Reelin Associated With Restricted and Stereotyped Behavior Based on Principal Component Analysis on Autism Diagnostic Interview-Revised

Tämä artikkeli ei ole avattavissa lehden sivuilta, koska linkit ja DOI vievät väärään artikkeliin samoin PDF sen ohessa. Kustantajalle ilmoitettu ja pyydetty korjausta.Abstract Background: Twin and family studies have indicated a strong genetic component in autism spectrum disorders, and genetic studies have revealed highly heterogeneous risk factors. The range and severity of the symptom presentation also vary in the spectrum. Thus, symptom-based phenotypes are putatively more closely related to the underlying biology of autism than the end-state diagnosis. Methods: We performed principal component analysis on Autism Diagnostic Interview-Revised algorithm for 117 Finnish families and 594 families from the Autism Genetic Research Exchange (AGRE). The resulting continuous component scores were used as quantitative phenotypes in family-based association analysis. In addition, K-means clustering was performed to cluster and visualize the results of the PCA. Unaffected siblings were included in the study. Results: The components were interpreted as Social Component (SC), communication component and Restricted and Stereotyped Behavior Component (RSBC). K-means clustering showed that, especially in SC, the range of the symptom severity was increased by the siblings. The association of neuroligin 1 with SC was increased, compared to a previous study where only the end-state diagnosis was used. In RSBC, the range of the symptom severity of siblings overlapped greatly with that of patients, which could explain why no association of reelin was found in previous studies in which only the end-state diagnosis was used, but a significant association of reelin with RSBC was now found in the Finnish families (Bonferroni-corrected p=0.029 for rs362644). Although, the Finnish sample is isolated and genetically very homogeneous, compared to the heterogeneous background of AGRE families, many single-nucleotide polymorphisms in reelin, showed modest association with RSBC in the AGRE sample, too. Conclusions: This study demonstrates how the quantitative phenotypes can affect the association analyses, and yields further support to the use of siblings in the study of complex neuropsychiatric disorders.Peer reviewe

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEX(TM) Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89-1.28, p = 0.51) and 0.92 (95% CI 0.80-1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.Peer reviewe

Heme oxygenase-1 repeat polymorphism in septic acute kidney injury

Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine-thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S-L (short to long) classification, and 27 and 34 repeats for the S-M-L2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01-1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (p<0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk

Regulation and governance supporting systemic MaaS innovations

Mobility-as-a-Service (MaaS) is an example of a systemic innovation, where mobility services addressing different customers’ transportation needs are integrated with real-time traveler information, ticketing, and payment services. This paper examines how the differences in institutional setup, stakeholder processes and viewpoints, and technological development have resulted in different approaches to regional governance when supporting systemic innovations in transportation. Two European regions with established collaboration networks in transportation and spatial planning are compared. These regions are the Growth Corridor Finland and the Basel metropolitan area in Switzerland. During August 2017, an invitation to online questionnaire was sent to 410 stakeholders, who had been participating in different stakeholder processes, such as pilot projects, strategy development groups, academic projects, and infrastructure projects in the field of mobility and commuting. With 99 completed questionnaires, the overallresponse rate was 24.1%. The answers were analyzed to collect stakeholder experiences from previous collaboration efforts, to assess the importance of transportation innovations to the work of these stakeholders, and to get insights about current barriers and supporting factors when developing these systemic innovations. As a result, managerial implications are discussed for these formal collaboration networks in their aspiration to support new mobility innovations.Peer reviewe

Regulation and governance supporting systemic MaaS innovations

Mobility-as-a-Service (MaaS) is an example of a systemic innovation, where mobility services addressing different customers' transportation needs are integrated with real-time traveler information, ticketing, and payment services. This paper examines how the differences in institutional setup, stakeholder processes and viewpoints, and technological development have resulted in different approaches to regional governance when supporting systemic innovations in transportation. Two European regions with established collaboration networks in transportation and spatial planning are compared. These regions are the Growth Corridor Finland and the Basel metropolitan area in Switzerland. During August 2017, an invitation to online questionnaire was sent to 410 stakeholders, who had been participating in different stakeholder processes, such as pilot projects, strategy development groups, academic projects, and infrastructure projects in the field of mobility and commuting. With 99 completed questionnaires, the overall response rate was 24.1%. The answers were analyzed to collect stakeholder experiences from previous collaboration efforts, to assess the importance of transportation innovations to the work of these stakeholders, and to get insights about current barriers and supporting factors when developing these systemic innovations. As a result, managerial implications are discussed for these formal collaboration networks in their aspiration to support new mobility innovations

Heme oxygenase-1 repeat polymorphism in septic acute kidney injury

Abstract Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine–thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S–L (short to long) classification, and 27 and 34 repeats for the S–M–L₂ (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01–1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (p&lt;0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk