Vitamin D levels and risk of type 1 diabetes:A Mendelian randomization study

[This corrects the article DOI: 10.1371/journal.pmed.1003536.]

Increased Burden of Common Risk Alleles in Children With a Significant Fracture History

Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 x 10(-5)). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 x 10(-10)). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. (c) 2020 American Society for Bone and Mineral Research.Peer reviewe

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10-9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD

Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study.

BACKGROUND: Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. METHODS AND FINDINGS: We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. CONCLUSIONS: In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease

The efficacy and safety of gonadotropin - releasing hormone analog treatment in childhood and adolescence: a single center, long-term, follow-up study

Objective: The objective of the study was to evaluate the long-term effect of GnRHanalog (GnRHa) treatment on final height (FH), body mass index (BMI), body composition, bone mineral density (BMD), and ovarian function. Subjects/Methods: Ninety-two females, evaluated in adulthood, were categorized as follows: group A, 47 girls with idiopathic central precocious puberty (ICPP) (33 GnRHa treated and 14 nontreated); group B, 24 girls with isolated GH deficiency (15 GnRHa and GH treated and nine GH treated); group C, 21 girls with idiopathic short stature (seven GnRHa andGHtreated, seven GnRHa treated, and seven nontreated). Results: FH, BMD, and percent fat mass of GnRHa-treated patients in all three groups were comparable with those of the respective nontreated subjects. BMI values of GnRHa-treated and nontreated subjects in groups A and C were comparable, whereas in group B, a higher BMI was found in subjects treated only with GH. Nontreated patients with ICPP had greater maximal ovarian volumes, higher LH and LH to FSH ratio, and more severe hirsutism than GnRHa-treated ones. Menstrual cycle characteristics were not different between treated and nontreated subjects. The prevalence of polycystic ovary syndrome in treated and untreated girls with ICPP was comparable, whereas in the entire cohort, it was 11.1% in GnRHa treated and 32.1% in the untreated (P 0.02). Conclusions: Girls treated in childhood with GnRHa have normal BMI, BMD, body composition, and ovarian function in early adulthood. FH is not increased in girls with ICPP in whom GnRHa was initiated at about 8 yr. There is no evidence that GnRHa treatment predisposes to polycystic ovary syndrome or menstrual irregularities.Υπάρχουσα γνώση. Τα ανάλογα της GnRH (GnRHa) έχουν χρησιμοποιηθεί για την αναστολή της εφηβείας σε παιδιά με κεντρική πρώιμη ήβη (CPP) και σε παιδιά με μειωμένο προσδόκιμο αύξησης κατά την έναρξη της εφηβείας, με στόχο τη βελτίωση του τελικού αναστήματος (FH). Παρά την μακροχρόνια χρήση των GnRHa και μεγάλο αριθμό σχετικών δημοσιεύσεων, η αποτελεσματικότητα της θεραπείας και οι πιθανές μακροχρόνιες επιπλοκές ακόμη ερευνώνται. Στην μονοκεντρική αυτή μελέτη αξιολογήσαμε την αποτελεσματικότητα της θεραπείας με GnRHa στη βελτίωση του FH, και την επίπτωση της θεραπείας στον δείκτη μάζας σώματος (ΒΜΙ), τη σύνθεση σώματος, την οστική πυκνότητα (BMD), την αναπαραγωγική λειτουργία και τη συχνότητα ανάπτυξης συνδρόμου πολυκυστικών ωοθηκών (PCOS). Ασθενείς και Μέθοδοι. Ενενήντα δύο νεαρές γυναίκες, που διαγνώσθηκαν και παρακολουθήθηκαν στην Μονάδα Ενδοκρινολογίας Μεταβολισμού και Διαβήτη της Α' Παιδιατρικής Κλινικής του Πανεπιστημίου Αθηνών στο Νοσοκομείο Παίδων “η Αγία Σοφία”, συμπεριλήφθηκαν στη μελέτη και κατηγοριοποιήθηκαν ως εξής: Ομάδα Α: 47 κορίτσια με ιδιοπαθή κεντρική πρώιμη ήβη [ICPP] (33 έλαβαν GnRHa και 14 δεν έλαβαν θεραπεία), Ομάδα Β: 24 κορίτσια με μονήρη ανεπάρκεια αυξητικής ορμόνης (iGHD) (15 έλαβαν GnRHa και GH και 9 μόνο GH), και Ομάδα C : 21 κορίτσια με ιδιοπαθές κοντό ανάστημα (ISS), εκ των οποίων 7 έλαβαν GnRHa και GH, 7 έλαβαν μόνο GnRHa, και 7 δεν έλαβαν καμία θεραπεία. Οι 92 ασθενείς επανεκτιμήθηκαν σε ηλικία 16-32,3 ετών με λεπτομερές γυναικολογικό ιστορικό, κλινική εξέταση, υπερηχογράφημα έσω γεννητικών οργάνων, μέτρηση οστικής πυκνότητας και βιοχημικό και ορμονικό έλεγχο. Αποτελέσματα. Τόσο τα κορίτσια που έλαβαν θεραπεία με GnRHa, όσο και αυτές που δεν έλαβαν θεραπεία και στις τρεις ομάδες (Α, Β, C) δεν διέφεραν ως προς τη χρονολογική ηλικία, την οστική ηλικία, το στάδιο εφηβείας και το ΒΜΙ κατά την έναρξη της θεραπείας και κατά την αρχική κλινική εκτίμηση. Οι διάμεσες τιμές του τελικού αναστήματος, της οστικής πυκνότητας και της λιπώδους μάζας των ασθενών που έλαβαν θεραπεία με GnRHa και στις 3 ομάδες δεν διέφεραν σε σύγκριση με τις διάμεσες αντίστοιχες τιμές των ασθενών, που δεν έλαβαν θεραπεία. Οι διάμεσες τιμές ΒΜΙ και BMI-SDS, δεν διέφεραν μεταξύ των ασθενών με ICPP που έλαβαν και δεν έλαβαν θεραπεία με GnRHa και μεταξύ των 3 υποομάδων των ασθενών με ISS. Στην ομάδα των ασθενών με iGHD, οι ασθενείς που έλαβαν μόνο GH, είχαν υψηλότερο ΒΜΙ και BMI-SDS σε σύγκριση με αυτές που έλαβαν GnRHa και GH. Οι ασθενείς με ιδιοπαθή κεντρική πρώιμη ήβη που δεν έλαβαν θεραπεία είχαν μεγαλύτερο όγκο ωοθηκών, υψηλότερες τιμές LH και λόγο LH/FSH και περισσότερη υπερτρίχωση σε σχέση με τις ασθενείς που έλαβαν GnRHa. Ολες οι ασθενείς εμφάνισαν εμμηναρχή περίπου 1 χρόνο μετά τη διακοπή της θεραπείας με GnRHa. Η εμμηναρχή εμφανίστηκε πιο αργά στις ασθενείς που έλαβαν GnRHa, αλλά δεν βρέθηκαν διαφορές στα χαρακτηριστικά του κύκλου μεταξύ των διαφόρων υποομάδων. Στο σύνολο των ασθενών, η συχνότητα PCOS, με βάση τα κριτήρια του ΝΙΗ, ήταν 32.1% στις γυναίκες χωρίς θεραπεία και 11.1% στις γυναίκες που έλαβαν GnRHa (p: 0.02). Συμπεράσματα. Στη μονοκεντρική αυτή μελέτη παρακολουθήθηκαν για μακρό χρονικό διάστημα κορίτσια με διαφορετικές ενδείξεις χορήγησης θεραπείας με GnRHa για βελτίωση του τελικού αναστήματος, και συμπεριλήφθηκαν και κορίτσια που δεν έλαβαν αντίστοιχη θεραπεία. Τα αποτελέσματα δείχνουν ότι οι νεαρές γυναίκες που έλαβαν GnRHa στην παιδική ηλικία, στη νεαρή ενήλικο ζωή έχουν φυσιολογικό ΒΜΙ, φυσιολογική οστική πυκνότητα, σύνθεση σώματος και ωοθηκική λειτουργία. Δεν παρατηρήθηκε βελτίωση του τελικού αναστήματος στα κορίτσια με ιδιοπαθή κεντρική πρώιμη ήβη, στα οποία η θεραπεία με GnRHa ξεκίνησε μετά την ηλικία των οκτώ ετών. Τέλος, η θεραπεία με GnRHa δε φαίνεται να προδιαθέτει σε εμφάνιση συνδρόμου πολυκυστικών ωοθηκών ή διαταραχών του κύκλου

Continuous Subcutaneous Insulin Infusion in Children: A Pilot Study Validating a Protocol to Avoid Hypoglycemia at Initiation

BackgroundThe occurrence of hypoglycemia and hyperglycemia during the first days after transition to continuous subcutaneous insulin infusion (CSII) in patients with type 1 diabetes has not been systematically studied in children. The aim of this prospective study was to demonstrate that the protocol applied in our diabetes clinic is safe at CSII initiation in children.MethodsWe assessed 22 pediatric patients with type 1 diabetes, using continuous glucose monitoring (CGM) before and after CSII initiation (±3 days).ResultsAfter CSII initiation, there was no difference in the rates of hypoglycemic events expressed as relative rates (RRs) per person-reading (RR = 0.85, p = 0.52, 95% CI 0.52–1.39), as well as in the number of prolonged hypoglycemic events (&gt;1 h) per day (RR = 1.12, p = 0.56, 95% CI 0.75–1.68). We observed only a trend toward prolonged episodes of hyperglycemia after pump initiation (RR = 1.52, p = 0.06, 95% CI 0.97–2.35).ConclusionOur study is the first to assess, through CGM and in a prospective way, the impact of a CSII initiation protocol on glycemic values. Our protocol provides a safe model to avoid hypoglycemia at CSII initiation in children.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT01840358