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Article ; Online: DNA methylation differences within INS, PTPN22 and IL2RA promoters in lymphocyte subsets in children with type 1 diabetes and controls

Sirpa Pahkuri / Ilse Ekman / Céline Vandamme / Kirsti Näntö-Salonen / Jorma Toppari / Riitta Veijola / Mikael Knip / Tuure Kinnunen / Jorma Ilonen / Johanna Lempainen

Autoimmunity, Vol 56, Iss

2023 Volume 1

Abstract: We elucidated the effect of four known T1D-susceptibility associated single nucleotide polymorphism (SNP) markers in three genes (rs12722495 and rs2104286 in IL2RA, rs689 in INS and rs2476601 in PTPN22) on CpG site methylation of their proximal promoters ...

Abstract	We elucidated the effect of four known T1D-susceptibility associated single nucleotide polymorphism (SNP) markers in three genes (rs12722495 and rs2104286 in IL2RA, rs689 in INS and rs2476601 in PTPN22) on CpG site methylation of their proximal promoters in different lymphocyte subsets using pyrosequencing. The study cohort comprised 25 children with newly diagnosed T1D and 25 matched healthy controls. The rs689 SNP was associated with methylation at four CpG sites in INS promoter: −234, −206, −102 and −69. At all four CpG sites, the susceptibility genotype AA was associated with a higher methylation level compared to the other genotypes. We also found an association between rs12722495 and methylation at CpG sites −373 and −356 in IL2RA promoter in B cells, where the risk genotype AA was associated with lower methylation level compared to the AG genotype. The other SNPs analyzed did not demonstrate significant associations with CpG site methylation in the examined genes. Additionally, we compared the methylation between children with T1D and controls, and found statistically significant methylation differences at CpG −135 in INS in CD8+ T cells (p = 0.034), where T1D patients had a slightly higher methylation compared to controls (87.3 ± 7.2 vs. 78.8 ± 8.9). At the other CpG sites analyzed, the methylation was similar. Our results not only confirm the association between INS methylation and rs689 discovered in earlier studies but also report this association in sorted immune cells. We also report an association between rs12722495 and IL2RA promoter methylation in B cells. These results suggest that at least part of the genetic effect of rs689 and rs12722495 on T1D pathogenesis may be conveyed by DNA methylation.
Keywords	type 1 diabetes ; dna methylation ; ins ; il2ra ; ptpn22 ; Internal medicine ; RC31-1245
Subject code	570
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Progression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories

Bum Chul Kwon / Vibha Anand / Peter Achenbach / Jessica L. Dunne / William Hagopian / Jianying Hu / Eileen Koski / Åke Lernmark / Markus Lundgren / Kenney Ng / Jorma Toppari / Riitta Veijola / Brigitte I. Frohnert / the T1DI Study Group

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 9

Abstract: Presence of islet autoantibodies precedes the onset of type 1 diabetes but it does not predict whether and how fast symptomatic disease appears. Here authors present a model to predict and visualize progression to diabetes by using a large longitudinal ... ...

Abstract	Presence of islet autoantibodies precedes the onset of type 1 diabetes but it does not predict whether and how fast symptomatic disease appears. Here authors present a model to predict and visualize progression to diabetes by using a large longitudinal data set on autoantibodies and clinical parameters as input.
Keywords	Science ; Q
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: RANKL regulates male reproductive function

Martin Blomberg Jensen / Christine Hjorth Andreassen / Anne Jørgensen / John Erik Nielsen / Li Juel Mortensen / Ida Marie Boisen / Peter Schwarz / Jorma Toppari / Roland Baron / Beate Lanske / Anders Juul

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 15

Abstract: There are few treatments for male infertility. Here, the authors show that the receptor activator of NF-κB ligand (RANKL) signalling pathway has important functions in sperm production and maturation, improves fertility in male mice and shows potential ... ...

Abstract	There are few treatments for male infertility. Here, the authors show that the receptor activator of NF-κB ligand (RANKL) signalling pathway has important functions in sperm production and maturation, improves fertility in male mice and shows potential as a male infertility target.
Keywords	Science ; Q
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Determining the timing of pubertal onset via a multicohort analysis of growth

Essi Syrjälä / Harri Niinikoski / Helena E. Virtanen / Jorma Ilonen / Mikael Knip / Nina Hutri-Kähönen / Katja Pahkala / Olli T. Raitakari / Wiwat Rodprasert / Jorma Toppari / Suvi M. Virtanen / Riitta Veijola / Jaakko Peltonen / Jaakko Nevalainen

PLoS ONE, Vol 16, Iss

2021 Volume 11

Abstract: Objective Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the ... ...

Abstract	Objective Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing. Design This multicohort study includes data from three Finnish cohorts—the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP). Methods The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model. Results The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference. Conclusions The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage–based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up.
Keywords	Medicine ; R ; Science ; Q
Subject code	360
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Determining the timing of pubertal onset via a multicohort analysis of growth.

Essi Syrjälä / Harri Niinikoski / Helena E Virtanen / Jorma Ilonen / Mikael Knip / Nina Hutri-Kähönen / Katja Pahkala / Olli T Raitakari / Wiwat Rodprasert / Jorma Toppari / Suvi M Virtanen / Riitta Veijola / Jaakko Peltonen / Jaakko Nevalainen

PLoS ONE, Vol 16, Iss 11, p e

2021 Volume 0260137

Abstract	Objective Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing. Design This multicohort study includes data from three Finnish cohorts-the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP). Methods The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model. Results The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference. Conclusions The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage-based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up.
Keywords	Medicine ; R ; Science ; Q
Subject code	360
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Gluten-free diet adherence in children with screening-detected celiac disease using a prospective birth cohort study.

Pooja Mehta / Qian Li / Marisa Stahl / Ulla Uusitalo / Katri Lindfors / Martha D Butterworth / Kalle Kurppa / Suvi Virtanen / Sibylle Koletzko / Carin Aronsson / William A Hagopian / Marian J Rewers / Jorma Toppari / Anette-G Ziegler / Beena Akolkar / Jeffrey P Krischer / Daniel Agardh / Edwin Liu / TEDDY Study Group

PLoS ONE, Vol 18, Iss 2, p e

2023 Volume 0275123

Abstract: Background Celiac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence- ... ...

Abstract	Background Celiac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence-related factors, and compare adherence to food records in a multinational prospective birth cohort study. Methods Children in The Environmental Determinants of Diabetes in the Young study with celiac disease were included. Subjects had at least annual measurement of adherence (parent-report) and completed 3-day food records. Descriptive statistics, t-tests, Kruskal-Wallis tests and multivariable logistic and linear regression were employed. Results Two hundred ninety (73%) and 199 (67%) of subjects were always adherent to a gluten-free diet at 2 and 5 years post celiac disease diagnosis respectively. The percentage of children with variable adherence increased from 1% at 2 years to 15% at 5 years. Children with a first-degree relative with celiac disease were more likely to be adherent to the gluten-free diet. Gluten intake on food records could not differentiate adherent from nonadherent subjects. Adherent children from the United States had more gluten intake based on food records than European children (P < .001 and P = .007 at 2 and 5 years respectively). Conclusion Approximately three-quarters of children with screening-identified celiac disease remain strictly adherent to a gluten-free diet over time. There are no identifiable features associated with adherence aside from having a first-degree relative with celiac disease. Despite good parent-reported adherence, children from the United States have more gluten intake when assessed by food records. Studies on markers of gluten-free diet adherence, sources of gluten exposure (particularly in the United States), and effects of adherence on mucosal healing are needed.
Keywords	Medicine ; R ; Science ; Q
Subject code	360
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Reconstruction of mouse testicular cellular microenvironments in long-term seminiferous tubule culture.

Juho-Antti Mäkelä / Jorma Toppari / Adolfo Rivero-Müller / Sami Ventelä

PLoS ONE, Vol 9, Iss 3, p e

2014 Volume 90088

Abstract: Research on spermatogonia is hampered by complex architecture of the seminiferous tubule, poor viability of testicular tissue ex vivo and lack of physiologically relevant long-term culture systems. Therefore there is a need for an in vitro model that ... ...

Abstract	Research on spermatogonia is hampered by complex architecture of the seminiferous tubule, poor viability of testicular tissue ex vivo and lack of physiologically relevant long-term culture systems. Therefore there is a need for an in vitro model that would enable long term survival and propagation of spermatogonia. We aimed at the most simplified approach to enable all different cell types within the seminiferous tubules to contribute to the creation of a niche for spermatogonia. In the present study we describe the establishment of a co-culture of mouse testicular cells that is based on proliferative and migratory activity of seminiferous tubule cells and does not involve separation, purification or differential plating of individual cell populations. The co-culture is composed of the constituents of testicular stem cell niche: Sertoli cells [identified by expression of Wilm's tumour antigen 1 (WT1) and secretion of glial cell line-derived neurotrophic factor, GDNF], peritubular myoid cells (expressing alpha smooth muscle actin, αSMA) and spermatogonia [expressing MAGE-B4, PLZF (promyelocytic leukaemia zinc finger), LIN28, Gpr125 (G protein-coupled receptor 125), CD9, c-Kit and Nanog], and can be maintained for at least five weeks. GDNF was found in the medium at a sufficient concentration to support proliferating spermatogonial stem cells (SSCs) that were able to start spermatogenic differentiation after transplantation to an experimentally sterile recipient testis. Gdnf mRNA levels were elevated by follicle-stimulating hormone (FSH) which shows that the Sertoli cells in the co-culture respond to physiological stimuli. After approximately 2-4 weeks of culture a spontaneous formation of cord-like structures was monitored. These structures can be more than 10 mm in length and branch. They are formed by peritubular myoid cells, Sertoli cells, fibroblasts and spermatogonia as assessed by gene expression profiling. In conclusion, we have managed to establish in vitro conditions that allow spontaneous reconstruction of testicular cellular microenvironments.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Generation, localization and functions of macrophages during the development of testis

Emmi Lokka / Laura Lintukorpi / Sheyla Cisneros-Montalvo / Juho-Antti Mäkelä / Sofia Tyystjärvi / Venla Ojasalo / Heidi Gerke / Jorma Toppari / Pia Rantakari / Marko Salmi

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 16

Abstract: The developmental origins and functions of testis macrophages remain incompletely characterized. Here, the authors show, using histology, high-dimensional mass cytometry and cell fate-mapping data, that interstitial and peritubular macrophages originate ... ...

Abstract	The developmental origins and functions of testis macrophages remain incompletely characterized. Here, the authors show, using histology, high-dimensional mass cytometry and cell fate-mapping data, that interstitial and peritubular macrophages originate from distinct precursors and contribute distinctly to spermatogenesis.
Keywords	Science ; Q
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Generation, localization and functions of macrophages during the development of testis

Emmi Lokka / Laura Lintukorpi / Sheyla Cisneros-Montalvo / Juho-Antti Mäkelä / Sofia Tyystjärvi / Venla Ojasalo / Heidi Gerke / Jorma Toppari / Pia Rantakari / Marko Salmi

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 16

Abstract	The developmental origins and functions of testis macrophages remain incompletely characterized. Here, the authors show, using histology, high-dimensional mass cytometry and cell fate-mapping data, that interstitial and peritubular macrophages originate from distinct precursors and contribute distinctly to spermatogenesis.
Keywords	Science ; Q
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Temporal changes in gastrointestinal fungi and the risk of autoimmunity during early childhood

Thomas A. Auchtung / Christopher J. Stewart / Daniel P. Smith / Eric W. Triplett / Daniel Agardh / William A. Hagopian / Anette G. Ziegler / Marian J. Rewers / Jin-Xiong She / Jorma Toppari / Åke Lernmark / Beena Akolkar / Jeffrey P. Krischer / Kendra Vehik / Jennifer M. Auchtung / Nadim J. Ajami / Joseph F. Petrosino

Nature Communications, Vol 13, Iss 1, Pp 1-

the TEDDY study

2022 Volume 8

Abstract: Here, via metagenomics and ITS2 sequencing analysis of children's stool samples from three months to four years, the authors show that the fungal composition changes and relative abundance increases at weaning, but unlike bacteria, the overall levels of ... ...

Abstract	Here, via metagenomics and ITS2 sequencing analysis of children's stool samples from three months to four years, the authors show that the fungal composition changes and relative abundance increases at weaning, but unlike bacteria, the overall levels of fungal diversity do not change substantially over time.
Keywords	Science ; Q
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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