Systematic analyses of GWAS summary statistics from UK Biobank identified novel susceptibility loci and genes for upper gastrointestinal diseases.

In recent decades, upper gastrointestinal (GI) diseases have been highly prevalent worldwide. Although genome-wide association studies (GWASs) have identified thousands of susceptibility loci, only a few of them were conducted for chronic upper GI disorders, and most of them were underpowered and with small sample sizes. Additionally, for the known loci, only a tiny fraction of heritability can be explained and the underlying mechanisms and related genes remain unclear. In this study, we conducted a multi-trait analysis by the MTAG software and a two-stage transcriptome-wide association study (TWAS) with UTMOST and FUSION for seven upper GI diseases (oesophagitis, gastro-oesophageal reflux disease, other diseases of oesophagus, gastric ulcer, duodenal ulcer, gastritis and duodenitis and other diseases of stomach and duodenum) based on summary GWAS statistics from UK Biobank. In the MTAG analysis, we identified 7 loci associated with these upper GI diseases, including 3 novel ones at 4p12 (rs10029980), 12q13.13 (rs4759317) and 18p11.32 (rs4797954). In the TWAS analysis, we revealed 5 susceptibility genes in known loci and identified 12 novel potential susceptibility genes, including HOXC9 at 12q13.13. Further functional annotations and colocalization analysis indicated that rs4759317 (A>G) driven the association for GWAS signals and expression quantitative trait loci (eQTL) simultaneously at 12q13.13. The identified variant acted by decreasing the expression of HOXC9 to affect the risk of gastro-oesophageal reflux disease. This study provided insights into the genetic nature of upper GI diseases.

Association between remnant cholesterol and subclinical carotid atherosclerosis among Chinese general population in health examination.

OBJECTIVE: Remnant cholesterol (RC) was associated with carotid atherosclerosis in patients with clinical settings. But the value of RC as a risk management indicator for subclinical carotid atherosclerosis in health examination has not been fully determined. METHODS: This was a real-world, cross-sectional study including 12317 Chinese general population. Carotid intima-media thickness (CIMT) and carotid atherosclerotic plaque (CAP) were assessed by ultrasound. RC was calculated by total cholesterol minus low density lipoprotein-cholesterol (LDL-C) minus high density lipoprotein-cholesterol (HDL-C).Carotid atherosclerosis (CAS) was defined as a composite of increased CIMT and CAP. Multivariable logistic regression models were used to investigate the association of RC and CAS, increased CIMT and CAP. RESULTS: Among 12317 participants (mean age: 51.21±13.76 years; 8303 men and 4014 women), the prevalence of CAS and increased CIMT was higher in participants with higher RC levels (P for trend<0.01). After multivariable adjustment, the highest quartile of RC was significantly associated with higher risk of CAS (OR: 1.45 95%CI: 1.26-1.67) and increased CIMT (OR: 1.48 95%CI: 1.29-1.71) with the lowest quartile of RC as reference. And the relationships remained significant even after adjustment of LDL-C and HDL-C. Every 1-SD increase of RC level was positively associated with 17% risk increment for CAS (6-30%) and 20% risk increment for increased CIMT (8-34%). CONCLUSION: Elevated serum RC levels were significantly associated with CAS and increased CIMT among Chinese general population, independent of LDL-C and HDL-C. RC evaluation could be applied for the risk management of early stage of subclinical carotid atherosclerosis in health examination.

Serum semaphorin 7A is associated with the risk of acute atherothrombotic stroke.

Semaphorin 7A (Sema7A), a neural guidance cue, was recently identified to regulate atherosclerosis in mice. However, the clinical relevance of Sema7A with atherosclerotic diseases remains unknown. The aim of this study was to investigate the association between serum Sema7A and the risk of acute atherothrombotic stroke (AAS). We measured serum concentrations of Sema7A in 105 newly onset AAS cases and 105 age- and sex-matched controls, showing that median Sema7A level in AAS cases was over three times of that in controls (5.86 vs 1.66 ng/mL). Adjusted for hypertension, body mass index, fasting blood glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, current smoking and alcohol consumption, multivariate logistic regression showed that higher Sema7A was independently associated with the odds of AAS (OR = 6.40, 95% CI: 2.88-14.25). Each 1-standard deviation increase in Sema7A was associated with a threefold higher odds of AAS (OR = 3.42, 95% CI: 1.84-6.35). Importantly, adding Sema7A to a multivariate logistic model containing conventional cardiovascular risk factors improved the area under receiver operating characteristic curves from 0.831 to 0.891 for the association with AAS. In conclusion, elevated serum Sema7A is independently associated with the risk of AAS, suggesting that it may play a potential role in AAS.

Increased Growth Differentiation Factor 15 Is Associated with Unfavorable Clinical Outcomes of Acute Ischemic Stroke.

BACKGROUND: Growth differentiation factor 15 (GDF-15), a stress-responsive biomarker, is known to be independently associated with mortality and cardiovascular events in different disease settings, but data on the prognostic value of GDF-15 after stroke are limited. METHODS: Baseline serum GDF-15 was measured in 3066 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite of death and major disability within 3 months. Secondary outcomes included death, major disability, vascular events, and stroke recurrence. The associations between GDF-15 and clinical outcomes after stroke were assessed by multivariate logistic regression or Cox proportional hazards models. RESULTS: At 3 months' follow-up, 676 (22.05%), 86 (2.80%), 81 (2.64%), and 51 (1.66%) patients had experienced major disability, death, vascular events, or stroke recurrence, respectively. After adjusting for age, sex, current smoking, alcohol consumption, and baseline National Institutes of Health Stroke Scale score, the odds ratio/hazard ratio (95% CI) of 1 SD higher of base-10 log-transformed GDF-15 was 1.26 (1.15-1.39) for primary outcome, 1.13 (1.02-1.25) for major disability, 1.79 (1.48-2.16) for death, and 1.26 (1.00-1.58) for vascular events. The addition of GDF-15 to established risk factors improved risk prediction of the composite outcome of death and major disability (c-statistic, net reclassification index, and integrated discrimination improvement, all P < 0.05). CONCLUSIONS: High GDF-15 concentrations are independently associated with adverse clinical outcomes of acute ischemic stroke, suggesting that baseline serum GDF-15 could provide additional information to identify ischemic stroke patients at high risk of poor prognosis.

Co-Effect of Serum Galectin-3 and High-Density Lipoprotein Cholesterol on the Prognosis of Acute Ischemic Stroke.

GOAL: The association of combined galectin-3 and high-density lipoprotein cholesterol (HDL-C) with prognosis of acute ischemic stroke remains unknown. This study aimed to evaluate the coeffect of galectin-3 and HDL-C on death and vascular events within 1 year after ischemic stroke. MATERIALS AND METHODS: Based on China Antihypertensive Trial in Acute Ischemic Stroke, a prospective study was conducted among 2970 patients with acute ischemic stroke. The primary outcome was a combination of death and vascular events within 1 year after ischemic stroke. The secondary outcomes were separately those of recurrent stroke, vascular events, and death. FINDINGS: The multivariate adjusted hazard ratios (95% confidence intervals) of primary outcome, recurrent stroke, and vascular events were 1.54 (1.07-2.20), 1.78 (1.08-2.95), and 1.92 (1.26-2.94), respectively, in patients with both high galectin-3 and low HDL-C compared to those with both low galectin-3 and high HDL-C. The addition of galectin-3 and HDL-C to conventional factors significantly improved predictive value. Net reclassification index was 15.7% for primary outcome, 18.3% for recurrent stroke, and 20.5% for vascular events. CONCLUSION: Combination of high galectin-3 and low HDL-C was associated with primary outcome, recurrent stroke, and vascular events within 1 year after ischemic stroke, suggesting that the combination of galectin-3 and HDL-C may be used to identify the individuals at risk of poor prognosis after ischemic stroke.

Urine caffeine metabolites are positively associated with cognitive performance in older adults: An analysis of US National Health and Nutrition Examination Survey (NHANES) 2011 to 2014.

The aim of this study was to explore urine caffeine metabolites in relation to cognitive performance among 2011-2014 National Health and Nutrition Examination Survey participants aged ≥60 years. We hypothesized that urine caffeine metabolites were positively associated with cognition in older adults. Caffeine and 14 of its metabolites were quantified in urine by use of high-performance liquid chromatography-electrospray ionization-tandem quadruple mass spectrometry with stable isotope labeled internal standards. Cognitive assessment was based on scores from the word learning and recall modules. Participants were categorized based on the quartiles of caffeine and its metabolites level. The association between caffeine metabolites and each cognitive dimension was analyzed using multiple logistic regression analysis in adjusted models. Stratification analyses by gender were also performed. For CERAD test, there was a significant association between 1-methyluric acid (OR=0.62, 95% CI: 0.42 to 0.92), 7-methylxanthine(OR=0.49, 95% CI: 0.27 to 0.89), theophylline (OR=0.52, 95% CI: 0.29 to 0.92), as well as paraxanthine (OR=0.49, 95% CI: 0.27 to 0.88) and cognitive function. For animal fluency test, there was a positive association between theophylline (TP) (OR=0.44, 95% CI: 0.22 to 0.89) and cognitive function. The trend that the risk of low cognitive function decreased with increasing concentration of 1-methylxanthine (P trend=0.0229) was also observed. Furthermore, the same trend existed for 3-methylxanthine (p trend = 0.0375) in men. In conclusion, there was a significant positive association between urine caffeine metabolites and cognitive performance in older adults, particularly for theophylline, paraxanthine and caffeine; and the association might be dependent on gender.

The U-shaped Relationship Between Serum Methylene Tetrahydrofolate Reductase and Large-artery Atherosclerotic Stroke.

BACKGROUND: Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with ischemic stroke. However, the association between serum MTHFR level and ischemic stroke has not yet been studied. We aimed to examine the association between them in patients with large-artery atherosclerotic stroke and community-based healthy controls. METHODS: This study includes three hundred ninety-five patients with large-artery atherosclerotic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and 395 age- and sex-matched healthy controls from Chinese communities. Serum MTHFR concentrations were examined and some conventional risk factors of stroke were collected. The association between serum MTHFR and large-artery atherosclerotic stroke was evaluated. RESULTS: A U-shaped association of serum MTHFR level with large-artery atherosclerotic stroke was observed (p for nonlinearity =0.008). After multivariate adjustment, the odds ratios (95% confidence intervals) of large-artery atherosclerotic stroke associated with the first, second, fourth, and fifth quintiles of MTHFR were 5.62 (1.10-28.87), 2.13 (0.51-8.99), 1.08 (0.21-5.56), and 2.31 (0.57-9.34), respectively, compared with the third quintiles of MTHFR. Adding MTHFR quintiles to a model containing conventional risk factors improved the predictive power for large-artery atherosclerotic stroke (continuous net reclassification improvement=63.78%, p<0.001; categorical net reclassification improvement=2.54%, p=0.012). CONCLUSION: There is a significant U-shaped relationship between serum MTHFR levels and largeartery atherosclerotic stroke. Our findings raise the possibility that serum MTHFR may have a potential role in the pathogenesis of large-artery atherosclerotic stroke.

Family history of stroke and death or vascular events within one year after ischemic stroke.

BACKGROUND AND AIMS: The association between family history of stroke and clinical outcomes after ischemic stroke remains unclear. METHODS: A total of 3878 acute ischemic stroke patients from CATIS were included. The participants with ischemic stroke were divided into groups according to types of family history of stroke, stroke onset age and stroke subtypes. The primary outcome was a composite outcome of death and vascular events within 1 year after stroke. Multivariable Cox proportional hazard models were used to analyze the association between family history of stroke and other variables and clinical outcomes. RESULTS: Among 3878 ischemic stroke patients, 708 (18.26%) had a history of stroke in their first-degree relatives and 399 experienced a composite outcome (172 patients died and 227 experienced vascular events) within 1 year after stroke. Overall family history was not associated with the primary outcome (HR, 1.08; 95% CI, 0.37-3.19). However, the patients with maternal stroke history (HR, 1.87; 95% CI, 1.31-2.97), stroke onset age<55 years with family history (HR, 2.02; 95% CI, 1.08-3.80) and thrombotic stroke in the patients with family history (HR, 1.46; 95% CI, 1.00-2.12) were associated with primary outcome, death and vascular events, respectively. CONCLUSION: This study suggests that maternal stroke history, age<55 years at stroke onset and thrombotic stroke in the patients with a family history are associated with poor outcomes after stroke. Further studies from other samples are needed to replicate our findings due to a reason for excluding some severe stroke patients in this study.

Elevated C-reactive Protein and Depressed High-density Lipoprotein Cholesterol are Associated with Poor Function Outcome After Ischemic Stroke.

AIMS: C-reactive protein is an established marker of inflammation that can impair the protective function of High Density Lipoprotein Cholesterol (HDL-C). The combined effect of Creactive protein and HDL-C on long-term outcomes in patients with stroke remains uncertain. METHODS: A total of 3124 acute ischemic stroke subjects from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) were included in this analysis. Participants were divided into four groups according to CRP and HDL-C levels on admission. The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at one year after stroke. RESULTS: Compared to participants with low CRP/ high HDL-C, adjusted odd ratios for primary outcome for those with low CRP /low HDL-C, high CRP /high HDL-C and high CRP /low HDL-C were 1.06(0.81-1.39),1.78(1.31-2.41) and 2.03(1.46-2.80), respectively, after multiple adjustments. Adding serum CRP and HDL-C status to a model containing conventional stroke risk factors significantly improve risk reclassification for the combined outcome of death and major disability (NRI: 6.85%, P=0.005; IDI: 2.57%, P=0.002). Moreover, no interaction was observed between CRP and HDL-C in relation to stroke outcomes (P-interaction >0.05 for all). CONCLUSIONS: High CRP with low HDL-C levels was associated with death and major disability within one year after ischemic stroke. The findings suggest that the ischemic patients with both high CRP and low HDL-C should be treated with reducing CRP and promoting HDL-C levels.

Prognostic Value of White Blood Cell in Acute Ischemic Stroke Patients.

BACKGROUND AND AIMS: It is unclear whether white blood cell on admission has a prognosis value on ischemic stroke and whether its function is affected by other inflammation factors. We hypothesized that elevated white blood cell is associated with stroke severity and 3-month mortality after acute ischemic stroke. METHODS: A total of 3891 acute ischemic stroke subjects from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) were included in this analysis. Participants were divided into four groups according to quartiles of white blood cell on admission (cutoff points for the quintiles: 5.60×109/L,6.83×109/L,8.50×109/L). The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 3 months. Secondary outcomes were major disability, death, and vascular events, respectively. RESULTS: After adjustment for major conventional risk factors, elevated white blood cell on admission was associated with poor primary and secondary outcomes after acute ischemic stroke. Compared with the lowest quartile, the ORs (95% CIs) for the highest quartile were 1.79 (1.37-2.91) and 1.62 (1.21-3.55) for primary outcome in model 1 and model 2. In addition, there was a linear association between white blood cell and primary outcome at 3-months (P for linear trend = 0.001). CONCLUSION: This analysis indicated that elevated white blood cell on admission is associated with 3-months poor prognosis in ischemic stroke patients independently of other inflammation factors. The results emphasize the need for further research on the application of anti-inflammatory therapy.