A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

• Main Authors: Bell, Steven, Allara, Elias, Ramond, Anna, Paul, Dirk, Howson, Joanna, Astle, William, Surendran, Praveen, Jiang, Tao, Akbari, Parsa, Kaptoge, Stephen, Wood, Angela, Peters, James, Soranzo, Nicole, Ouwehand, Willem, Butterworth, Adam, Danesh, John, Di Angelantonio, Emanuele
• Format: Article in Journal/Newspaper
• Language: English
• Published: Nature Research 2021
• Subjects: Humans; Anemia; Iron-Deficiency; Biomarkers; Denmark; Ferritins; Genetic Loci; Genetic Variation; Genome-Wide Association Study; Genotype; Homeostasis; Iceland; Iron; Iron Overload; Phenotype; Risk Assessment; Risk Factors; Transferrin; United Kingdom
• Online Access: https://www.repository.cam.ac.uk/handle/1810/311851; https://doi.org/10.17863/CAM.58942

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N=246,139), total iron binding capacity (N=135,430), iron (N=163,511) and transferrin saturation (N=131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation. Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University ...