRP and IA was 0.16 (SE = 0.04, p = 0.0003). The genetic correlation diminished after conditioning IA on blood pressure (0.07 ± 0.05, p = 0.16), smoking (0.02 ± 0.05, p = 0.65), or blood pressure plus smoking (-0.03 ± 0.05, p = 0.53). CONCLUSION: Using associated genetic variants as instrument variables, two-sample MR analyses showed no evidence that circulating sIL6R and CRP levels were associated with IA risk. Although a positive genetic correlation was found between CRP levels and IA risk, it was mainly driven by the shared genetic background of blood pressure and smoking with both CRP and IA.

MIA-Directed 2-Pyridione-Enabled Selective Ortho-C-H Arylation of Phenylalanine: A Mechanistic Study.

The 2-methoxyiminoacyl-mediated arylation of substituted phenylalanines has been examined. Selective monoarylation at the ortho position was achieved using pyridone ligands which decelerate the arylation process. Density functional theory (DFT) study of a continuous C-H arylation process that included the first and second arylation stage was performed. The computational result shows that the introduction of a pyridone ligand obviously disfavors the second arylation stage, which directly contributes to the selectivity between the mono/diarylated products. Furthermore, results of the kinetic isotope effect and a control experiment are agreed with DFT study.

Serum Uric Acid Level and Multiple Sclerosis: A Mendelian Randomization Study.

Previous observational studies have shown that the serum uric acid (UA) level is decreased in persons with multiple sclerosis (MS). We used the two-sample Mendelian randomization (MR) method to determine whether the serum UA level is causally associated with the risk of MS. We screened 26 single-nucleotide polymorphisms (SNPs) in association with serum UA level (p < 5 × 10-8) from a large genome-wide meta-analysis involving 110,347 individuals. The SNP outcome effects were obtained from two large international genetic studies of MS involving 38,589 individuals and 27,148 individuals. A total of 18 SNPs, including nine proxy SNPs, were included in the MR analysis. The estimate based on SNP rs12498742 that explained the largest proportion of variance showed that the odds ratio (OR) of UA (per mg/dl increase) for MS was 1.00 [95% confidence interval (CI) 0.90-1.11; p = 0.96]. The main MR analysis based on the random effects inverse variance weighted method showed that the pooled OR was 1.05 (95% CI 0.92-1.19; p = 0.50). Although there was no evidence of net horizontal pleiotropy in MR-Egger regression (p = 0.48), excessive heterogeneity was found via Cochran's Q statistic (p = 9.6 × 10-4). The heterogeneity showed a substantial decrease after exclusion of two outlier SNPs (p = 0.17). The pooled ORs for the other MR methods ranged from 0.89 (95% CI 0.65-1.20; p = 0.45) to 1.05 (95% CI 0.96-1.14; p = 0.29). The results of sensitivity analyses and additional analyses all showed similar pooled estimates. MR analyses by using 81 MS -associated SNPs as instrumental variables showed that genetically predicted risk of MS was not significantly associated with serum UA level. The pooled OR was 1.00 (95% CI 0.99-1.02; p = 0.74) for the main MR analysis. This MR study does not support a causal effect of genetically determined serum UA level on the risk of MS, nor does it support a causal effect of genetically determined risk of MS on serum UA level.

The Association Between Serum Apelin-13 and the Prognosis of Acute Ischemic Stroke.

While a number of studies have reported an association between apelin-13 and ischemic stroke, few have verified its clinical effect. We investigated the prognostic value of serum apelin-13 levels in patients with acute ischemic stroke (AIS). We prospectively recruited 244 AIS patients within 24 h after stroke onset, and 167 healthy controls. We assessed the serum apelin-13 levels using ELISA, and the severity of AIS using the National Institutes of Health Stroke Scale (NIHSS). The primary outcomes included death or major disability (modified Rankin Scale score, 3-6) and major disability (modified Rankin Scale score, 3-5). Secondary outcomes included recurrent stroke and combined events (all-cause death, or cardiovascular and cerebrovascular events). We found that the serum apelin-13 levels in the patients (38.63 ng/mL (interquartile range [IQR], 29.86-50.99)) were lower than those in the healthy controls (42.50 ng/mL [IQR, 31.25-59.17]) (P = 0.017). Patients with a NIHSS score ≤ 3 had higher apelin-13 levels than those with a NIHSS score > 3 (P = 0.048). At the 3-month follow-up, multivariate logistic regression analysis indicated an association between apelin-13 and death or major disability (OR 0.31; 95% CI 0.11-0.86; P = 0.024) and major disability (OR 0.32; 95% CI 0.11-0.90; P = 0.030). At the 1-year follow-up, the patients with high apelin-13 levels showed a lower incidence of stroke and combined events (Log-rank test P < 0.05). Our findings indicate that serum apelin-13 may be a potential prognostic biomarker for AIS.

Vessel wall differences between middle cerebral artery and basilar artery plaques on magnetic resonance imaging.

A recent study showed that posterior circulation plaques have a greater capacity for positive remodeling in a non-Asian population. We aimed to investigate if the features of plaques in the middle cerebral artery (MCA) were different from those in the basilar artery (BA) in a northern Chinese population. We retrospectively analysed the records of 71 consecutive patients with acute ischemic stroke. All patients had at least one MCA or BA plaque with early or mild (<50% stenosis) atherosclerosis identified using vessel wall magnetic resonance imaging. The remodeling ratio, eccentricity index, and plaque range were compared between MCA and BA plaques using multilevel analysis. A total of 101 plaques were included. There were 70 plaques located in the MCA and 31 plaques located in the BA. The features of non-advanced atherosclerotic plaques did not differ between the MCA and BA when accounting for the degree of stenosis or plaque burden in a northern Chinese population. Symptomatic plaques were associated with a higher eccentricity index and smaller plaque range than asymptomatic plaques under the same plaque burden. Further studies are warranted to investigate the progression of atherosclerosis in different intracranial arteries.

Effectiveness and Safety of Transcatheter Patent Foramen Ovale Closure for Migraine (EASTFORM) Trial.

We evaluated the safety and effectiveness of transcatheter patent foramen ovale (PFO) closure for the treatment of migraine in a Chinese population. This non-randomized clinical trial enrolled 258 consecutive substantial or severe migraineurs with a right-to-left shunt (RLS) (grade II-IV) and grouped subjects according to their election or refusal of PFO closure. Migraine was diagnosed according to the International Classification of Headache Disorders III-beta and evaluated using the Headache Impact Test-6 (HIT-6). In total, 241 participants (125 in the transcatheter closure group and 116 in the control group) were included in the study. In general, the PFO closure procedure was found to be safe. At 1 month after closure, 76.1% of patients returned for c-TCD evaluation; of these, 85.7% were downgraded to negative status or a grade-I shunt. Residual shunts and placebo effects were thought to resolve by 12 months post-procedure, when migraine impact was reported to decrease by 73.6%. Transcatheter PFO closure was demonstrated to be effective for the treatment of migraine by comparing HIT-6 scores between the transcatheter closure and control groups (p < 0.001). Our results suggest that transcatheter PFO closure is a safe and effective approach for the treatment of migraine in the Chinese population, especially in females with constant RLS. Clinical trial no. NCT02127294 (registered on April 29, 2014).