Financiado en parte por Novo Nordisk Fonden
Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis
Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, Medina-Gómez C, Voortman T, van der Velde N, Melhus H, Robinson-Cohen C, Cousminer DL, Nethander M, Vandenput L, Noordam R, Forgetta V, Greenwood CMT, Biggs ML, Psaty BM, Rotter JI, Zemel BS, Mitchell JA, Taylor B, Lorentzon M, Karlsson M, Jaddoe VVW, Tiemeier H, Campos-Obando N, Franco OH, Utterlinden AG, Broer L, van Schoor NM, Ham AC, Ikram MA, Karasik D, de Mutsert R, Rosendaal FR, den Heijer M, Wang TJ, Lind L, Orwoll ES, Mook-Kanamori DO, Michaëlsson K, Kestenbaum B, Ohlsson C, Mellström D, de Groot LCPGM, Grant SFA, Kiel DP, Zillikens MC, Rivadeneira F, Sawcer S, Timpson NJ, Richards JB
American journal of human genetics · 106 citas
Etiquetas de revisión
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Cómo se estudió
- Diseño
- Metaanálisis (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Eventos clínicos como enfermedad o muerte
Quién lo pagó
- Financiación
- Financiado por la industria
- Organización sin fines de lucro
- Wellcome Trust
- Organización sin fines de lucro
- Cancer Research UK
- Gobierno
- National Institute for Health and Care Research
- Universidad u hospital
- University of Tasmania
- Empresa
- Novo Nordisk Fonden
- Gobierno
- National Institutes of Health
- Gobierno
- National Heart, Lung, and Blood Institute
- Gobierno
- National Center for Advancing Translational Sciences
- Gobierno
- Medical Research Council
- Gobierno
- NHLBI NIH HHS
- Gobierno
- NCATS NIH HHS
- Gobierno
- National Institute for Health Research (NIHR)
- Gobierno
- European Research Council
- Subvenciones
- National Center for Advancing Translational Sciences (UL1TR002369); Novo Nordisk Fonden (NNF14OC0010513); National Institute for Health and Care Research (ACF-2014-25-009); National Heart, Lung, and Blood Institute (R01-HL120393); Novo Nordisk Fonden (NNF14OC0009883); National Institutes of Health (UL1TR000124); National Heart, Lung, and Blood Institute (U01HL130114); Novo Nordisk Fonden (NNF13OC0005785); National Heart, Lung, and Blood Institute (R01 HL105756); Wellcome Trust (202802/Z/16/Z); National Heart, Lung, and Blood Institute (U01HL-120393); University of Tasmania (BT000001); Novo Nordisk Fonden (NNF15OC0016220); Cancer Research UK (19169); National Heart, Lung, and Blood Institute (K01HL123612); Novo Nordisk Fonden (NNF13OC0004839)
Según 13 financiadores declarados.
Publicación
- Publicado
- 2017-07-27 · Am J Hum Genet · vol. 101 · número 2 · págs. 227–238
- Editorial
- Elsevier BV
- Citado
- 135 citas · más que el 99% de estudios similares · 13.2× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 36 trabajos
- Acceso
- Acceso abierto (revista híbrida) · OTHER-OA
- Áreas de investigación
- Vitamin D Research Studies · Genetic Associations and Epidemiology · Multiple Sclerosis Research Studies
- Palabras clave
- CYP2R1, vitamin D insufficiency, 25-hydroxyvitamin D, multiple sclerosis, low-frequency variants, vitamin D metabolism, genetic susceptibility, European populations
- MeSH
- humans, multiple sclerosis, vitamin d deficiency, genetic predisposition to disease, vitamin d, risk factors, gene frequency, polymorphism, single nucleotide, genome, human, genome-wide association study, cholestanetriol 26-monooxygenase, cytochrome p450 family 2
53 autores
- Despoina Manousaki🇨🇦Jewish General Hospital; Lady Davis Institute for Medical Research; McGill University
- Tom Dudding🇬🇧University of Bristol; MRC Integrative Epidemiology Unit
- Simon J. Haworth🇬🇧University of Bristol; MRC Integrative Epidemiology Unit
- Yi‐Hsiang Hsu🇺🇸Broad Institute; Harvard University; Hebrew SeniorLife; Massachusetts Institute of Technology
- Ching‐Ti Liu🇺🇸Boston University
- Carolina Medina‐Gómez🇳🇱Erasmus MC
- Trudy Voortman🇳🇱Erasmus MC
- Nathalie van der Velde🇳🇱Erasmus MC; Amsterdam UMC Location University of Amsterdam
- Håkan Melhus🇸🇪Uppsala University
- Cassianne Robinson‐Cohen🇺🇸University of Washington
- Diana L. Cousminer🇺🇸Children's Hospital of Philadelphia; University of Pennsylvania
- Maria Nethander🇸🇪University of Gothenburg
- Liesbeth Vandenput🇸🇪University of Gothenburg
- Raymond Noordam🇳🇱Leiden University; Leiden University Medical Center
- Vincenzo Forgetta🇨🇦Jewish General Hospital; Lady Davis Institute for Medical Research; McGill University
- Celia M.T. Greenwood🇨🇦Jewish General Hospital; Lady Davis Institute for Medical Research; McGill University
- Mary Lou Biggs🇺🇸University of Washington
- Bruce M. Psaty🇺🇸Kaiser Permanente; Kaiser Permanente Washington Health Research Institute; University of Washington
- Jerome I. Rotter🇺🇸University of California, Los Angeles; The Lundquist Institute; Harbor–UCLA Medical Center
- Babette S. Zemel🇺🇸Children's Hospital of Philadelphia; University of Pennsylvania
- Jonathan A. Mitchell🇺🇸Children's Hospital of Philadelphia; University of Pennsylvania
- Bruce V. Taylor🇦🇺University of Tasmania; Menzies Institute for Medical Research
- Mattias Lorentzon🇸🇪Sahlgrenska University Hospital; University of Gothenburg
- Magnus K. Karlsson🇸🇪Lund University; Skåne University Hospital
- Vincent V. W. Jaddoe🇳🇱Erasmus MC
- Henning W. Tiemeier🇳🇱Erasmus MC
- Natalia Campos‐Obando🇳🇱Erasmus MC
- Oscar H. Franco🇳🇱Erasmus MC
- André Gerardus Uitterlinden🇳🇱Erasmus MC
- Linda Broer🇳🇱Erasmus MC
- Natasja M. van Schoor🇳🇱Amsterdam Public Health; Amsterdam UMC Location Vrije Universiteit Amsterdam
- Annelies C. Ham🇳🇱Erasmus MC
- M. Arfan Ikram🇳🇱Erasmus MC
- David Karasik🇺🇸Hebrew SeniorLife
- Renée de Mutsert🇳🇱Leiden University Medical Center
- Frits Richard Rosendaal🇳🇱Leiden University Medical Center
- Martin den Heijer🇳🇱Amsterdam UMC Location Vrije Universiteit Amsterdam
- Thomas J. Wang🇺🇸Vanderbilt University; Vanderbilt University Medical Center
- Lars Lind🇸🇪Uppsala University
- ERIC S. ORWOLL🇺🇸Oregon Health & Science University
- Dennis Owen Mook-Kanamori🇳🇱Leiden University; Leiden University Medical Center
- Karl Michaëlsson🇸🇪Uppsala University
- Bryan R. Kestenbaum🇺🇸University of Washington
- Claes Ohlsson🇸🇪University of Gothenburg
- Dan Mellström🇸🇪University of Gothenburg
- C.P.G.M. de Groot🇳🇱Wageningen University & Research
- Struan F.A. Grant🇺🇸Children's Hospital of Philadelphia; University of Pennsylvania
- Douglas P. Kiel🇺🇸Broad Institute; Beth Israel Deaconess Medical Center; Harvard University; Hebrew SeniorLife; Massachusetts Institute of Technology
- M. Carola Zillikens🇳🇱Erasmus MC
- Fernando Rivadeneira🇳🇱Erasmus MC
- Stephen J. Sawcer🇬🇧University of Cambridge
- Nicholas John Timpson🇬🇧University of Bristol; MRC Integrative Epidemiology Unit
- John Brent Richards🇬🇧🇨🇦 · autor de correspondenciaKing's College London; Jewish General Hospital; Lady Davis Institute for Medical Research; McGill University
Resumen
El texto original del estudio, en el idioma en que se publicó.
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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