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Common genetic determinants of vitamin D insufficiency: a genome-wide association study.

Artikel i vetenskaplig tidskrift
Författare Thomas J Wang
Feng Zhang
J Brent Richards
Bryan Kestenbaum
Joyce B van Meurs
Diane Berry
Douglas P Kiel
Elizabeth A Streeten
Claes Ohlsson
Daniel L Koller
Leena Peltonen
Jason D Cooper
Paul F O'Reilly
Denise K Houston
Nicole L Glazer
Liesbeth Vandenput
Munro Peacock
Julia Shi
Fernando Rivadeneira
Mark I McCarthy
Pouta Anneli
Ian H de Boer
Massimo Mangino
Bernet Kato
Deborah J Smyth
Sarah L Booth
Paul F Jacques
Greg L Burke
Mark Goodarzi
Ching-Lung Cheung
Myles Wolf
Kenneth Rice
David Goltzman
Nick Hidiroglou
Martin Ladouceur
Nicholas J Wareham
Lynne J Hocking
Deborah Hart
Nigel K Arden
Cyrus Cooper
Suneil Malik
William D Fraser
Anna-Liisa Hartikainen
Guangju Zhai
Helen M Macdonald
Nita G Forouhi
Ruth Jf Loos
David M Reid
Alan Hakim
Elaine Dennison
Yongmei Liu
Chris Power
Helen E Stevens
Laitinen Jaana
Ramachandran S Vasan
Nicole Soranzo
Jörg Bojunga
Bruce M Psaty
Mattias Lorentzon
Tatiana Foroud
Tamara B Harris
Albert Hofman
John-Olov Jansson
Jane A Cauley
Andre G Uitterlinden
Quince Gibson
Marjo-Riitta Järvelin
David Karasik
David S Siscovick
Michael J Econs
Stephen B Kritchevsky
Jose C Florez
John A Todd
Josee Dupuis
Elina Hyppönen
Timothy D Spector
Publicerad i Lancet
Volym 376
Nummer/häfte 9736
Sidor 180-8
ISSN 1474-547X
Publiceringsår 2010
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Centre for Bone and Arthritis Research
Institutionen för medicin, avdelningen för invärtesmedicin
Sidor 180-8
Språk en
Länkar dx.doi.org/10.1016/S0140-6736(10)60...
Ämneskategorier Endokrinologi

Sammanfattning

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

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