| 1. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 2. |
- Wang, Ningjian, et al.
(författare)
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Long-term night shift work is associated with the risk of atrial fibrillation and coronary heart disease
- 2021
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:40, s. 4180-
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Tidskriftsartikel (refereegranskat)abstract
- AimsThe aim of this study was to test whether current and past night shift work was associated with incident atrial fibrillation (AF) and whether this association was modified by genetic vulnerability. Its associations with coronary heart disease (CHD), stroke, and heart failure (HF) were measured as a secondary aim.Methods and resultsThis cohort study included 283657 participants in paid employment or self-employed without AF and 276009 participants free of CHD, stroke, and HF at baseline in the UK Biobank. Current and lifetime night shift work information was obtained. Cox proportional hazard models were used. Weighted genetic risk score for AF was calculated. During a median follow-up of 10.4years, 5777 incident AF cases were documented. From 'day workers', 'shift but never/rarely night shifts', and 'some night shifts' to 'usual/permanent night shifts', there was a significant increasing trend in the risk of incident AF (P for trend 0.013). Usual or permanent night shifts were associated with the highest risk [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.02-1.32]. Considering a person's lifetime work schedule and compared with shift workers never working nights, participants with a duration over 10years and an average 3-8 nights/month frequency of night shift work exposure possessed higher AF risk (HR 1.18, 95% CI 0.99-1.40 and HR 1.22, 95% CI 1.02-1.45, respectively). These associations between current and lifetime night shifts and AF were not modified by genetic predisposition to AF. Usual/permanent current night shifts, >= 10years and 3-8 nights/month of lifetime night shifts were significantly associated with a higher risk of incident CHD (HR 1.22, 95% CI 1.11-1.35, HR 1.37, 95% CI 1.20-1.58 and HR 1.35, 95% CI 1.18-1.55, respectively). These associations in stroke and HF were not significant.ConclusionBoth current and lifetime night shift exposures were associated with increased AF risk, regardless of genetic AF risk. Night shift exposure also increased the risk of CHD but not stroke or HF. Whether decreasing night shift work frequency and duration might represent another avenue to improve heart health during working life and beyond warrants further study.
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| 3. |
- Li, Doudou, et al.
(författare)
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Gut microbiota-derived metabolite trimethylamine-N-oxide and multiple health outcomes : an umbrella review and updated meta-analysis
- 2022
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Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press. - 0002-9165 .- 1938-3207. ; 116:1, s. 230-243
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Forskningsöversikt (refereegranskat)abstract
- Background: Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO concentrations are linked to a wide range of health outcomes.Objectives: This study aimed to summarize health outcomes related to circulating TMAO concentrations.Methods: We searched the Embase. Medline, Web of Science, and Scopus databases from inception to 15 February, 2022 to identify and update meta-analyses examining the associations between 'TAO and multiple health outcomes. For each health outcome, we estimated the summary effect size. 95% prediction CI. between-study heterogeneity. evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate the evidence credibility of the identified associations.Results: This umbrella review identified 24 meta-analyses that investigated the association between circulating 'TAO concentrations and health outcomes including all-cause mortality, cardiovascular diseases (CVDs), diabetes mellitus (DM), cancer. and renal function. We updated these meta-analyses by including a total of 82 individual studies on 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found 6 (33%) associations (i.e., all-cause mortality, CVD mortality, major adverse cardiovascular events, hypertension. DM, and glomerular filtration rate) to present highly suggestive evidence.Conclusions: TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension. CVD, DM. cancer, and kidney function. Further studies are needed to investigate whether circulating 'MAO concentrations could be an intervention target for chronic disease.
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| 4. |
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| 5. |
- Sui, Yu fei, et al.
(författare)
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Engineering cofactor metabolism for improved protein and glucoamylase production in Aspergillus niger
- 2020
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Ingår i: Microbial Cell Factories. - : Springer Science and Business Media LLC. - 1475-2859. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nicotinamide adenine dinucleotide phosphate (NADPH) is an important cofactor ensuring intracellular redox balance, anabolism and cell growth in all living systems. Our recent multi-omics analyses of glucoamylase (GlaA) biosynthesis in the filamentous fungal cell factory Aspergillus niger indicated that low availability of NADPH might be a limiting factor for GlaA overproduction. Results: We thus employed the Design-Build-Test-Learn cycle for metabolic engineering to identify and prioritize effective cofactor engineering strategies for GlaA overproduction. Based on available metabolomics and 13C metabolic flux analysis data, we individually overexpressed seven predicted genes encoding NADPH generation enzymes under the control of the Tet-on gene switch in two A. niger recipient strains, one carrying a single and one carrying seven glaA gene copies, respectively, to test their individual effects on GlaA and total protein overproduction. Both strains were selected to understand if a strong pull towards glaA biosynthesis (seven gene copies) mandates a higher NADPH supply compared to the native condition (one gene copy). Detailed analysis of all 14 strains cultivated in shake flask cultures uncovered that overexpression of the gsdA gene (glucose 6-phosphate dehydrogenase), gndA gene (6-phosphogluconate dehydrogenase) and maeA gene (NADP-dependent malic enzyme) supported GlaA production on a subtle (10%) but significant level in the background strain carrying seven glaA gene copies. We thus performed maltose-limited chemostat cultures combining metabolome analysis for these three isolates to characterize metabolic-level fluctuations caused by cofactor engineering. In these cultures, overexpression of either the gndA or maeA gene increased the intracellular NADPH pool by 45% and 66%, and the yield of GlaA by 65% and 30%, respectively. In contrast, overexpression of the gsdA gene had a negative effect on both total protein and glucoamylase production. Conclusions: This data suggests for the first time that increased NADPH availability can indeed underpin protein and especially GlaA production in strains where a strong pull towards GlaA biosynthesis exists. This data also indicates that the highest impact on GlaA production can be engineered on a genetic level by increasing the flux through the pentose phosphate pathway (gndA gene) followed by engineering the flux through the reverse TCA cycle (maeA gene). We thus propose that NADPH cofactor engineering is indeed a valid strategy for metabolic engineering of A. niger to improve GlaA production, a strategy which is certainly also applicable to the rational design of other microbial cell factories.[Figure not available: see fulltext.].
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| 6. |
- 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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| 7. |
- Zhang, Haojie, et al.
(författare)
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Sleep Patterns, Genetic Susceptibility, and Incident Chronic Kidney Disease : A Prospective Study of 370 671 Participants
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesUnhealthy sleep behaviors may be potential risk factors for chronic kidney disease (CKD). We aimed to examine the associations of combined sleep patterns and genetic susceptibility with incident CKD. MethodsThis large-scale prospective cohort study included 370,671 participants without CKD at baseline (2006-2010) in UK Biobank data. Five sleep behaviors were made up of sleep duration, insomnia, snoring, chronotype, and daytime sleepiness according to questionnaire. Overall sleep patterns by summing the five scores were created. Weighted genetic risk score of kidney function was calculated. Incident CKD was recorded from death register, primary care, and hospital inpatient records. A subset of 41,130 individuals who participated both the initial assessment visit and follow-up visit (2012+) was also used. ResultsDuring a median follow-up of 10.6 years (about 3.9 million person-years), we documented 6,365 patients with incident CKD. In five sleep behaviors, sleep 7-8 h/day, free of insomnia and no frequent daytime sleepiness were independently associated with incident CKD, with a 12% (95%CI 7-16), 9% (3-14), 13% (9-18) lower risk, respectively. Compared to those with a sleep score of 0-1, participants with a score of 5 had a 21% (10-31%) lower risk of CKD. 17.1% of CKD in this cohort could be attributed to total poor sleep pattern. Participants with high genetic risk and intermediate or poor sleep pattern showed the highest risk of CKD (OR = 2.58, 95%CI 2.24-2.96; OR = 2.59, 95%CI 2.02-3.32, respectively), although there was no significant interaction between sleep patterns and genetic risk categories. Among individuals who participated both the initial assessment visit and follow-up visit, we found that the association between amelioration of sleep pattern and risk of CKD was significant after fully adjustment (OR = 0.60, 95%CI 0.36-0.99), compared with group of stable sleep pattern. ConclusionIn this large prospective study, participants with a healthy sleep pattern was associated with a significant reduction of incident CKD risk no matter they had a high, intermediate, or low genetic risk.
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