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- Ibrahim, Hazem, et al.
(författare)
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RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function
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Ingår i: Diabetologia. - 0012-186X.
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Regulatory factor X 6 (RFX6) is crucial for pancreatic endocrine development and differentiation. The RFX6 variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown. Methods: To understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice. Results: Stem cell models of the homozygous variant RFX6−/− predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell–Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers NEUROG3 and SOX9, accompanied by increased apoptosis. Intriguingly, heterozygous RFX6+/− SC-islets exhibited RFX6 haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However, RFX6 haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes. Conclusions/interpretation: Our allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that RFX6 haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes. Data availability: Ultra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 RFX6 genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley (https://data.mendeley.com/datasets/g75drr3mgw/2). Graphical Abstract: (Figure presented.).
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- Salminen, M, et al.
(författare)
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Prediction of the Future Need for Institutional Care in Finnish Older People: A Comparison of Two Birth Cohorts
- 2018
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Ingår i: Gerontology. - : S. Karger AG. - 1423-0003 .- 0304-324X. ; 64:1, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> More recent birth cohorts of older people have better physical and cognitive status than earlier cohorts. As such, this could be expected to diminish the need for institutional care. The prediction of the future need for institutional care provides essential information for the planning and delivery of future care and social services as well as the resources needed. <b><i>Objective:</i></b> To predict the future need for institutional care among older Finnish people born in 1940. <b><i>Methods:</i></b> Representative samples of home-dwelling 70-year-olds from Turku, Finland were examined with similar methods in 1991 (those born in 1920) (<i>n</i> = 1,032) and in 2011 (those born in 1940) (<i>n</i> = 956). Predictors of institutionalization rates from the earlier 1920 cohort, together with data of sociodemographic factors, health, psychosocial and physical status, the need for help, and health behavior, were used to predict the future institutionalization rate among the 1940 cohort in this study using Cox regression models. <b><i>Results:</i></b> Health as well as psychosocial and physical status were significantly better in the 1940 cohort compared to the earlier cohort. In the 1940 cohort, the predicted rates of institutionalization were 1.8, 10.4, and 26.0% at the ages of 80 (year 2020), 85 (year 2025), and 90 years (year 2030), respectively. At every age (80, 85, and 90 years), the predicted rates of institutionalization by Mini-Mental State Examination (MMSE) were about two-fold among those with MMSE scores 18-26 (3.0-38.8%) compared to those with scores 27-30 (1.6-23.7%) and those with a body mass index (BMI) <25 (2.5-34.3%) compared to those with a BMI of 25-29.9 (1.4-20.9%), and about three-fold among participants with several falls (5.3-57.0%) compared to participants with no falls (1.5-23.1%). <b><i>Conclusions:</i></b> The 1940 cohort performed better in health as well as psychosocial and physical status than the 1920 cohort. Nevertheless, the predicted rates of future need for institutional care were high, especially at the ages of 85 and 90 years, among those with a lowered cognitive or physical status.
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- Vire, J, et al.
(författare)
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The Association of the Brief Dementia Risk Index and Incident Dementia among Finnish 70-Year-Olds: A 5-Year Follow-Up Study
- 2021
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Ingår i: Gerontology. - : S. Karger AG. - 1423-0003 .- 0304-324X. ; 67:4, s. 441-444
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- <b><i>Background:</i></b> An accurate identification of older individuals at increased risk of developing dementia is very important. Various dementia risk prediction models have been developed, but not all models are applicable among older population. <b><i>Objectives:</i></b> To examine the association of the Brief Dementia Risk Index (BDRI) and incidence of dementia among community-dwelling Finnish older adults. <b><i>Methods:</i></b> Participants were community-dwelling nondemented 70-year-olds examined in 2011 (<i>n</i> = 943). Cox regression model with death as a competing risk was used to analyze the association of BDRI and incident dementia (ICD-10 codes F00-03 and G30) during the 5-year follow-up (<i>n</i> = 883). <b><i>Results:</i></b> The rate of dementia incidence was 4.9% during the follow-up. Having at least moderate risk according to BDRI significantly predicted incident dementia (hazard ratio 3.18, 95% confidence interval: 1.71–5.92, <i>p</i> < 0.001), also after adjustment with education level (2.93, 1.52–5.64, <i>p</i> = 0.001). No interaction between gender and BDRI was found. <b><i>Conclusion:</i></b> BDRI could be an applicable tool for identification of older individuals at increased risk of developing dementia in clinical settings.
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