| 1. |
|
|
| 2. |
- de las Fuentes, Lisa, et al.
(author)
-
Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
-
In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
-
Journal article (peer-reviewed)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.
|
|
| 3. |
- Löfstedt Gilljam, John, et al.
(author)
-
Is Ongoing Sulfluramid Use in South America a Significant Source of Perfluorooctanesulfonate (PFOS)? Production Inventories, Environmental Fate, and Local Occurrence
- 2016
-
In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 50:2, s. 653-659
-
Journal article (peer-reviewed)abstract
- Despite international phase-out initiatives, production and use of perfluorooctanesulfonate (PFOS) and related substances continues in some countries. In Brazil, the PFOS-precursor N-ethyl perfluorooctane sulfonamide (EtFOSA) is used in Sulfluramid, a pesticide for controlling leaf-cutting ants. New data on production, environmental fate, and occurrence of Brazilian Sulfluramid are reported herein. From 2003 to 2013, Brazilian Sulfluramid manufacturing increased from 30 to 60 tonnes yr(-1) EtFOSA. During this time <1.3 tonnes yr(-1) were imported, while exports increased from similar to 0.3 to 2 tonnes yr(-1). From 2004 to 2015, most EtFOSA was exported to Argentina (7.2 tonnes), Colombia (2.07 tonnes), Costa Rica (1.13 tonnes), Equador (2.16 tonnes), and Venezuela (2.4 tonnes). Within Brazil, sales occurred primarily in the states of Minas Gerais, Sao Paulo, Mato Grosso do Sul, Espirito Santo, and Bahia. Model simulations predict EtFOSA will partition to soils, while transformation products perfluorooctane sulfonamide (FOSA) and PFOS are sufficiently mobile to leach into surface waters. In support of these predictions, up to 3400 pg L(-)1 of FOSA and up to 1100 pg L(-)1 of PFOS were measured in Brazilian surface water, while EtFOSA was not detected. The high FOSA/PFOS ratio observed here (up to 14:1) is unprecedented in the scientific literature to our knowledge. Depending on the extent of conversion of EtFOSA, cumulative Brazilian Sulfluramid production and import from 2004 to 2015 may contribute between 167 and 487 tonnes of PFOS/FOSA to the environment. These levels are clearly nontrivial and of concern since production is continuing unabated.
|
|
| 4. |
- Swift, Imogen J, et al.
(author)
-
A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
- 2024
-
In: Alzheimer's Research & Therapy. - 1758-9193. ; 16:1
-
Journal article (peer-reviewed)abstract
- Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p=0.007) with a trend in non-carriers (p=0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
|
|
| 5. |
- Ulugut, Hulya, et al.
(author)
-
Clinical recognition of frontotemporal dementia with right anterior temporal predominance : A multicenter retrospective cohort study
- 2024
-
In: Alzheimer's and Dementia. - 1552-5260.
-
Journal article (peer-reviewed)abstract
- INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. Highlights: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.
|
|
