| 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. |
- 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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| 3. |
- 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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| 4. |
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| 6. |
- Maghsoodi, N., et al.
(författare)
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Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass
- 2017
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Ingår i: Annals of Clinical Biochemistry. - : SAGE Publications. - 0004-5632. ; 54:4, s. 495-500
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Tidskriftsartikel (refereegranskat)abstract
- Background Roux-en-Y gastric bypass increases circulating bile acid concentrations, known mediators of postprandial suppression of markers of bone resorption. Long-term data, however, indicate that Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients. Methods Thirty-six obese individuals, median age 44 (26-64) with median body mass index at baseline of 42.5 (40.4-46) were studied before and 15 months after Roux-en-Y gastric bypass. After an overnight fast, patients received a 400kcal mixed meal. Blood samples were collected premeal then at 30-min periods for 120min. Pre and postmeal samples were analysed for total bile acids, parathyroid hormone and C-terminal telopeptide. Results Body weight loss post Roux-en-Y gastric bypass was associated with a median 4.9-fold increase in peak postprandial total bile acid concentration, and a median 2.4-fold increase in cumulative food evoked bile acid response. Median fasting parathyroid hormone, postprandial reduction in parathyroid hormone and total parathyroid hormone release over 120min remained unchanged after surgery. After surgery, median fasting C-terminal telopeptide increased 2.3-fold, peak postprandial concentrations increased 3.8-fold and total release was increased 1.9-fold. Conclusions Fasting and postprandial total bile acids and C-terminal telopeptide are increased above reference range after Roux-en-Y gastric bypass. These changes occur in spite of improved vitamin D status with supplementation. These results suggest that post-Roux-en-Y gastric bypass increases in total bile acids do not effectively oppose an ongoing resorptive signal operative along the gut-bone axis. Serial measurement of C-terminal telopeptide may be of value as a risk marker for long-term skeletal pathology in patients post Roux-en-Y gastric bypass.
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| 7. |
- van de Ven, Johannes P. H., et al.
(författare)
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A functional variant in the CFI gene confers a high risk of age-related macular degeneration
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:7, s. 813-813
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Tidskriftsartikel (refereegranskat)abstract
- Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants(1-5). Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 x 10(-6); odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.
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| 8. |
- Abdeen, G. N., et al.
(författare)
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Sugar Detection Threshold After Laparoscopic Sleeve Gastrectomy in Adolescents
- 2018
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Ingår i: Obesity Surgery. - : Springer Science and Business Media LLC. - 0960-8923 .- 1708-0428. ; 28:5, s. 1302-1307
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Tidskriftsartikel (refereegranskat)abstract
- Obesity in young people is one of the most serious public health problems worldwide. Moreover, the mechanisms preventing obese adolescents from losing and maintaining weight loss have been elusive. Laparoscopic sleeve gastrectomy (LSG) is successful at achieving long-term weight loss in patients across all age groups, including children and adolescents. Anecdotal clinical observation as well as evidence in rodents suggests that LSG induces a shift in preference of sugary foods. However, it is not known whether this shift is due to a change in the threshold for gustatory detection of sucrose, or whether LSG induces behavioral change without affecting the gustatory threshold for sugar. The objective of this study was to determine whether adolescents who undergo LSG experience a change in their threshold for detecting sweet taste. We studied the sucrose detection threshold of 14 obese adolescents (age 15.3 +/- 0.5 years, range 12-18) who underwent LSG 2 weeks before surgery and at 12 and 52 weeks after surgery. Matched non-surgical subjects were tested on two occasions 12 weeks apart to control for potential learning of the test that may have confounded the results. Seven sucrose concentrations were used and were tested in eight blocks with each block consisting of a random seven sucrose and seven water stimuli. The subjects were asked to report whether the sample contained water or not after they tasted 15 ml of the fluid for 10 s. The bodyweight of the LSG group decreased from 136.7 +/- 5.4 to 109.6 +/- 5.1 and 86.5 +/- 4.0 kg after 12 and 52 weeks, respectively (p < 0.001). There was no significant difference after surgery in taste detection threshold of patients after LSG (p = 0.60), and no difference was observed comparing the taste detection threshold of the LSG group with the non-surgical controls (p = 0.38). LSG did not affect the taste detection threshold for sucrose, suggesting that the shift in preference for sugary foods may be due to factors other than fundamental changes in taste sensitivity.
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| 9. |
- Abdeen, G. N., et al.
(författare)
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Vertical sleeve gastrectomy in adolescents reduces the appetitive reward value of a sweet and fatty reinforcer in a progressive ratio task
- 2019
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Ingår i: Surgery for Obesity and Related Diseases. - : Elsevier BV. - 1550-7289. ; 15:2, s. 194-199
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adolescent obesity is challenging to treat even if good multidisciplinary approaches are started early. Vertical sleeve gastrectomy (VSG) is an effective intervention for long-term weight loss, but the underlying mechanisms that result in reduced calorie intake are controversial. Anecdotal evidence from the clinic and evidence in rodents after VSG suggest a decrease in the reward value of high-calorie dense foods. Objectives: To determine changes in appetitive behavior of candies (high in sugar and fat) after VSG in adolescents with obesity. Setting: University hospital. Methods: Sixteen adolescents with obesity (age 15.3 ±.5 yr) who had VSG and 10 control patients (age 13.8 ±.6 yr) who had not undergone surgery were studied. Both groups completed a progressive ratio task by clicking a computer mouse on a progressive ratio schedule to receive a candy high in sugar and fat. In the task, patients were required to expend an increasing amount of effort to obtain the reinforcer until they reach a breakpoint (measure of the reward value of the reinforcer). The task was performed before VSG and 12 and 52 weeks after VSG. Results: The VSG group's bodyweight decreased from the baseline 136.6 ± 5.1 to 110.9 ± 5.2 to 87.4 ± 3.7 kg after 12 and 52 weeks, respectively (P <.001). The median breakpoint for candies decreased after VSG from the baseline 320 (160–640) to 80 (50–320) to 160 (80–560) after 12 and 52 weeks, respectively (P =.01). Breakpoints for the control patients did not change (480 [160–640] versus 640 [280–640], P =.17). Conclusion: VSG resulted in a reduction in the reward value of a candy, as suggested by the reduced amount of effort adolescents were prepared to expend to obtain the high-sugar and high-fat candy. The effect was most pronounced 12 weeks after surgery but was largely maintained at 1 year. Long-term attenuation of appetitive behavior may be the key to weight loss and weight loss maintenance after VSG in adolescents. © 2018
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| 10. |
- Abegg, K., et al.
(författare)
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Effect of bariatric surgery combined with medical therapy versus intensive medical therapy or calorie restriction and weight loss on glycemic control in Zucker diabetic fatty rats
- 2015
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Ingår i: American Journal of Physiology-Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 308:4
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Tidskriftsartikel (refereegranskat)abstract
- Bariatric surgery rapidly improves Type 2 diabetes mellitus (T2DM). Our objective was to profile and compare the extent and duration of improved glycemic control following Roux-en-Y gastric (RYGB) bypass surgery and vertical sleeve gastrectomy (SG) and compare against calorie restriction/weight loss and medical combination therapy-based approaches using the Zucker diabetic fatty rat (ZDF) rodent model of advanced T2DM. Male ZDF rats underwent RYGB (n = 15) or SG surgery (n = 10) at 18 wk of age and received postsurgical insulin treatment, as required to maintain mid-light-phase glycemia within a predefined range (10-15 mmol/l). In parallel, other groups of animals underwent sham surgery with ad libitum feeding (n = 6), with body weight (n = 8), or glycemic matching (n = 8) to the RYGB group, using food restriction or a combination of insulin, metformin, and liraglutide, respectively. Both bariatric procedures decreased the daily insulin dose required to maintain mid-light-phase blood glucose levels below 15 mmol/l, compared with those required by body weight or glycemia-matched rats (P < 0.001). No difference was noted between RYGB and SG with regard to initial efficacy. SG was, however, associated with higher food intake, weight regain, and higher insulin requirements vs. RYGB at study end (P < 0.05). Severe hypoglycemia occurred in several rats after RYGB. RYGB and SG significantly improved glycemic control in a rodent model of advanced T2DM. While short-term outcomes are similar, long-term efficacy appears marginally better after RYGB, although this is tempered by the increased risk of hypoglycemia.
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