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- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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| 2. |
- Forssman, Linda, et al.
(författare)
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Regulatory variant of the TPH2 gene and early life stress are associated with heightened attention to social signals of fear in infants
- 2014
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Ingår i: Journal of Child Psychology and Psychiatry. - : Wiley. - 0021-9630 .- 1469-7610. ; 55:7, s. 793-801
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cross-species evidence suggests that genetic and experiential factors act early in development to establish individual emotional traits, but little is known about the mechanisms that emerge during this period to mediate long-term outcomes. Here, we tested the hypothesis that known genetic and environmental risk conditions may heighten infants' natural tendency to attend to threat-alerting stimuli, resulting in a cognitive bias that may contribute to emotional vulnerability.METHODS: Data from two samples of 5-7-month-old infants (N = 139) were used to examine whether established candidate variations in the serotonin-system genes, i.e., TPH2 SNP rs4570625 (-703 G/T) and HTR1A SNP rs6295 (-1019 G/C), and early rearing condition (maternal stress and depressive symptoms) are associated with alterations in infants' attention to facial expressions. Infants were tested with a paradigm that assesses the ability to disengage attention from a centrally presented stimulus (a nonface control stimulus or a neutral, happy, or fearful facial expression) toward the location of a new stimulus in the visual periphery (a geometric shape).RESULTS: TPH2 -703 T-carrier genotype (i.e., TT homozygotes and heterozygotes), presence of maternal stress and depressive symptoms, and a combination of the T-carrier genotype and maternal depressive symptoms were associated with a relatively greater difficulty disengaging attention from fearful facial expressions. No associations were found with infants' temperamental traits.CONCLUSIONS: Alterations in infants' natural attentional bias toward fearful facial expressions may emerge prior to the manifestation of emotional and social behaviors and provide a sensitive marker of early emotional development.
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| 3. |
- Latva-Rasku, Aino, et al.
(författare)
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The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity : A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients.
- 2019
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:5, s. 931-937
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS: This randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA1c 6.5-10.5% (48-91 mmol/mol) and ≥3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [18F]-fluorodeoxyglucose and positron emission tomography during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed.RESULTS: After 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA1c -0.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (-3.74%, P < 0.01), liver volume (-0.10 L, P < 0.05), visceral adipose tissue volume (-0.35 L, P < 0.01), interleukin-6 (-1.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (-96 ng/L, P = 0.03).CONCLUSIONS: In this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed.
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| 6. |
- Salminen, Simo-Pekko, et al.
(författare)
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Genetic risk scores associated with temperament clusters in finnish depression patients
- 2023
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press. - 0924-2708 .- 1601-5215.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cloninger's temperament dimensions have been studied widely in relation to genetics. In this study, we examined Cloninger's temperament dimensions grouped with cluster analyses and their association with single nucleotide polymorphisms (SNPs). This study included 212 genotyped Finnish patients from the Ostrobothnia Depression Study.Methods: The temperament clusters were analysed at baseline and at six weeks from the beginning of the depression intervention study. We selected depression related catecholamine and serotonin genes based on a literature search, and 59 SNPs from ten different genes were analysed. The associations of single SNPs with temperament clusters were studied. Using the selected genes, genetic risk score (GRS) analyses were conducted considering appropriate confounding factors.Results: No single SNP had a significant association with the temperament clusters. Associations between GRSs and temperament clusters were observed in multivariate models that were significant after permutation analyses. Two SNPs from the DRD3 gene, two SNPs from the SLC6A2 gene, one SNP from the SLC6A4 gene, and one SNP from the HTR2A gene associated with the HHA/LRD/LP (high harm avoidance, low reward dependence, low persistence) cluster at baseline. Two SNPs from the HTR2A gene associated with the HHA/LRD/LP cluster at six weeks. Two SNPs from the HTR2A gene and two SNPs from the COMT gene associated with the HP (high persistence) cluster at six weeks.Conclusion: GRSs seem to associate with an individual's temperament profile, which can be observed in the clusters used. Further research needs to be conducted on these types of clusters, and their clinical applicability.
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