OBJECTIVE: N6-methyladenosine (m ⁶A) is a common epigenetic modification in eukaryotes. In this study, we explore the potential impact of m ⁶A-associated single nucleotide polymorphisms (m ⁶A-SNPs) on heart failure (HF). METHODS: Data from genome-wide association studies (GWAS) investigating HF in humans and from m ⁶A-SNPs datasets were used to identify HF-associated m ⁶A-SNPs. Their functions were explored using expression quantitative trait locus (eQTL), gene expression, and gene enrichment analyses. Mediation protein quantitative trait locus (pQTL)-Mendelian randomization (MR) was used to investigate the potential mechanism between critical protein levels and risk factors for HF. RESULTS: We screened 44 HF-associated m ⁶A-SNPs, including 10 m ⁶A-SNPs that showed eQTL signals and differential expressions in HF. The SNP rs1801270 in CDKN1A showed the strongest association with HF ( P = 7.75 × 10 ^-6). Additionally, MR verified the genetic association between the CDKN1A protein and HF, as well as the mediating effect of blood pressure (BP) in this pathway. Higher circulating level of CDKN1A was associated with a lower risk of HF (odds ratio [ OR] = 0.82, 95% confidence interval [ CI]: 0.69 to 0.99). The proportions of hypertension, systolic BP, and diastolic BP were 48.10%, 28.94%, and 18.02%, respectively. Associations of PDIA6 ( P = 1.30 × 10 ^-2) and SMAD3 ( P = 4.80 × 10 ^-2) with HF were also detected. CONCLUSION Multiple HF-related m ⁶A-SNPs were identified in this study. Genetic associations of CDKN1A and other proteins with HF and its risk factors were demonstrated, providing new ideas for further exploration of the molecular mechanisms of HF.
Humans ; Polymorphism, Single Nucleotide ; Heart Failure/genetics* ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Cyclin-Dependent Kinase Inhibitor p21/metabolism* ; Quantitative Trait Loci ; Adenosine/metabolism* ; Male ; Female ; Genetic Predisposition to Disease

Background::Genome-wide association studies (GWAS) have identified more than a thousand loci for blood pressure (BP). Functional genes in these loci are cell-type specific. The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification-associated single-nucleotide polymorphisms (RNAm-SNPs).Methods::Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium, we identified associations between RNAm-SNPs and BP. The association between RNAm-SNPs, gene expression, and BP were examined.Results::A total of 355 RNAm-SNPs related to m 6A, m 1A, m 5C, m 7G, and A-to-I modification were associated with BP. The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway. The BP GWAS signals were significantly enriched with m 6A-SNPs, highlighting the potential functional relevance of m 6A in physiological processes influencing BP. Notably, m 6A-SNPs in CYP11B1, PDE3B, HDAC7, ACE, SLC4A7, PDE1A, FRK, MTHFR, NPPA, CACNA1D, and HDAC9 were identified. Differential methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were detected. RNAm-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection (AD) cases and controls. In scRNA-seq study, we identified ARID5A, HLA-DPB1, HLA-DRA, IRF1, LINC01091, MCL1, MLF1, MLXIPL, NAA16, NADK, RERG, SRM, and USP53 as differential expression genes for AD in aortic cells. Conclusion::The present study identified RNAm-SNPs in BP loci and elucidated the associations between the RNAm-SNPs, gene expression, and BP. The identified BP-associated genes in aortic cells were associated with AD.

Background::Genome-wide association studies (GWAS) have identified more than a thousand loci for blood pressure (BP). Functional genes in these loci are cell-type specific. The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification-associated single-nucleotide polymorphisms (RNAm-SNPs).Methods::Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium, we identified associations between RNAm-SNPs and BP. The association between RNAm-SNPs, gene expression, and BP were examined.Results::A total of 355 RNAm-SNPs related to m 6A, m 1A, m 5C, m 7G, and A-to-I modification were associated with BP. The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway. The BP GWAS signals were significantly enriched with m 6A-SNPs, highlighting the potential functional relevance of m 6A in physiological processes influencing BP. Notably, m 6A-SNPs in CYP11B1, PDE3B, HDAC7, ACE, SLC4A7, PDE1A, FRK, MTHFR, NPPA, CACNA1D, and HDAC9 were identified. Differential methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were detected. RNAm-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection (AD) cases and controls. In scRNA-seq study, we identified ARID5A, HLA-DPB1, HLA-DRA, IRF1, LINC01091, MCL1, MLF1, MLXIPL, NAA16, NADK, RERG, SRM, and USP53 as differential expression genes for AD in aortic cells. Conclusion::The present study identified RNAm-SNPs in BP loci and elucidated the associations between the RNAm-SNPs, gene expression, and BP. The identified BP-associated genes in aortic cells were associated with AD.

Background::High sodium intake is an important risk factor for hypertension and cardiovascular disease. However, the association between gut microbiota composition and metabolomic profiles with dietary sodium intake and blood pressure (BP) is not well-understood. The metabolome, microbiome, and dietary salt intervention (MetaSalt) study aimed to investigate microbial and metabolomic profiles related to dietary sodium intake and BP regulation.Methods::This family-based intervention study was conducted in four communities across three provinces in rural northern China in 2019. Probands with untreated prehypertension or stage-1 hypertension were identified through community-based BP screening, and family members including siblings, offspring, spouses, and parents were subsequently included. All participants participated in a 3-day baseline examination with usual diet consumption, followed by a 10-day low-salt diet (3 g/d of salt or 51.3 mmol/d of sodium) and a 10-day high-salt diet (18 g/d of salt or 307.8 mmol/d of sodium). Differences in mean BP levels were compared according to the intervention phases using a paired Student's t-test.Results::A total of 528 participants were included in this study, with a mean age of 48.1 years, 36.7% of whom were male, 76.8% had a middle school (69.7%) or higher (7.1%) diploma, 23.4% had a history of smoking, and 24.4% were current drinkers. The mean arterial pressure at baseline was 97.2 ± 10.5 mm Hg for all participants, and significantly decreased during the low-salt intervention (93.8 ± 9.3, P < 0.0001) and subsequently increased during the high-salt intervention (96.4 ± 10.0, P < 0.0001). Conclusions::Our dietary salt intervention study has successfully recruited participants and will facilitate to evaluate the effects of gut microbiota and metabolites on BP regulation in response to sodium burden, which will provide important evidence for investigating the underlying mechanisms in the development of hypertension and subsequent cardiovascular diseases.Trial registration::The study was registered in the Chinese Clinical Trial Registry database (ChiCTR1900025171).

Background::High sodium intake is an important risk factor for hypertension and cardiovascular disease. However, the association between gut microbiota composition and metabolomic profiles with dietary sodium intake and blood pressure (BP) is not well-understood. The metabolome, microbiome, and dietary salt intervention (MetaSalt) study aimed to investigate microbial and metabolomic profiles related to dietary sodium intake and BP regulation.Methods::This family-based intervention study was conducted in four communities across three provinces in rural northern China in 2019. Probands with untreated prehypertension or stage-1 hypertension were identified through community-based BP screening, and family members including siblings, offspring, spouses, and parents were subsequently included. All participants participated in a 3-day baseline examination with usual diet consumption, followed by a 10-day low-salt diet (3 g/d of salt or 51.3 mmol/d of sodium) and a 10-day high-salt diet (18 g/d of salt or 307.8 mmol/d of sodium). Differences in mean BP levels were compared according to the intervention phases using a paired Student's t-test.Results::A total of 528 participants were included in this study, with a mean age of 48.1 years, 36.7% of whom were male, 76.8% had a middle school (69.7%) or higher (7.1%) diploma, 23.4% had a history of smoking, and 24.4% were current drinkers. The mean arterial pressure at baseline was 97.2 ± 10.5 mm Hg for all participants, and significantly decreased during the low-salt intervention (93.8 ± 9.3, P < 0.0001) and subsequently increased during the high-salt intervention (96.4 ± 10.0, P < 0.0001). Conclusions::Our dietary salt intervention study has successfully recruited participants and will facilitate to evaluate the effects of gut microbiota and metabolites on BP regulation in response to sodium burden, which will provide important evidence for investigating the underlying mechanisms in the development of hypertension and subsequent cardiovascular diseases.Trial registration::The study was registered in the Chinese Clinical Trial Registry database (ChiCTR1900025171).

Objective To study clinical value of percutaneous intrabiliary expandable metallic biliary stenting (EMBS) for treatment of malignant obstructive jaundice. Methods One hundred and sixty patients with malignant obstructive jaundice were treated with EMBS ( EMBS group) . Thirty patients underwent only external drainage by PTCD were recruited as control. The patency rate of stent,decline of bilirubin and the complication were analyzed retrospectively. Both groups were followed up for three months. The Kaplan-Meier method (log-rank test) was used to compare the survival period between the two groups. Results Anorexia,skin pruritus and color of urine alleviated at a certain degree in both groups.In the EMBS group,plasma total bilirubin was(218. 78 ±2. 29) μmol/L pre-stent,and decreased to (134. 90 ±2. 34), (83. 18 ±2.40) , (40. 74 ±2. 29) μmol/L at the 7,14,21 days after the stenting, respectively; direct bilirubin was (128.82 ±2.40) μmol/L pre-stent, and decreased to (81.28 ± 2. 34), (51. 29 ±2. 45) and (25. 70 ±2.40)μmol/L at the 7,14,21 days after the stenting ( P =0. 000). In the PTCD group,plasma total bilirubin was (223. 57 ± 2. 58) μmol/L pe-stent, and decreased to ( 145. 68 ± 2. 57 ) ,(87.57 ±2.58) ,(38.65 ±2. 20) μmol/L at the 7,14,21 days after the stenting,respectively;direct bilirubin was (127. 6 ±2. 59)μmol/L pre-stent,and decreased to (79. 78 ±2. 70) ,(58. 36 ±2. 46) and (29.46 ±2. 20)μmol/L at the 7,14,21 days after the stenting,respectively ( P <0.001 ). No significant difference was found between the two groups at any time point ( P > 0. 05). Complications occurred in 34 patients in the EMBS group and the incidence rate was 20. 62% . Two or more complications occurred in 9 patients. In the PTCD group, complications occurred in 60.00% of the patients. In the EMBS group, 14 patients were failed to follow up, and 136 died. The median length was 214 days. In the PTCD group,all patients were followed up and all died,with a median length of survival of 75. 5 days. The survival analysis showed that the EMBS group survived longer than the PTCD group (P =0. 000). Conclusions EMBS placement showed better effect than PTCD. Compared to PTCD, internal drainage of metallic stents lead few complications and faster recover, and can improve the life quality and prolong survival time of patient with malignant obstructive jaundice. The placement of metallic stents is recommended as a preference for palliative therapy of malignant biliary obstruction.

Objective To assess the relationship between the polymorphisms of heme oxygenase-1 gene and blood pressure level.Methods With the whole-gene based tagging SNP approach,3 tag SNPs of heme oxygenase-1 gene were selected for study.These tag SNPs were genotyped in 503 essential hypertension cases Blood pressure lev-els among different genotypes of each SNP were compared with ANOVA.The haplo.stats program wa8 employed to test haplotype frequency with blood pressure level.Results Subjects with rs2071749 A allele had the lower blood pressure levels than subjects with GG genotypes(SBP:159.5 mm Hg vs.168.5 mm Hg and DBP:97.6 mm Hg vs.101.3 mm Hg respectively.P<0.05).In the haplotype analyses.Haplotype T-T-A which carried the rs2071749 A allele was found significantly associated with SBP and DBP after adjustment for age,gender,body mass index.8n10k.illg and drinking·Conclusion The genetic variants of heine oxygenase.1 gene misht be associated with blood pres-sure levels.

Objective To study the efficiency and safety of short-term combination therapy with e-tanercept, methotrexate and eyclophosphamide in the patients with active rheumatoid arthritis. Methods Eighty-four patients with rheumatoid arthritis were included into this study. However, only fifty-six patients were treated with either twice-weekly subcutaneous etanercept, weekly oral MTX and CTX injection every three weeks or twice-weekly subcutaneous etanercept only. The American College of Rheumamatology (ACR) criteria for improvement was used for clinical efficacy assessment and the following laboratory papameters were analyzed:blood routine test, ESR, liver enzymes and renal function parameters, RF and anti-CCP antibody at baseline and the 2,4,8,12,24,36,52 weeks .At the same time ,all the adverse events were monitored throughout the study. Results The improvement of patients who received etanercept shortly, MTX and CTX periodically was as rapid as that of the patients who only received etanercept in ACR20, ACRYO, ESR and CRP (P>0.05). At the end of 36 weeks treatment, the level of anti-CCP antibody in the control group was higher than that of the test group. There was no significant difference between the two groups in adverse events (P<0.05). Conclusion The efficacy and safety of treatment with etanercept, methotrexate and cyclophosphamide in the patients with active rheumatoid arthritis is good.

Objective To study the genome DNA methylation in SLE and the related factors of DNA methylation. Methods Twenty-six cases with SLE and 20 controls were recruited to participate the study. Plasma Hcy, SAM, SAH and the MTHFR gene C677T polymorphism were measured in all patients and controls. Results {1} The SAM levels were lower significantly in SLE groups than in controls. The SAH levels were higher significantly in SLE groups than in controls. {2} There was significant inverse correlation between plasma Hcy level and SAM level (r=-0.897, P

Objective To study the patients with ankylosing spondylitis (AS) complicated with Sjgren′s syndrome (SS).Method Five patients were diagnosed and clinical features were analyzed.Results The 5 patients (5 AS/SS) had a mean age 46 8 years (range 33～63) at onset of the disease, 1 male and 4 females.The main clinical features of patients with both AS and SS were axial inflammatory back pain,sacroiliitis,dry eyes and/or dry mouth.HLA B27 in 3 patients and RF in 2 patients was positive.Conclusion The coexistence of AS and SS can be seen in clinical works.