| 1. |
- Kato, Norihiro, et al.
(författare)
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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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| 2. |
- Xiang, Yusen, et al.
(författare)
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Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay
- 2023
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Ingår i: International Journal of Biological Macromolecules. - : Elsevier. - 0141-8130 .- 1879-0003. ; 226, s. 780-792
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Tidskriftsartikel (refereegranskat)abstract
- Targeting the interaction between the spike protein receptor binding domain (S-RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2) is a potential therapeutic strategy for treating coronavirus disease 2019 (COVID-19). However, we still lack small-molecule drug candidates for this target due to the missing knowledge in the hot spots for the protein-protein interaction. Here, we used NanoBiT technology to identify three Ginkgolic acids from an in-house traditional Chinese medicine (TCM) library, and they interfere with the S-RBD/ACE2 interplay. Our pseudovirus assay showed that one of the compounds, Ginkgolic acid C17:1 (GA171), significantly inhibits the entry of original SARS-CoV-2 and its variants into the ACE2-overexpressed HEK293T cells. We investigated and proposed the binding sites of GA171 on S-RBD by combining molecular docking and molecular dynamics simulations. Site-directed mutagenesis and surface plasmon resonance revealed that GA171 specifically binds to the pocket near R403 and Y505, critical residues of S-RBD for S-RBD interacting with ACE2. Thus, we provide structural insights into developing new small-molecule inhibitors and vaccines against the proposed S-RBD binding site.
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| 3. |
- Yuan, Shuai, et al.
(författare)
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Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- Background: To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy.Methods: The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue -specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence.Findings: PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects.Interpretation: This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoim-mune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects.
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| 4. |
- Cheng, Ye, et al.
(författare)
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Genetic variants in the HLA region contribute to the risk of cerebral palsy
- 2024
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Ingår i: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE. - 0925-4439 .- 1879-260X. ; 1870:3
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral palsy (CP) is the most common physical disability in childhood, and genetic factors play an important role in its pathogenesis. However, the genetic contributions remain incompletely elucidated. Here, we conducted a two-stage association study between 1090 CP cases and 1100 healthy controls after whole exome sequencing. The human leukocyte antigen (HLA) allelic predispositions were further analyzed in overall CP and subgroups using multivariate logistic regression. We found a strong signal in the HLA region on chromosome 6, where rs3131787 harbored the most significant association with CP (P = 2.05 x 10-14, OR = 2.22). In comparison to controls, the carrier frequencies of HLA-B*13:02 were significantly higher in children with CP (9.82 % in control vs 19.27 % in CP, P = 1.03 x 10-4, OR = 2.17). Furthermore, the effect of HLA-B*13:02 on increasing the risk of CP mainly existed in cryptogenic CP without exposure to premature birth, low birth weight, birth asphyxia, or periventricular leukomalacia. This study indicated a strong association of HLA variants with CP, which implied that immune dysregulation resulting from immunogenetic variants might underlie the pathogenesis of CP. Our findings provide genetic evidence that an immunomodulator may serve as a promising therapeutic intervention for patients with CP by reinstating the neuroinflammation hemostasis.
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| 5. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 6. |
- de Vries, Paul S., et al.
(författare)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Tidskriftsartikel (refereegranskat)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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| 7. |
- Ding, Yunmei, et al.
(författare)
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Factors influencing kinesiophobia during the “blanking period” after radiofrequency catheter ablation in patients with atrial fibrillation by the fear-avoidance model
- 2022
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 363, s. 49-55
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Tidskriftsartikel (refereegranskat)abstract
- Background: The influencing factors of kinesiophobia (fear of movement) in patients with atrial fibrillation(AF)during the post-operative “Blanking Period” are not known. The aims were to investigate the status of kinesiophobia in patients with AF during the post-operative “Blanking Period”, then further describe the occurrence and analyze the influencing factors of patients' kinesiophobia by the Fear-Avoidance Model. Materials and methods: In total,400 patients diagnosed with atrial fibrillation, during the post-operative “Blanking Period” from the selected hospital were included in this study. The Tampa Scale for Kinesiophobia Heart (TSK-SV Heart), the Self-efficacy for Exercise (SEE) scale, and the Geriatric Locomotive Function Scale (GLFS) were used to assess kinesiophobia, exercise self-efficacy, and physical function. The study adopted a cross-sectional design. Results: The score of kinesiophobia during the “Blanking Period” after operation in patients with atrial fibrillation was (44.06 ± 10.77), and the rate of high kinesiophobia was 71.61%.Logistic regression results showed that age, education, household monthly income, resting heart rate, EHRA symptom classification, exercise self-efficacy, and physical function influenced the kinesiophobia of patients during the post-operative “Blanking Period”(p<0.05， p<0.01). Conclusions: Kinesiophobia is common in patients with atrial fibrillation during the postoperative “Blanking Period”, and the fear of movement is related to age, education, household monthly income, resting heart rate, EHRA symptom classification, exercise self-efficacy, and physical function. Clinical and nursing staff should pay close attention to the psychological problems in the post-operation “Blanking Period” of exercise rehabilitation in patients with atrial fibrillation, make timely interventions to reduce patients' fear of movement, and improve patients' compliance with exercise rehabilitation.
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| 8. |
- Ding, Yunmei, et al.
(författare)
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Factors influencing self-management behavior during the “Blanking Period” in patients with atrial fibrillation : A cross-sectional study based on the information-motivation-behavioral skills model
- 2023
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Ingår i: Heart and Lung. - : Elsevier BV. - 0147-9563. ; 58, s. 62-68
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Tidskriftsartikel (refereegranskat)abstract
- Background: Atrial fibrillation (AF) is becoming increasingly common. Effective self-management during the “Blanking Period” is critical. The Information-Motivation-Behavioral skills (IMB) model can be used to study health behaviors in chronic disease patients, but it has not been studied in AF patients. Objective: The goal of this study was to explore the influencing factors and interaction pathways of self-management behavior in AF patients during the "Blanking Period" using the IMB model. Methods: From June to December 2021, a cross-sectional design was conducted. Patients with AF during the "Blanking Period" (N=220) were recruited. They filled out several quantitative questionnaires, including the Jessa Atrial Fibrillation Knowledge Questionnaire, the Confidence in Atrial Fibrillation Management Scale, the Perceived Social Support Scale, the All Aspects of Health Literacy Scale, and the Self-care Scale for Chronic Atrial Fibrillation Patients. Data were analyzed using correlation analysis, multiple regression analysis, and path analysis. Results: Total score of self-management behavior was (33.83 ± 10.66). AF knowledge (β = 0.252, P < 0.001), self-management confidence (β = 0.219, P < 0.001), social support (β = 0.291, P < 0.001), and health literacy (β = 0.262, P < 0.001) were all positively correlated with patients' self-management behavior, accounting for 66.50 percent of the total variance. Conclusions: During the "Blanking Period", the IMB model can be used to predict the factors that influence self-management behavior in AF patients. By using IMB model, interventions targeting patient-specific influencing factors could improve self-management behavior and quality of life in AF patients.
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| 9. |
- Ding, Yun Mei, et al.
(författare)
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Effect of social support on illness perception in patients with atrial fibrillation during “Blanking Period” : Mediating role of sense of mastery
- 2023
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Ingår i: Nursing Open. - : Wiley. - 2054-1058. ; 10:1, s. 115-122
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To explore whether sense of mastery can mediate the relationship between social support and illness perception in patients with atrial fibrillation (AF) who were at the “Blanking Period.”. Design: A cross-sectional design. Methods: 405 patients with AF who were at the “Blanking Period” in the Affiliated Hospital of Qingdao University were recruited; they completed a set of questionnaires, including the Perceived Social Support Scale, the Personal Mastery Scale and the Brief Illness Perception Questionnaire. Results: Social support and sense of mastery were both adversely connected to illness perception. The indirect effect of social support on illness perception through sense of mastery was negative, accounting for 86.04% of the total effect. Conclusion: During the “Blanking Period,” better social support and sense of mastery contribute to a positive illness perception of AF patients. Social support also can influence patients' illness perception indirectly via the mediator of sense of mastery.
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| 10. |
- Feitosa, Mary F., et al.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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