Unravelling CD4+ T cell diversity and tissue adaptation of Tregs in abdominal aortic aneurysms through single-cell sequencing.

Immune cell infiltration is a significant pathological process in abdominal aortic aneurysms (AAA). T cells, particularly CD4+ T cells, are essential immune cells responsible for substantial infiltration of the aorta. Regulatory T cells (Tregs) in AAA have been identified as tissue-specific; however, the time, location, and mechanism of acquiring the tissue-specific phenotype are still unknown. Using single-cell RNA sequencing (scRNA-seq) on CD4+ T cells from the AAA aorta and spleen, we discovered heterogeneity among CD4+ T cells and identified activated, proliferating and developed aorta Tregs. These Tregs originate in the peripheral tissues and acquire the tissue-specific phenotype in the aorta. The identification of precursors for Tregs in AAA provides new insight into the pathogenesis of AAA.

Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis.

Myocardial infarction (MI) is defined as sudden ischemic death of myocardial tissue. Amphiregulin (Areg) regulates cell survival and is crucial for the healing of tissues after damage. However, the functions and mechanisms of Areg after MI remain unclear. Here, we aimed to investigate Areg's impact on myocardial remodeling. Mice model of MI was constructed and Areg-/- mice were used. Expression of Areg was analyzed using western blotting, RT-qPCR, flow cytometry, and immunofluorescence staining. Echocardiographic analysis, Masson's trichrome, and triphenyltetrazolium chloride staining were used to assess cardiac function and structure. RNA sequencing was used for unbiased analysis. Apoptosis and autophagy were determined by western blotting, TUNEL staining, electron microscopy, and mRFP-GFP-LC3 lentivirus. Lysosomal acidity was determined by Lysotracker staining. Areg was elevated in the infarct border zone after MI. It was mostly secreted by macrophages. Areg deficiency aggravated adverse ventricular remodeling, as reflected by worsening cardiac function, a lower survival rate, increased scar size, and interstitial fibrosis. RNA sequencing analyses showed that Areg related to the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR) signaling pathways, V-ATPase and lysosome pathways. Mechanistically, Areg exerts beneficial effects via increasing lysosomal acidity to promote autophagosome clearance, and activating the EGFR/PI3K/Akt/mTOR signaling pathway, subsequently inhibiting excessive autophagosome formation and apoptosis in cardiomyocytes. This study provides a novel evidence for the role of Areg in inhibiting ventricular remodeling after MI by regulating autophagy and apoptosis and identifies Areg as a potential therapeutic target in ventricular remodeling after MI.

Polymorphism of IL-12/IL-23 axis is associated with coronary heart disease.

IL12B encodes the shared p40 subunit (IL-12p40) of IL-12 and IL-23, which have diverse immune functions and are closely related to the occurrence and development of atherosclerosis (AS). However, the exact role of IL12B in coronary heart disease (CHD) was still unknown. A case-control association analysis was performed between five single nucleotide polymorphisms (SNPs) of IL12B (rs1003199, rs3212219, rs2569254, rs2853694 and rs3212227) and CHD in Chinese Han population (1824 patients with CHD vs. 2784 controls). Logistic regression analyses were used to study the relationships between SNPs and CHD, while multiple linear regression analyses were used to test the association between the SNP and the severity of CHD. In addition, the plasma IL12B concentration of CHD patients were detected by ELISA. We detected a significant association between one of the SNPs, rs2853694-G and CHD (padj = 2.075 × 10-5 , OR, 0.773 [95% CI, 0.686-0.870]). Stratified analysis showed that rs2853694 was associated with CHD in both male and female populations and was significantly associated with both early- and late-onset CHD. In addition, rs2853694 is also related to the different types of CHD including clinical-CHD and anatomical-CHD. Moreover, there are significant differences in serum IL12B concentrations between rs2853694-TT carriers and rs2853694-GT carriers in CHD patients (p = 0.010). A common variant of IL12B was found significantly associated with CHD and its subgroups. As a shared subunit of IL-12 and IL-23, IL-12p40 may play a key role in IL-12/IL-23 axis mediated AS, which is expected to be an effective therapeutic target for CHD.

Increased expression of protein tyrosine phosphatase nonreceptor type 22 alters early T-cell receptor signaling and differentiation of CD4+ T cells in chronic heart failure.

CD4+ T-cell counts are increased and activated in patients with chronic heart failure (CHF), whereas regulatory T-cell (Treg) expansion is inhibited, probably due to aberrant T-cell receptor (TCR) signaling. TCR signaling is affected by protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in autoimmune disorders, but whether PTPN22 influences TCR signaling in CHF remains unclear. This observational case-control study included 45 patients with CHF [18 patients with ischemic heart failure versus 27 patients with nonischemic heart failure (NIHF)] and 16 non-CHF controls. We used flow cytometry to detect PTPN22 expression, tyrosine phosphorylation levels, zeta-chain-associated protein kinase, 70 kDa (ZAP-70) inhibitory residue tyrosine 292 and 319 phosphorylation levels, and CD4+ T cell and Treg proportions. We conducted lentivirus-mediated PTPN22 RNA silencing in isolated CD4+ T cells. PTPN22 expression increased in the CD4+ T cells of patients with CHF compared with that in controls. PTPN22 expression was positively correlated with left ventricular end-diastolic diameter and type B natriuretic peptide but negatively correlated with left ventricular ejection fraction in the NIHF group. ZAP-70 tyrosine 292 phosphorylation was decreased, which correlated positively with PTPN22 overexpression in patients with NIHF and promoted early TCR signaling. PTPN22 silencing induced Treg differentiation in CD4+ T cells from patients with CHF, which might account for the reduced frequency of peripheral Tregs in these patients. PTPN22 is a potent immunomodulator in CHF and might play an essential role in the development of CHF by promoting early TCR signaling and impairing Treg differentiation from CD4+ T cells.

Association between Dietary Choline Intake and Cardiovascular Diseases: National Health and Nutrition Examination Survey 2011-2016.

Choline is an essential nutrient for human body, but dietary choline is metabolized into the hazard metabolite for the cardiovascular system. Because of the conflicting results between dietary choline intake and cardiovascular disease (CVD) risk in previous studies, we aimed to investigate this in US adults. Non-pregnant participants and those aged >20 years from National Health and Nutrition Examination Survey 2011-2016, with CVD assessment and reliable dietary recall status, were included. The dietary choline intake was assessed as a mean value of two total dietary choline intakes, including dietary choline intake and supplemental choline intake, in 24-h dietary recall interviews. The association between dietary choline intake and the presence of CVD was examined using logistic regression. We enrolled 14,323 participants. The participants without CVD had substantially higher dietary choline intakes (318.4 mg/d vs. 297.2 mg/d) compared to those with CVD (p < 0.05). After multivariable adjustments, the highest quartile of dietary choline intake was associated with a lower CVD risk, OR 0.693, 95%CI [0.520, 0.923], when compared to the lowest quartile. Consistent results were also found for stroke. Subgroup analyses also supported these, especially in participants aged ≥60 years and in those with BMI < 30 kg/m2. We found that a higher dietary choline intake was associated with a lower CVD risk, especially the risk of stroke. Further clinical trials are needed in order to confirm this finding and to provide dietary suggestions for the appropriate amount of choline intake.

Genetic Association and Potential Mediators between Sarcopenia and Coronary Heart Disease: A Bidirectional Two-Sample, Two-Step Mendelian Randomization Study.

OBJECTIVE: To elucidate the bidirectional correlation of sarcopenia with coronary heart disease (CHD), as well as to investigate the mediating role of cardiometabolic factors and inflammatory biomarkers, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. METHODS: Summary statistics were obtained from genome-wide association studies (GWAS). In our bidirectional two-sample MR, genetic variants associated with sarcopenia-related traits and CHD were instrumented for the estimation of bidirectional correlations. Besides, genetic variants associated with thirteen cardiometabolic factors and six inflammatory biomarkers were selected for further mediation analyses. To confirm the consistency of the results, several sensitivity analyses were carried out. RESULTS: Genetically predicted higher appendicular lean mass (OR = 0.835, 95% CI: 0.790-0.882), left hand grip strength (OR = 0.703, 95% CI: 0.569-0.869), right hand grip strength (OR = 0.685, 95% CI: 0.555-0.844), and walking pace (OR = 0.321, 95% CI: 0.191-0.539) reduced CHD risk, while genetic predisposition to CHD did not affect any of the sarcopenia-related traits. Seven mediators were identified for the effects of appendicular lean mass on CHD, including waist-to-hip ratio, hip circumference, systolic blood pressure, low-density lipoprotein cholesterol, total cholesterol, triglycerides, and fasting insulin. The mediation proportion ranged from 10.23% for triglycerides to 35.08% for hip circumference. Hip circumference was found to mediate the relationships between both left (mediation proportion: 24.61%) and right-hand grip strength (24.14%) and CHD, and the link between walking pace and CHD was partially mediated by waist-to-hip ratio (31.15%) and body mass index (26.66%). CONCLUSION: Our results showed that higher appendicular lean mass, hand grip strength, and walking pace reduced CHD risk, but the causal relationship was not bidirectional. Several mediators were found to mediate the causal pathways between sarcopenia-related traits and CHD, and intervention of these factors may be helpful in terms of CHD prevention in sarcopenia patients.

Crosstalk between KIF1C and PRKAR1A in left atrial myxoma.

Cardiac myxoma (CM) is the most common benign cardiac tumor, and most CMs are left atrial myxomas (LAMs). Six variations of KIF1C, c.899 A > T, c.772 T > G, c.352 A > T, c.2895 C > T, c.3049 G > A, and c.*442_*443dup in left atrial myxoma tissues are identified by whole-exome sequencing (WES) and Sanger sequencing. RNA-seq and function experiments show the reduction of the expression of KIF1C and PRKAR1A caused by rare variations of KIF1C. KIF1C is observed to be located in the nucleus, bind to the promoter region of PRKAR1A, and regulate its transcription. Reduction of KIF1C decreases PRKAR1A expression and activates the PKA, which causes an increase in ERK1/2 phosphorylation and SRC-mediated STAT3 activation, a reduction of CDH1, TP53, CDKN1A, and BAX, and eventually promotes tumor formation both in vitro and in vivo. The results suggest that inhibition of KIF1C promotes the pathogenesis of LAM through positive feedback formed by the crosstalk between KIF1C and PRKAR1A.

Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms.

BACKGROUND: Both the crystalline and soluble forms of cholesterol increase macrophage secretion of interleukin 1ß (IL-1ß), aggravating the inflammatory response in atherosclerosis (AS). However, the link between cholesterol and regulatory T cells (Tregs) remains unclear. This study aimed to investigate the effect of cholesterol treatment on Tregs. METHODS: Differentiation of induced Tregs (iTregs) was analyzed using flow cytometry. The expression of hypoxia-inducible factor-1a (HIF-1a) and its target genes was measured by western blotting and/or RT-qPCR. Two reporter jurkat cell lines were constructed by lentiviral transfection. Mitochondrial function and the structure of natural Tregs (nTregs) were determined by tetramethylrhodamine (TMRM) and mitoSOX staining, Seahorse assay, and electron microscopy. The immunoregulatory function of nTregs was determined by nTreg-macrophage co-culture assay and ELISA. RESULTS: Cholesterol treatment suppressed iTreg differentiation and impaired nTreg function. Mechanistically, cholesterol induced the production of mitochondrial reactive oxygen species (mtROS) in naïve T cells, inhibiting the degradation of HIF-1α and unleashing its inhibitory effects on iTreg differentiation. Furthermore, cholesterol-induced mitochondrial oxidative damage impaired the immunosuppressive function of nTregs. Mixed lymphocyte reaction and nTreg-macrophage co-culture assays revealed that cholesterol treatment compromised the ability of nTregs to inhibit pro-inflammatory conventional T cell proliferation and promote the anti-inflammatory functions of macrophages. Finally, mitoTEMPO (MT), a specific mtROS scavenger, restored iTreg differentiation and protected nTreg from further deterioration. CONCLUSION: Our findings suggest that cholesterol may aggravate inflammation within AS plaques by acting on both iTregs and nTregs, and that MT may be a promising anti-atherogenic drug.

Gene polymorphism in IL17A and gene-gene interaction in the IL23R/IL17A axis are associated with susceptibility to coronary artery disease.

AIMS: Studies have confirmed that the IL-23R/IL-17A axis plays an important role in the development of autoimmune and inflammatory diseases. However, its role in coronary artery disease (CAD) remains unclear. Here, we conducted a large sample case-control study to investigate the association between the IL23R/IL17A axis and CAD in the Chinese Han population. METHODS: Two SNPs, rs2275913: G>A (IL17A) and rs6682925: T>C (IL23R), were genotyped in 3042 CAD cases and 3216 controls using the high-resolution melt technology (HRM). Logistic regression analyses were used to adjust the traditional risk factors for CAD and perform the gene interaction analyses. Multiple linear regression analyses were used to study the relationships between the selected SNPs and the levels of serum lipids. In addition, meta-analysis also was performed for the association between rs6682925 and rs2275913 with CAD in different popolations. RESULTS: Our case-control and meta-analysis for single SNPs demonstrated that the frequencies of the alleles and the distribution of the genotypes had no significant differences in CAD cases compared with controls. In the stratified analysis, we observed that the frequency of the IL17A rs2275913-A allele was more epidemic in early-onset CAD than in the controls (Padj = 0.005, OR = 1.209, 95% CI: 1.059-1.382), and the minor allele C of rs6682925 was associated with a decreased level of serum total cholesterol under a recessive model (Padj = 0.011). We demonstrated a significant interaction between rs6682925 and rs2275913 and CAD in the Chinese Han population. Four genotypes (CTGG, CCAA, CCAG, CCGG) were significantly associated with CAD (Padj = 2.94 × 10-4, OR = 0.619, 95% CI: 0.478-0.803; Padj = 0.01, OR = 1.808, 95% CI: 1.152-1.869; Padj = 6 × 10-6, OR = 2.179, 95% CI: 1.558-3.049; Padj = 0.001, OR = 1.883, 95% CI: 1.282-2.762, respectively). CONCLUSION: Our study found no single SNP of rs2275913 in IL17A and rs6682925 in IL23R was associated with CAD in the Chinese population, but the interaction of them were significantly associated with CAD susceptibility, highlighting the key role of the IL-23R/IL-17A axis in the development of CAD. In addition, we also found rs2275913 was associated with early-onset CAD and rs6682925 was associated with total cholesterol levels, which will contribute to the clinical stratified management of this common disease.

Genetic Analysis Reveals Different Mechanisms of IL-5 Involved in the Development of CAD in a Chinese Han Population.

Background: Coronary artery disease (CAD) is a complex disease and the leading cause of death worldwide. It is caused by genetic and environmental factors or their interactions. Candidate gene association studies are an important genetic strategy for the study of complex diseases, and multiple variants of inflammatory cytokines have been found to be associated with CAD using this method. Interleukin-5 (IL-5) is an important inflammatory immune response factor that plays a role in a various inflammatory disease. Clinical tests and animal experiments indicated that IL-5 is involved in CAD development, but the exact mechanisms are unclear. This study investigated the genetic relationship between the single nucleotide polymorphisms (SNPs) in IL5 and CAD. Materials and Methods: Based on the Chinese Han population, we collected 1,824 patients with CAD and 1,920 control subjects and performed a two-stage case-control association analysis for three SNPs in IL5 (rs2057687, rs78546665, and rs2069812) using the high resolution melt (HRM) technology. Logistic regression analyses were applied to adjust for traditional risk factors for CAD and to perform haplotype and gene interaction analyses. Multiple linear regression analyses were used to study relationships between the selected SNPs and serum lipid levels. Results: In this study, two-stage case-control association analysis revealed that the allele and genotype frequency distributions of the three IL5 SNPs were not statistically significant between the case and control groups. In addition, none of the IL5 haplotypes were associated with CAD. Further stratified analyses were conducted by sex, age, hypertension, and disease status, respectively, and the results revealed that the rs2057687 and rs2069812 of IL5 were associated with CAD in the male group (p adj = 0.025, OR, 0.77 (95% CI, 0.62-0.97); p adj = 0.016, OR, 0.82 (95% CI, 0.70-0.97), respectively); the rs2057687 and rs78546665 of IL5 were associated with late-onset CAD (p adj = 0.039, OR, 0.78 (95% CI, 0.62-0.99); p adj = 0.036, OR, 1.46 (95% CI, 1.02-1.53), respectively); the rs2069812 of IL5 was associated with CAD in the hypertension group (p adj = 0.036, OR, 0.84 (95% CI, 0.71-0.99)); and none of the SNPs in IL5 were associated with different CAD states (anatomical CAD and clinical CAD). In addition, the association between SNPs and the serum lipid levels indicated that rs78546665 was positively correlated with triglyceride levels (p = 0.012). Finally, SNP-SNP interaction analyses revealed that interactions of rs2057687 and rs2069812 were associated with CAD (p adj = 0.046, OR, 0.77 (95% CI, 0.13-4.68)). Conclusion: This study suggested that the common variants of IL5 might play a role in CAD by affecting the risk factors for CAD and through SNP-SNP interactions, which provides a new target for specific treatment of CAD patients and a theoretical basis for personalized medicine.

The effects of RNA methylation on immune cells development and function.

Among the more than 170 known RNA modifications, methylation modification is the most frequent and well-studied. Depending on where the methylation occurs, RNA methylation can be classified as N6 -methyladenosine, N1 -methyladenosine, 5-methylcytosine, N7 -methylguanosine, and others. The methylation of RNA is constantly and dynamically modified in the complex microenvironment by methyltransferases, demethylases, and methylation reading proteins. These changes affect the proliferation and differentiation of immune cells as well as their effector activities by affecting RNA location, activity, stability, and translation efficiency. This review outlines how diverse RNA methylation alterations affect immune cell development and biological activity, as well as the role of RNA methylation in health and disease, to provide a molecular basis for future immunotherapies.

The Risk of Atrial Fibrillation Increases with Earlier Onset of Obesity: A Mendelian Randomization Study.

Background: Obesity is a well-established risk factor for atrial fibrillation (AF). Previous epidemiological research on obesity and AF often focused on adult populations and now broadened to earlier in life. Therefore, this study aimed to determine the relationships between obesity at different periods of life and the risk of AF. Methods: A two-sample Mendelian randomization (MR) study design using summarised data from 6 genome-wide association studies (GWASs) was employed in this study. Single nucleotide polymorphisms (SNPs) associated with adult obesity, childhood obesity, childhood body mass index (BMI), waist-to-hip ratio adjusted for BMI (WHRadjBMI), birth weight and AF were independently retrieved from large-scale GWASs. For SNP identification, the genome-wide significance threshold was set at p <5.00×10-8. To obtain causal estimates, MR analysis was conducted using the inverse variance-weighted (IVW) method. The weighted median, MR-Egger methods and MR-robust adjusted profile score (MR-RAPS) were used to evaluate the robustness of MR analysis. Results: A total of 204 SNPs were identified as the genetic instrumental variables (5 SNPs for childhood obesity, 13 SNPs for childhood BMI, 137 SNPs for birth weight, 35 SNPs for adult WHRadjBMI, and 14 SNPs for adult obesity). The results of MR analysis demonstrated that the genetically predicted adult obesity, childhood BMI, and birth weight were associated with AF risk. Notably, a 1 unit standard deviation (1-SD) increase in adult obesity was related to a 13% increased risk of AF [p=6.51×10-7, OR, 1.13 (95% CI, 1.08-1.19)], a 1-SD increase in childhood BMI was related to a 18% increased risk of AF [p=1.77×10-4, OR, 1.18 (95% CI, 1.08-1.29)], and a 1-SD increase in birth weight was related to a 26% increased risk of AF [p=1.27×10-7, OR, 1.26 (95% CI, 1.16-1.37)]. There was no evidence of pleiotropy or heterogeneity between the MR estimates obtained from multiple SNPs. Conclusion: Our study reveals the association of genetic susceptibility to obesity with a higher risk of AF. Moreover, an earlier age at obesity was associated with an increased risk of AF. Therefore, public awareness of the dangers of obesity and active early weight control may prevent the development of AF.

Causal Association of Type 2 Diabetes Mellitus and Glycemic Traits With Cardiovascular Diseases and Lipid Traits: A Mendelian Randomization Study.

Objective: We aimed to evaluate the causal effect of type 2 diabetes mellitus (T2DM) and glycemic traits on the risk of a wide range of cardiovascular diseases (CVDs) and lipid traits using Mendelian randomization (MR). Methods: Genetic variants associated with T2DM, fasting glucose, fasting insulin, and hemoglobin A1c were selected as instrumental variables to perform both univariable and multivariable MR analyses. Results: In univariable MR, genetically predicted T2DM was associated with higher odds of peripheral artery disease (pooled odds ratio (OR) =1.207, 95% CI: 1.162-1.254), myocardial infarction (OR =1.132, 95% CI: 1.104-1.160), ischemic heart disease (OR =1.129, 95% CI: 1.105-1.154), heart failure (OR =1.050, 95% CI: 1.029-1.072), stroke (OR =1.087, 95% CI: 1.068-1.107), ischemic stroke (OR =1.080, 95% CI: 1.059-1.102), essential hypertension (OR =1.013, 95% CI: 1.010-1.015), coronary atherosclerosis (OR =1.005, 95% CI: 1.004-1.007), and major coronary heart disease event (OR =1.003, 95% CI: 1.002-1.004). Additionally, T2DM was causally related to lower levels of high-density lipoprotein cholesterol (OR =0.965, 95% CI: 0.958-0.973) and apolipoprotein A (OR =0.982, 95% CI: 0.977-0.987) but a higher level of triglycerides (OR =1.060, 95% CI: 1.036-1.084). Moreover, causal effect of glycemic traits on CVDs and lipid traits were also observed. Finally, most results of univariable MR were supported by multivariable MR. Conclusion: We provided evidence for the causal effects of T2DM and glycemic traits on the risk of CVDs and dyslipidemia. Further investigations to elucidate the underlying mechanisms are warranted.

MED12 Regulates Smooth Muscle Cell Functions and Participates in the Development of Aortic Dissection.

Aortic dissection (AD) is a life-threatening disease with high morbidity and mortality, and effective pharmacotherapeutic remedies for it are lacking. Therefore, AD's molecular pathogenesis and etiology must be elucidated. The aim of this study was to investigate the possible mechanism of mediator complex subunit 12 (human: MED12, mouse: Med12)involvement in AD. Firstly, we examined the expression of MED12 protein (human: MED12, mouse: Med12) in the aortic tissues of AD patients and AD mice. Subsequently, Med12 gene silencing was accomplished with RNA interference (siRNA). The effects of Med12 on AD and the possible biological mechanisms were investigated based on the proliferation, senescence, phenotypic transformation, and its involved signal pathway of mouse aortic smooth muscle cells (MOVAS), s. The results show that the expression of MED12 in the aortae of AD patients and AD mice was decreased. Moreover, the downregulation of Med12 inhibited the proliferation of MOVAS and promoted senescence. Further research found that Med12, as an inhibitor of the TGFß1 signaling pathway, reduced the expression of Med12 and enhanced the activity of the TGFß1 nonclassical signaling pathway, while TGFß1 inhibited the phenotype transformation and proliferation of MOVAS by inhibiting Med12 synthesis. In conclusion, Med12 affected the phenotype, proliferation, and senescence of MOVAS through the TGFß signaling pathway. This study provides a potential new target for the prevention and treatment of AD.

Genetic association analysis between IL9 and coronary artery disease in a Chinese Han population.

Interleukin-9 (IL-9) plays important role in coronary artery disease (CAD). However, the exact relationship between them is not explored yet. Here, four tag SNPs covering IL9 (rs31563, rs2069868, rs2069870 and rs31564) were selected to conduct case-control association analyses in a total of 3704 individuals from Chinese Han population (1863 CAD vs 1841 control). Results showed that: first, rs2069868 was associated with CAD combined with hypertension (Padj = 0.027); second, IL9 haplotype (CGAT) was associated with CAD (Padj = 0.035), and the combination genotype of "rs31563_CC/rs31564_TT" would remarkably decrease the risk of CAD (Padj = 0.001); third, significant associations were found between rs2069870 and decreased LDL-c levels and decreased total cholesterol levels, and between rs31563 and increased HDL-c levels (Padj < 0.05). Therefore, we conclude that IL9 might play a causal role in CAD by interacted with CAD traditional risk factors, which might confer a new way to improve the prevention and treatment of CAD.

Effects of Insomnia on Peptic Ulcer Disease Using Mendelian Randomization.

OBJECTIVES: Observational studies indicate that insomnia may increase risk of peptic ulcer disease (PUD). Our purpose is to clarify the possible causal relationship between insomnia and PUD by Mendelian randomization analyses. METHODS: We carried out analyses using summary statistics data for genetic variants reported from a GWAS of insomnia (N = up to 1,331,010 individuals) and from a GWAS of PUD (N = up to 456,327 individuals). Three Mendelian randomization approaches were used to explore whether insomnia might play a causal role in PUD, and pathway and functional enrichment analyses were conducted to anticipate the underlying mechanisms. RESULTS: Conventional Mendelian randomization analysis showed clear causality between insomnia and PUD; 1 SD increased insomnia incident was related to a 19% higher risk of PUD (P = 6.69 × 10-16; OR, 1.19 (95% CI, 1.14-1.24)). The associations between insomnia and PUD were consistent in the other two analyses performed using the weighted median method (P = 7.75 × 10-7; OR, 1.16 (95% CI, 1.09-1.23)) and MR-Egger regression (P = 5.00 × 10-3; OR, 1.27 (95% CI, 1.07-1.50)). Moreover, no evidence indicated a reverse causality between PUD events and insomnia symptoms. Pathway and functional enrichment analyses indicated that the mechanisms of insomnia effect on PUD may be through various ways, such as the immune system and oxidative stress. CONCLUSIONS: This Mendelian randomization study suggests insomnia as a causal risk factor for PUD. The potential mechanisms included may be immune and oxidative stress. These findings indicate that improving sleep quality could have substantial health benefits.

Causal Association between Periodontal Diseases and Cardiovascular Diseases.

Observational studies have revealed that dental diseases such as periodontitis and dental caries increase the risk of cardiovascular diseases (CVDs). However, the causality between periodontal disease (PD) and CVDs is still not clarified. In the present study, two-sample Mendelian randomization (MR) studies were carried out to assess the association between genetic liability for periodontal diseases (dental caries and periodontitis) and major CVDs, including coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), and stroke-including ischemic stroke as well as its three main subtypes-based on large-scale genome-wide association studies (GWASs). Our two-sample MR analyses did not provide evidence for dental caries and periodontitis as the causes of cardiovascular diseases; sensitivity analyses, including MR-Egger analysis and weighted median analysis, also supported this result. Gene functional annotation and pathway enrichment analyses indicated the common pathophysiology between cardiovascular diseases and periodontal diseases. The associations from observational studies may be explained by shared risk factors and comorbidities instead of direct consequences. This also suggests that addressing the common risk factors-such as reducing obesity and improving glucose tolerance-could benefit both conditions.

Genetic Regulation of the Thymic Stromal Lymphopoietin (TSLP)/TSLP Receptor (TSLPR) Gene Expression and Influence of Epistatic Interactions Between IL-33 and the TSLP/TSLPR Axis on Risk of Coronary Artery Disease.

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10-5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10-7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10-6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant (Padj = 6.99 × 10-4, OR = 4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj = 3.67 × 10-4, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.