| 1. |
- Solé Navais, Pol, et al.
(författare)
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Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
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Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
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Tidskriftsartikel (refereegranskat)abstract
- The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n=195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n=136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
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| 2. |
- Bauer, Michael, et al.
(författare)
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Association between solar insolation and a history of suicide attempts in bipolar I disorder.
- 2019
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Ingår i: Journal of psychiatric research. - : Elsevier BV. - 1879-1379 .- 0022-3956. ; 113, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p<0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.
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| 3. |
- Chen, Jie, et al.
(författare)
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Long-term exposure to ambient air pollution and bladder cancer incidence in a pooled European cohort : the ELAPSE project
- 2022
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 126:10, s. 1499-1507
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Tidskriftsartikel (refereegranskat)abstract
- Background: The evidence linking ambient air pollution to bladder cancer is limited and mixed.Methods: We assessed the associations of bladder cancer incidence with residential exposure to fine particles (PM2.5), nitrogen dioxide (NO2), black carbon (BC), warm season ozone (O3) and eight PM2.5 elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) in a pooled cohort (N = 302,493). Exposures were primarily assessed based on 2010 measurements and back-extrapolated to the baseline years. We applied Cox proportional hazard models adjusting for individual- and area-level potential confounders.Results: During an average of 18.2 years follow-up, 967 bladder cancer cases occurred. We observed a positive though statistically non-significant association between PM2.5 and bladder cancer incidence. Hazard Ratios (HR) were 1.09 (95% confidence interval (CI): 0.93–1.27) per 5 µg/m3 for 2010 exposure and 1.06 (95% CI: 0.99–1.14) for baseline exposure. Effect estimates for NO2, BC and O3 were close to unity. A positive association was observed with PM2.5 zinc (HR 1.08; 95% CI: 1.00–1.16 per 10 ng/m3).Conclusions: We found suggestive evidence of an association between long-term PM2.5 mass exposure and bladder cancer, strengthening the evidence from the few previous studies. The association with zinc in PM2.5 suggests the importance of industrial emissions.
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| 4. |
- Chen, Jie, et al.
(författare)
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Long-Term Exposure to Source-Specific Fine Particles and Mortality-A Pooled Analysis of 14 European Cohorts within the ELAPSE Project
- 2022
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:13, s. 9277-9290
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Tidskriftsartikel (refereegranskat)abstract
- We assessed mortality risks associated with sourcespecific fine particles (PM2.5) in a pooled European cohort of 323,782 participants. Cox proportional hazard models were applied to estimate mortality hazard ratios (HRs) for source-specific PM2.5 identified through a source apportionment analysis. Exposure to 2010 annual average concentrations of source-specific PM2.5 components was assessed at baseline residential addresses. The source apportionment resulted in the identification of five sources: traffic, residual oil combustion, soil, biomass and agriculture, and industry. In single-source analysis, all identified sources were significantly positively associated with increased natural mortality risks. In multisource analysis, associations with all sources attenuated but remained statistically significant with traffic, oil, and biomass and agriculture. The highest association per interquartile increase was observed for the traffic component (HR: 1.06; 95% CI: 1.04 and 1.08 per 2.86 mu g/m(3) increase) across five identified sources. On a 1 mu g/m(3) basis, the residual oil-related PM2.5 had the strongest association (HR: 1.13; 95% CI: 1.05 and 1.22), which was substantially higher than that for generic PM2.5 mass, suggesting that past estimates using the generic PM2.5 exposure response function have underestimated the potential clean air health benefits of reducing fossil-fuel combustion. Source-specific associations with cause-specific mortality were in general consistent with findings of natural mortality.
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| 5. |
- Havelka, A. Mandic, et al.
(författare)
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Maternal plasma level of antimicrobial peptide LL37 is a major determinant factor of neonatal plasma LL37 level
- 2010
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Ingår i: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 99:6, s. 836-841
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To determine cathelicidin antimicrobial peptide LL37subcellular distribution in cord neutrophils and normal plasma LL37 levels in mothers and neonates, relate them to delivery mode and relevant biochemical markers, including 25-OHvitamin D [25(OH)D] as this molecules increases cathelicidin gene expression. Methods: A total of 115 infants were included, n = 68 with normal delivery and n = 47 with elective Caesarean section (C-section), a subset of these being 50 mother-infant pairs. Biomarkers were determined in maternal and cord blood. Subcellular peptide LL37 distribution was analysed with immunoelectron microscopy. Results: Cord plasma LL37 levels were three-times higher after normal delivery compared with C-section. A highly significant correlation was observed between maternal and cord plasma LL37 levels, regardless of delivery mode. No relationship was found between LL37 and 25(OH)D levels. Neutrophils from cord blood after normal delivery contained 10-times more cytoplasmatic cathelicidin peptide compared with corresponding cells after C-section where a strict granular localization was found. Conclusion: These data are consistent with a placental transfer of LL37 and identifies maternal stores as the critical factor determining neonatal plasma LL37 level. An additional enhancement of neonatal cathelicidin mobilization and release is connected to normal delivery stress.
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| 6. |
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| 7. |
- Skotte, Line, et al.
(författare)
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Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:2, s. 555-568
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Tidskriftsartikel (refereegranskat)abstract
- Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
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| 8. |
- Soehnlein, Oliver, et al.
(författare)
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Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages.
- 2008
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 118:10, s. 3491-3502
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Tidskriftsartikel (refereegranskat)abstract
- In acute inflammation, infiltrating polymorphonuclear leukocytes (also known as PMNs) release preformed granule proteins having multitudinous effects on the surrounding environment. Here we present what we believe to be a novel role for PMN-derived proteins in bacterial phagocytosis by both human and murine macrophages. Exposure of macrophages to PMN secretion markedly enhanced phagocytosis of IgG-opsonized Staphylococcus aureus both in vitro and in murine models in vivo. PMN secretion activated macrophages, resulting in upregulation of the Fcgamma receptors CD32 and CD64, which then mediated the enhanced phagocytosis of IgG-opsonized bacteria. The phagocytosis-stimulating activity within the PMN secretion was found to be due to proteins released from PMN primary granules; thorough investigation revealed heparin-binding protein (HBP) and human neutrophil peptides 1-3 (HNP1-3) as the mediators of the macrophage response to PMN secretion. The use of blocking antibodies and knockout mice revealed that HBP acts via beta(2) integrins, but the receptor for HNP1-3 remained unclear. Mechanistically, HBP and HNP1-3 triggered macrophage release of TNF-alpha and IFN-gamma, which acted in an autocrine loop to enhance expression of CD32 and CD64 and thereby enhance phagocytosis. Thus, we attribute what may be a novel role for PMN granule proteins in regulating the immune response to bacterial infections.
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| 9. |
- Sørensen, Ole E, et al.
(författare)
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Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 124:10, s. 4539-4548
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Tidskriftsartikel (refereegranskat)abstract
- Papillon-Lefevre syndrome (PLS) results from mutations that inactivate cysteine protease cathepsin C (CTSC), which processes a variety of serine proteases considered essential for antimicrobial defense. Despite serine protease-deficient immune cell populations, PLS patients do not exhibit marked immunodeficiency. Here, we characterized a 24-year-old woman who had suffered from severe juvenile periodontal disease, but was otherwise healthy, and identified a homozygous missense mutation in CTSC indicative of PLS. Proteome analysis of patient neutrophil granules revealed that several proteins that normally localize to azurophil granules, including the major serine proteases, elastase, cathepsin G, and proteinase 3, were absent. Accordingly, neutrophils from this patient were incapable of producing neutrophil extracellular traps (NETs) in response to ROS and were unable to process endogenous cathelicidin hCAP-18. into the antibacterial peptide LL-37 in response to ionomycin. In immature myeloid cells from patient bone marrow, biosynthesis of CTSC and neutrophil serine proteases appeared normal along with initial processing and sorting to cellular storage. In contrast, these proteins were completely absent in mature neutrophils, indicating that CTSC mutation promotes protease degradation in more mature hematopoietic subsets, but does not affect protease production in progenitor cells. Together, these data indicate CTSC protects serine proteases from degradation in mature immune cells and suggest that neutrophil serine proteases are dispensable for human immunoprotection.
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| 10. |
- Van Schijndel, Jessica E., et al.
(författare)
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Dual association of a TRKA polymorphism with schizophrenia
- 2011
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Ingår i: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 21:3, s. 125-131
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.METHODS: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.RESULT: Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor.CONCLUSION: An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.
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