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| 2. |
- Mahajan, Anubha, et al.
(author)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Journal article (peer-reviewed)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 3. |
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| 4. |
- Tin, A, et al.
(author)
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Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 7173-
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Journal article (peer-reviewed)abstract
- Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
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| 5. |
- Schlosser, P, et al.
(author)
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Meta-analyses identify DNA methylation associated with kidney function and damage
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 7174-
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Journal article (peer-reviewed)abstract
- Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
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| 6. |
- Soininen, E.M., et al.
(author)
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Location of studies and evidence of effects of herbivory on Arctic vegetation: a systematic map
- 2021
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In: Environmental Evidence. - : BioMed Central (BMC). - 2047-2382. ; 10:1
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Journal article (peer-reviewed)abstract
- Background: Herbivores modify the structure and function of tundra ecosystems. Understanding their impacts is necessary to assess the responses of these ecosystems to ongoing environmental changes. However, the effects of herbivores on plants and ecosystem structure and function vary across the Arctic. Strong spatial variation in herbivore effects implies that the results of individual studies on herbivory depend on local conditions, i.e., their ecological context. An important first step in assessing whether generalizable conclusions can be produced is to identify the existing studies and assess how well they cover the underlying environmental conditions across the Arctic. This systematic map aims to identify the ecological contexts in which herbivore impacts on vegetation have been studied in the Arctic. Specifically, the primary question of the systematic map was: “What evidence exists on the effects of herbivores on Arctic vegetation?”.Methods: We used a published systematic map protocol to identify studies addressing the effects of herbivores on Arctic vegetation. We conducted searches for relevant literature in online databases, search engines and specialist websites. Literature was screened to identify eligible studies, defined as reporting primary data on herbivore impacts on Arctic plants and plant communities. We extracted information on variables that describe the ecological context of the studies, from the studies themselves and from geospatial data. We synthesized the findings narratively and created a Shiny App where the coded data are searchable and variables can be visually explored.Review findings: We identified 309 relevant articles with 662 studies (representing different ecological contexts or datasets within the same article). These studies addressed vertebrate herbivory seven times more often than invertebrate herbivory. Geographically, the largest cluster of studies was in Northern Fennoscandia. Warmer and wetter parts of the Arctic had the largest representation, as did coastal areas and areas where the increase in temperature has been moderate. In contrast, studies spanned the full range of ecological context variables describing Arctic vertebrate herbivore diversity and human population density and impact.Conclusions: The current evidence base might not be sufficient to understand the effects of herbivores on Arctic vegetation throughout the region, as we identified clear biases in the distribution of herbivore studies in the Arctic and a limited evidence base on invertebrate herbivory. In particular, the overrepresentation of studies in areas with moderate increases in temperature prevents robust generalizations about the effects of herbivores under different climatic scenarios.
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| 7. |
- Barbero-Palacios, Laura, et al.
(author)
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Herbivore diversity effects on Arctic tundra ecosystems : a systematic review
- 2024
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In: Environmental Evidence. - : BioMed Central (BMC). - 2047-2382. ; 13:1
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Research review (peer-reviewed)abstract
- Background: Northern ecosystems are strongly influenced by herbivores that differ in their impacts on the ecosystem. Yet the role of herbivore diversity in shaping the structure and functioning of tundra ecosystems has been overlooked. With climate and land-use changes causing rapid shifts in Arctic species assemblages, a better understanding of the consequences of herbivore diversity changes for tundra ecosystem functioning is urgently needed. This systematic review synthesizes available evidence on the effects of herbivore diversity on different processes, functions, and properties of tundra ecosystems.Methods: Following a published protocol, our systematic review combined primary field studies retrieved from bibliographic databases, search engines and specialist websites that compared tundra ecosystem responses to different levels of vertebrate and invertebrate herbivore diversity. We used the number of functional groups of herbivores (i.e., functional group richness) as a measure of the diversity of the herbivore assemblage. We screened titles, abstracts, and full texts of studies using pre-defined eligibility criteria. We critically appraised the validity of the studies, tested the influence of different moderators, and conducted sensitivity analyses. Quantitative synthesis (i.e., calculation of effect sizes) was performed for ecosystem responses reported by at least five articles and meta-regressions including the effects of potential modifiers for those reported by at least 10 articles.Review findings: The literature searches retrieved 5944 articles. After screening titles, abstracts, and full texts, 201 articles including 3713 studies (i.e., individual comparisons) were deemed relevant for the systematic review, with 2844 of these studies included in quantitative syntheses. The available evidence base on the effects of herbivore diversity on tundra ecosystems is concentrated around well-established research locations and focuses mainly on the impacts of vertebrate herbivores on vegetation. Overall, greater herbivore diversity led to increased abundance of feeding marks by herbivores and soil temperature, and to reduced total abundance of plants, graminoids, forbs, and litter, plant leaf size, plant height, and moss depth, but the effects of herbivore diversity were difficult to tease apart from those of excluding vertebrate herbivores. The effects of different functional groups of herbivores on graminoid and lichen abundance compensated each other, leading to no net effects when herbivore effects were combined. In turn, smaller herbivores and large-bodied herbivores only reduced plant height when occurring together but not when occurring separately. Greater herbivore diversity increased plant diversity in graminoid tundra but not in other habitat types.Conclusions: This systematic review underscores the importance of herbivore diversity in shaping the structure and function of Arctic ecosystems, with different functional groups of herbivores exerting additive or compensatory effects that can be modulated by environmental conditions. Still, many challenges remain to fully understand the complex impacts of herbivore diversity on tundra ecosystems. Future studies should explicitly address the role of herbivore diversity beyond presence-absence, targeting a broader range of ecosystem responses and explicitly including invertebrate herbivores. A better understanding of the role of herbivore diversity will enhance our ability to predict whether and where shifts in herbivore assemblages might mitigate or further amplify the impacts of environmental change on Arctic ecosystems.
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| 8. |
- Lagou, Vasiliki, et al.
(author)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 10. |
- Zhao, J. H., et al.
(author)
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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
- 2023
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In: Nature Immunology. - : Springer Nature. - 1529-2908 .- 1529-2916. ; 24:9, s. 1540-1551
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Journal article (peer-reviewed)abstract
- Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.
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| 12. |
- Zhang, Yuan, et al.
(author)
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Adiponectin Associates with Rheumatoid Arthritis Risk in Overweight and Obesity Independently of Other Adipokines
- 2021
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In: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 10:13
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Journal article (peer-reviewed)abstract
- We recently reported that increased serum adiponectin was associated with rheumatoid arthritis (RA) risk in subjects with obesity. We hereby aim to determine if other adipokines associate with RA risk and if the association between adiponectin and RA is independent of other adipokines. Two nested-case control studies were performed in two different cohorts: 82 participants of the Swedish Obese Subjects (SOS) study who developed RA during follow-up matched with 410 controls, and 88 matched pairs from the Medical Biobank of Northern Sweden. Baseline levels of circulating adipokines were measured using ELISA. In a multivariable analysis in the SOS cohort, higher adiponectin was associated with an increased risk of RA independently of other adipokines (OR for RA risk: 1.06, 95% CI: 1.01-1.12, p = 0.02). No association between leptin, resistin, and visfatin levels and the risk of RA was detected. In the cohort from the Medical Biobank of Northern Sweden, higher adiponectin was associated with an increased risk of RA only in participants with overweight/obesity (OR: 1.17, 95% CI: 1.01-1.36, p = 0.03), independently of other adipokines. Our results show that in individuals with overweight/obesity, higher circulating levels of adiponectin, but not leptin, resistin, or visfatin, were associated with an increased RA risk.
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| 13. |
- Zhang, Y, et al.
(author)
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Elevated adiponectin predicts the development of rheumatoid arthritis in subjects with obesity
- 2020
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In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 49:6, s. 452-460
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Journal article (peer-reviewed)abstract
- Objective: The aim of the current study is to determine whether baseline serum adiponectin levels predict the development of rheumatoid arthritis (RA). Method: The current report includes 3693 individuals from the Swedish Obese Subjects (SOS) study. The original SOS study is a longitudinal non-randomized controlled study aiming to assess the effect of bariatric surgery on obesity-related mortality and morbidity. Participants included in the present report had adiponectin measurement available at baseline and no prevalent RA. The diagnosis of RA was retrieved through the Swedish National Patient Register. Results: During a follow-up for up to 29years, 82 study participants developed RA. Elevated baseline adiponectin levels were associated with a higher risk of developing RA independently of other factors, including C-reactive protein (CRP) and smoking [hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.12–2.60 for an increase in adiponectin of 10 mg/L, p =0.01]. After stratifying the population according to adiponectin and CRP median at baseline, study participants with both adiponectin and CRP above the median had a higher risk of developing RA compared to subjects with adiponectin and CRP below the median (HR 2.80, 95% CI 1.25–6.31, p =0.01). Conclusions: In this cohort of subjects with obesity followed up for up to 29years, high serum adiponectin levels at baseline were associated with an increased risk for RA. Moreover, subjects with both high adiponectin and CRP levels at baseline were at particular risk of developing RA. ClinicalTrials.gov Identifier: NCT01479452. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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| 14. |
- Broadaway, K Alaine, et al.
(author)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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In: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Journal article (peer-reviewed)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 15. |
- Brown, Richard J. P., et al.
(author)
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Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice
- 2020
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In: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 6:45
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Journal article (peer-reviewed)abstract
- Hepatitis C virus (HCV) has no animal reservoir, infecting only humans. To investigate species barrier determinants limiting infection of rodents, murine liver complementary DNA library screening was performed, identifying transmembrane proteins Cd302 and Cr1l as potent restrictors of HCV propagation. Combined ectopic expression in human hepatoma cells impeded HCV uptake and cooperatively mediated transcriptional dysregulation of a noncanonical program of immunity genes. Murine hepatocyte expression of both factors was constitutive and not interferon inducible, while differences in liver expression and the ability to restrict HCV were observed between the murine orthologs and their human counterparts. Genetic ablation of endogenous Cd302 expression in human HCV entry factor transgenic mice increased hepatocyte permissiveness for an adapted HCV strain and dysregulated expression of metabolic process and host defense genes. These findings highlight human-mouse differences in liver-intrinsic antiviral immunity and facilitate the development of next-generation murine models for preclinical testing of HCV vaccine candidates.
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| 16. |
- Georgakis, Marios K., et al.
(author)
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Association of Circulating Monocyte Chemoattractant Protein-1 Levels with Cardiovascular Mortality : A Meta-analysis of Population-Based Studies
- 2021
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In: JAMA Cardiology. - : American Medical Association (AMA). - 2380-6583. ; 6:5, s. 587-592
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Journal article (peer-reviewed)abstract
- Importance: Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored. Objective: To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population. Data Sources and Selection: Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points. Data Extraction and Synthesis: Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses. Main Outcomes and Measures: Incident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes). Results: The meta-analysis included 7 cohort studies involving 21401 individuals (mean [SD] age, 53.7 [10.2] years; 10012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11]; P =.01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13]; P =.02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20]; P <.001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity; the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein. Conclusions and Relevance: Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease..
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| 17. |
- Maglio, Cristina, et al.
(author)
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Bariatric surgery and the incidence of rheumatoid arthritis - a Swedish Obese Subjects study.
- 2020
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In: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 59:2, s. 303-309
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Journal article (peer-reviewed)abstract
- The aim of this study was to determine the effect of bariatric surgery on the incidence of RA in participants of the Swedish Obese Subjects (SOS) study.The SOS is a longitudinal study aiming to assess the effect of bariatric surgery on mortality and obesity-related diseases. This report includes 2002 subjects with obesity who underwent bariatric surgery and 2034 matched controls; none of them had RA at baseline. Cases of incident RA were identified through the Swedish National Patient Register by searching for International Classification of Diseases codes. Both intention-to-treat analyses and per-protocol analyses are reported. In the per-protocol analysis, participants from the control group who underwent bariatric surgery later on during follow-up were censored at the time of surgery.During follow-up, 92 study participants developed RA. The median follow-up was 21 years (range 0-29). Bariatric surgery was neither associated with the incidence of RA in the intention-to-treat analysis [hazard ratio (HR) 0.92 (95% CI 0.59, 1.46), P = 0.74], nor in the per-protocol analysis [HR 0.86 (95% CI 0.54, 1.38), P = 0.53]. Weight change at the 2 year follow-up, expressed as the change in BMI compared with baseline, did not associate with the development of RA. Higher serum CRP levels and smoking associated with the future development of RA independent of other factors.We did not detect any association between bariatric surgery and the incidence of RA in subjects affected by obesity followed up for up to 29 years.(http://clinicaltrials.gov): NCT01479452.
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