| 1. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 2. |
- Donaldson, M., et al.
(författare)
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Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy
- 2019
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Ingår i: Hormone Research in Paediatrics. - : S. Karger AG. - 1663-2818 .- 1663-2826. ; 91:3, s. 153-163
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most girls with Turner syndrome (TS) require pubertal induction with estrogen, followed by long term replacement. However, no adequately powered prospective studies comparing transdermal with oral 17 beta-estradiol administration exist. This reflects the difficulty of securing funding to study a rare condition with relatively low morbidity/mortality when competing against conditions such as cancer and vascular disease. Protocol Consensus: The TS Working Group of the European Society for Paediatric Endocrinology (ESPE) has agreed to both a 3-year oral and a 3-year transdermal regimen for pubertal induction. Prerequisites include suitable 17 beta-estradiol tablets and matrix patches to allow the delivery of incremental doses based on body weight. Study Proposal: An international prospective cohort study with single centre analysis is proposed in which clinicians and families are invited to choose either of the agreed regimens, usually starting at 11 years. We hypothesise that pubertal induction with transdermal estradiol will result in better outcomes for some key parameters. The primary outcome measure chosen is height gain during the induction period. Analysis: Assessment of the demographics and drop-out rates of patients choosing either oral or transdermal preparations; and appropriate analysis of outcomes including pubertal height gain, final height, liver enzyme and lipid profile, adherence/acceptability, cardiovascular health, including systolic and diastolic blood pressure and aortic root diameter and bone health. Conclusion: The proposed model of prospective data collection according to internationally agreed protocols aims to break the current impasse in obtaining evidence-based management for TS and could be applied to other rare paediatric endocrine conditions. (C) 2019 S. Karger AG, Basel
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| 3. |
- Savendahl, L., et al.
(författare)
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Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study
- 2020
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Ingår i: Lancet Diabetes & Endocrinology. - : Elsevier BV. - 2213-8587. ; 8:8, s. 683-692
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Tidskriftsartikel (refereegranskat)abstract
- Background Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. Methods This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). Findings The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1.1, 95% CI 0.9-1.3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1.5, CI 1.1-1.9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3.8, 3.3-4.4; and 17.1, 15.6-18.7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. Interpretation In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
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| 4. |
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| 5. |
- Paquette, J., et al.
(författare)
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Risk of autoimmune diabetes in APECED : association with short alleles of the 5 ' insulin VNTR
- 2010
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 11:7, s. 590-597
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autoimmune disease causing a wide spectrum of autoimmune dysfunction potentially including diabetes of an autoimmune etiology. We have previously described a pair of discordant APECED siblings and pointed to a possible role of 5' insulin variable number of tandem repeats (VNTR) locus IDDM2 in the appearance of diabetes within this disease. In vitro studies have previously suggested that class I VNTR alleles were associated with decreased fetal thymic insulin expression. We genotyped the 5' INS VNTR locus and several flanking 11p15.5 markers in 5' Finnish APECED subjects and explored the possible contribution of IDDM2 in the development of diabetes. The shorter 5' INS VNTR class I alleles (<35 repeats) were more prevalent in the diabetic Finnish APECED subjects than in non-diabetic APECED subjects. Logistic regression analysis revealed that having 1 short (<35) VNTR allele did not increase the risk of developing diabetes (95% CI 0.6-27.0), whereas having 2 short alleles conferred a 43.5-fold increased risk (95% CI 3.0-634.6). We conclude that short 5' INS VNTR class I alleles play a role in susceptibility to autoimmune diabetes in the context of APECED.
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| 6. |
- Simon, M P, et al.
(författare)
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Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.
- 1997
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 15:1, s. 95-8
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Tidskriftsartikel (refereegranskat)abstract
- Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy, presents specific features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from the t(17;22). In this report, the breakpoints from translocations and rings in DP and its juvenile form, giant cell fibroblastoma (GCF), were characterised on the genomic and RNA level. These rearrangements fuse the platelet-derived growth factor B-chain (PDGFB, c-sis proto-oncogene) and the collagen type I alpha 1 (COL1A1) genes. PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes is not fully understood. COL1A1 is a major constituent of the connective tissue matrix. Neither PDGFB nor COL1A1 have so far been implicated in any tumour translocations. These gene fusions delete exon 1 of PDGFB, and release this growth factor from its normal regulation.
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| 7. |
- Doody, A., et al.
(författare)
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Validating the association between plasma tumour necrosis factor receptor 1 levels and the presence of renal injury and functional decline in patients with Type 2 diabetes
- 2018
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Ingår i: Journal of Diabetes and Its Complications. - : Elsevier BV. - 1056-8727. ; 32:1, s. 95-99
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Elevated plasma soluble tumour necrosis factor receptor 1 (TNFR1) predicts long-term progression of chronic kidney disease. We investigated the association between elevated TNFR1 and the presence of renal disease in patients with Type 2 diabetes mellitus registering a haemoglobin Mc (HbA1c) >48 mmol/mol despite medical therapy. Methods: Using sensitivity, specificity and regression analyses we interrogated the association between plasma TNFR1 and presence of chronic kidney disease as assessed by the presence of microalbuminuria and/or an estimated glomerular filtration rate of less than 60 ml/min/1.73 m(2) (stages 3-5 chronic kidney disease). The association of TNFR1 with C-reactive protein and leptin-adiponectin ratio as plasma markers of systemic inflammation and adipose stress respectively was also investigated. Results: Upper quartile TNFR1 is independently associated with elevated urinary albumin-creatinine ratios, reductions in eGFR and strongly predicts the presence of stages 3-5 chronic kidney disease in regression modelling. Elevated TNFR1 levels are associated with increased plasma C-reactive protein and augmented leptin-adiponectin ratio. Conclusions: Our study confirms plasma TNFR1 as a surrogate of renal structural and functional impairment in patients with type 2 diabetes mellitus. Association of TNFR1 with markers of systemic inflammation and adipose stress indicates that TNFR1 may be a biomarker of these processes as components of the pathogenesis of diabetic kidney disease. (C) 2017 Elsevier Inc. All rights reserved.
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| 8. |
- Hochberg, Z., et al.
(författare)
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Child health, developmental plasticity, and epigenetic programming
- 2011
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Ingår i: Endocrine reviews. - : The Endocrine Society. - 0163-769X .- 1945-7189. ; 32:2, s. 159-224
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Forskningsöversikt (refereegranskat)abstract
- Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
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| 9. |
- Cohen, R., et al.
(författare)
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Role of proximal gut exclusion from food on glucose homeostasis in patients with Type 2 diabetes
- 2013
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 30, s. 1482-1486
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To report Type 2 diabetes-related outcomes after the implantation of a duodenal-jejunal bypass liner device and to investigate the role of proximal gut exclusion from food in glucose homeostasis using the model of this device. Methods: Sixteen patients with Type 2 diabetes and BMI <36kg/m2 were evaluated before and 1, 12 and 52weeks after duodenal-jejunal bypass liner implantation and 26weeks after explantation. Mixed-meal tolerance tests were conducted over a period of 120min and glucose, insulin and C-peptide levels were measured. The Matsuda index and the homeostatic model of assessment of insulin resistance were used for the estimation of insulin sensitivity and insulin resistance. The insulin secretion rate was calculated using deconvolution of C-peptide levels. Results: Body weight decreased by 1.3kg after 1week and by 2.4kg after 52weeks (P<0.001). One year after duodenal-jejunal bypass liner implantation, the mean (sem) HbA1c level decreased from 71.3 (2.4) mmol/mol (8.6[0.2]%) to 58.1 (4.4) mmol/mol (7.5 [0.4]%) and mean (sem) fasting glucose levels decreased from 203.3 (13.5) mg/dl to 155.1 (13.1) mg/dl (both P<0.001). Insulin sensitivity improved by >50% as early as 1week after implantation as measured by the Matsuda index and the homeostatic model of assessment of insulin resistance (P<0.001), but there was a trend towards deterioration in all the above-mentioned variables 26weeks after explantation. Fasting insulin levels, insulin area under the curve, fasting C-peptide, C-peptide area under the curve, fasting insulin and total insulin secretion rates did not change during the duodenal-jejunal bypass liner implantation period or after explantation. Conclusions: The duodenal-jejunal bypass liner improves glycaemia in overweight and obese patients with Type 2 diabetes by rapidly improving insulin sensitivity. A reduction in hepatic glucose output is the most likely explanation for this improvement. Diabetic Medicine © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.
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| 10. |
- Martin, W. P., et al.
(författare)
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Parallel assessment of albuminuria and plasma sTNFR1 in people with type 2 diabetes and advanced chronic kidney disease provides accurate prognostication of the risks of renal decline and death
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Identification of people with diabetes and chronic kidney disease at high-risk of early mortality is a priority to guide intensification of therapy. We aimed to investigate the complementary prognostic value of baseline urine albumin-to-creatinine ratio (uACR) and plasma soluble tumour necrosis factor receptor-1 (sTNFR1) with respect to early mortality and renal functional decline in a population with type 2 diabetes and advanced chronic kidney disease. We measured plasma sTNFR1 in people with type 2 diabetes (HbA(1c)>= 48 mmol/mol) at 2 hospital sites in Dublin between October 15th, 2014 and July 17th, 2015. In a subgroup of patients with advanced chronic kidney disease at baseline (estimated glomerular filtration rate (eGFR)<= 60 mL/min/BSA) (n=118), we collected clinical and longitudinal laboratory data to investigate relationships between sTNFR1 and renal and mortality endpoints by multivariable linear mixed-effects models and Cox proportional hazards regression models. The cohort was 64% male and 97% Caucasian. Mean age was 74 years, with a median type 2 diabetes duration of 16 years. Mean CKD-EPI eGFR was 42 mL/min/BSA and median [IQR] uACR was 3 [11] mg/mmol. Twenty-three (39%) people in quartiles 3 and 4 for plasma sTNFR1 died over 4-year follow-up. After adjustment for clinical variables, annual CKD-EPI eGFR decreased by -0.56 mL/min/BSA/year for each logarithm unit increase in baseline uACR, corresponding to an annual loss of renal function of 3% per year. Furthermore, elevated uACR, but not sTNFR1, increased the risk of >= 40% decline in CKD-EPI eGFR (HR 1.5, p=0.001) and doubling of serum creatinine (HR 2.0, p<0.001). Plasma sTNFR1 did not predict a more negative trajectory in eGFR slope. However, for those people in quartiles 3 and 4 for plasma sTNFR1, an increased risk of incident mortality was detected (HR 4.9, p=0.02). No such association was detected for uACR. In this elderly cohort of patients with type 2 diabetes and chronic kidney disease, sTNFR1 predicted short-to-medium term mortality risk but not risk of progressive renal functional decline. In contrast, parallel assessment of uACR predicted renal functional decline but not mortality, highlighting the complementary prognostic information provided by both parameters.
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