| 1. |
- Martinez, Cristina A., et al.
(författare)
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Expression of Stress-Mediating Genes is Increased in Term Placentas of Women with Chronic Self-Perceived Anxiety and Depression
- 2020
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Ingår i: Genes. - : MDPI. - 2073-4425. ; 11:8, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Anxiety, chronical stress, and depression during pregnancy are considered to affect the offspring, presumably through placental dysregulation. We have studied the term placentae of pregnancies clinically monitored with the Beck's Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 classed patients into an Index group (>10,n= 23) and a Control group (<10,n= 23). Cortisol concentrations in hair (HCC) were periodically monitored throughout pregnancy and delivery. Expression differences of main glucocorticoid pathway genes, i.e., corticotropin-releasing hormone (CRH), 11 beta-hydroxysteroid dehydrogenase (HSD11B2), glucocorticoid receptor (NR3C1), as well as other key stress biomarkers (Arginine Vasopressin, AVP and O-GlcNAc transferase, OGT) were explored in medial placentae using real-time qPCR and Western blotting. Moreover, gene expression changes were considered for their association with HCC, offspring, gender, and birthweight. A significant dysregulation of gene expression for CRH, AVP, and HSD11B2 genes was seen in the Index group, compared to controls, while OGT and NR3C1 expression remained similar between groups. Placental gene expression of the stress-modulating enzyme 11 beta-hydroxysteroid dehydrogenase (HSD11B2) was related to both hair cortisol levels (Rho = 0.54;p< 0.01) and the sex of the newborn in pregnancies perceived as stressful (Index,p< 0.05). Gene expression of CRH correlated with both AVP (Rho = 0.79;p< 0.001) and HSD11B2 (Rho = 0.45;p< 0.03), and also between AVP with both HSD11B2 (Rho = 0.6;p< 0.005) and NR3C1 (Rho = 0.56;p< 0.03) in the Control group but not in the Index group; suggesting a possible loss of interaction in the mechanisms of action of these genes under stress circumstances during pregnancy.
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| 2. |
- Fava, Cristiano, et al.
(författare)
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Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:3, s. 413-418
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Tidskriftsartikel (refereegranskat)abstract
- Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1 000 000, in Sweden, suggesting that similar to 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.
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| 3. |
- Mannes, Marco, et al.
(författare)
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Combined Heterozygous Genetic Variations in Complement C2 and C8B : An Explanation for Multidimensional Immune Imbalance?
- 2023
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Ingår i: Journal of Innate Immunity. - : S. Karger. - 1662-811X .- 1662-8128. ; 15:1, s. 412-427
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Tidskriftsartikel (refereegranskat)abstract
- The complement system plays a crucial role in host defense, homeostasis, and tissue regeneration and bridges the innate and the adaptive immune systems. Although the genetic variants in complement C2 (c.839_849+17del; p.(Met280Asnfs*5)) and C8B (c.1625C>T; p.(Thr542Ile)) are known individually, here, we report on a patient carrying their combination in a heterozygous form. The patient presented with a reduced general condition and suffers from a wide variety of autoimmune diseases. While no autoimmune disease-specific autoantibodies could be detected, genetic analysis revealed abnormalities in the two complement genes C2 and C8B. Therefore, we performed a comprehensive investigation of the innate immune system on a cellular and humoral level to define the functional consequences. We found slightly impaired functionality of neutrophils and monocytes regarding phagocytosis and reactive oxygen species generation and a diminished expression of the C5aR1. An extensive complement analysis revealed a declined activation potential for the alternative and classical pathway. Reconstitution with purified C2 and C8 into patient serum failed to normalize the dysfunction, whereas the addition of C3 improved the hemolytic activity. In clinical transfer, in vitro supplementation of the patient's plasma with FFP as a complement source could fully restore full complement functionality. This study describes for the first time a combined heterozygous genetic variation in complement C2 and C8B which, however, cannot fully explain the overall dysfunctions and calls for further complement deficiency research and corresponding therapies.
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| 4. |
- Einarsdottir, Elisabet, et al.
(författare)
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Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family
- 2015
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 134:11-12, s. 1239-1248
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Tidskriftsartikel (refereegranskat)abstract
- Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated.
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| 5. |
- Andersson, Evelyn, et al.
(författare)
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Genetics of response to cognitive behavior therapy in adults with major depression : a preliminary report
- 2019
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 24:4, s. 484-490
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Asberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Asberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.
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| 6. |
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