| 1. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 2. |
- 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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| 3. |
- Han, Shengyi, et al.
(författare)
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Probiotic Gastrointestinal Transit and Colonization After Oral Administration : A Long Journey
- 2021
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 11
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Forskningsöversikt (refereegranskat)abstract
- Orally administered probiotics encounter various challenges on their journey through the mouth, stomach, intestine and colon. The health benefits of probiotics are diminished mainly due to the substantial reduction of viable probiotic bacteria under the harsh conditions in the gastrointestinal tract and the colonization resistance caused by commensal bacteria. In this review, we illustrate the factors affecting probiotic viability and their mucoadhesive properties through their journey in the gastrointestinal tract, including a discussion on various mucosadhesion-related proteins on the probiotic cell surface which facilitate colonization.
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| 4. |
- Lin, Hao, et al.
(författare)
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Stable and efficient hybrid Ag-In-S/ZnS@SiO2-carbon quantum dots nanocomposites for white light-emitting diodes
- 2020
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Ingår i: Chemical Engineering Journal. - : Elsevier. - 1385-8947 .- 1873-3212. ; 393
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Tidskriftsartikel (refereegranskat)abstract
- As a promising energy-saving technique, the eco-friendly and low-cost solid-state white light-emitting diodes (WLEDs) based on quantum dots (QDs) have been widely studied. Herein, a WLED device prepared by core-shell structure nanocomposites based on Ag-In-S/ZnS@SiO2 quantum dots (AIS@SiO2) and carbon quantum dots (CDs) was successfully constructed. CDs were combined onto the surface of AIS@SiO2 QDs to synthesize Ag-In-S/ZnS@SiO2-Carbon quantum dots (AIS-CDs) nanocomposites with a white-light emission, which successfully overcome the quenching effect of CDs induced by conventional aggregation. The as-prepared AIS-CDs nanocomposites presented high stability and a photoluminescence quantum yield (PLQY) of 35%. Moreover, the corresponding AIS-CDs nanocomposites-based WLEDs demonstrated the color coordinate of (0.32, 0.33), which is comparable to the pure white light (0.33, 0.33); furthermore, the luminous efficiency of the as-prepared WLEDs showed 15.1 lm W-1. These results reported herein may open up a new avenue for the development of high-performance, low-cost, and environmentally-friendly WLEDs.
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| 5. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 6. |
- Shi, Yuanping, et al.
(författare)
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Comprehensive lipidomics in apoM−/− mice reveals an overall state of metabolic distress and attenuated hepatic lipid secretion into the circulation
- 2020
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Ingår i: Journal of Genetics and Genomics. - : Elsevier BV. - 1673-8527. ; 47:9, s. 523-534
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein M (apoM) participates in both high-density lipoprotein and cholesterol metabolism. Little is known about how apoM affects lipid composition of the liver and serum. In this study, we systemically investigated the effects of apoM on liver and plasma lipidomes and how apoM participates in lipid cycling, via apoM knockout in mice and the human SMMC-7721 cell line. We used integrated mass spectrometry–based lipidomics approaches to semiquantify more than 600 lipid species from various lipid classes, which include free fatty acids, glycerolipids, phospholipids, sphingolipids, glycosphingolipids, cholesterol, and cholesteryl esters (CEs), in apoM−/− mouse. Hepatic accumulation of neutral lipids, including CEs, triacylglycerols, and diacylglycerols, was observed in apoM−/− mice; while serum lipidomic analyses showed that, in contrast to the liver, the overall levels of CEs and saturated/monounsaturated fatty acids were markedly diminished. Furthermore, the level of ApoB-100 was dramatically increased in the liver, whereas significant reductions in both ApoB-100 and low-density lipoprotein (LDL) cholesterol were observed in the serum of apoM−/− mice, which indicated attenuated hepatic LDL secretion into the circulation. Lipid profiles and proinflammatory cytokine levels indicated that apoM−/− leads to hepatic steatosis and an overall state of metabolic distress. Taken together, these results revealed that apoM knockout leads to hepatic steatosis, impaired lipid secretion, and an overall state of metabolic distress.
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| 7. |
- Song, Jie, et al.
(författare)
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THE IMPACT OF EDUCATIONAL ATTAINMENT, INTELLIGENCE AND INTELLECTUAL DISABILITY ON SCHIZOPHRENIA : A SWEDISH POPULATION-BASED REGISTER AND GENETIC STUDY
- 2021
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Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 51, s. e137-e138
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Schizophrenia (SCZ) is highly heterogenous and no subtypes have been established to have good clinical utility in characterizing treatment response or longitudinal course. Cognitive impairment is one of the core clinical features of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive ability is complex, with limited studies of comprehensive epidemiological and genomic evidence.Methods: To comprehensively examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two samples from Sweden: a national cohort (13 738 SCZ cases and 3 677 172 controls) and a subsample with comprehensive genetic data (4 992 cases and 6 009 controls).Results: Population-based analyses showed worse cognition as risk factors for SCZ, and the pedigree genetic correlations between them were comparable with estimations from common genetic variants. In the genotyped subsample, premorbid cognitive ability and EDU were associated positively with their genetic risk score (GRS) and negatively with total number of rare exonic variants. The total size of copy number variants (CNV) deletions was associated with premorbid cognitive ability in controls. Finally, by applying an empirical clustering method, we dissect SCZ cases into four subgroups, defined by sex and ID. In particular, female cases with ID showed higher suicide-related events in the population cohort, and male-ID cases in genetic subsample had higher CNV and rare exonic burdens.Discussion: In conclusion, we found extensive evidence of a robust relation between cognitive ability and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.
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| 8. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 9. |
- Zhang, Wei, et al.
(författare)
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Tannic acid-mediated dual peptide-functionalized scaffolds to direct stem cell behavior and osteochondral regeneration
- 2020
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Ingår i: Chemical Engineering Journal. - : Elsevier. - 1385-8947 .- 1873-3212. ; 396
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Tidskriftsartikel (refereegranskat)abstract
- The development of cell-instructive scaffolds, which provide biochemical cues to direct endogenous bone marrow-derived mesenchymal stem cells (BMSCs) behavior, has the potential to revolutionize osteochondral tissue engineering. However, scaffold material itself is generally lacking the inductive signals. Here, a novel peptide-functionalized scaffold was prepared by prime-coating Ca-alginate scaffold with tannic acid (TA) followed by conjugation of E7/P15 peptides (CA-TA-E7/P15). The system leveraged TA as a reactive intermediate between Ca-alginate and peptides due to the multiple functional groups of TA. These interactions induced by TA prime-coating contributed to enhanced scaffold stability and mechanical properties, increased peptide conjugation and sustained release of peptides without affecting their bioactivity, in a TA concentration-dependent manner. The conjugation of E7/P15 peptides endowed the scaffold with the potential to enhance BMSCs recruitment and deposition of cartilage and bone extracellular matrix (ECM). Furthermore, the prepared CA-TA-E7/P15 scaffold showed a promoted biological performance of simultaneous cartilage and subchondral bone regeneration in rabbit osteochondral defect model. These findings indicate that TA is an effective surface modification intermediate and crosslinking aid, and that the CA-TA-E7/P15 scaffold developed in this study serves as a promising cell-instructive scaffold for osteochondral regeneration.
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