Blood, 2019-04, Vol.133 (17), p.1888-1898
2019
Details
- Autor(en) / Beteiligte
- Titel
- A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene
- Ist Teil von
- Blood, 2019-04, Vol.133 (17), p.1888-1898
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Standard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor–encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6 variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism. •An exome scan for recessive effects reveals FGF6 as a hemochromatosis-susceptibility gene.•FGF-6 decreases ferrous iron uptake in liver cells and induces increased hepcidin expression. [Display omitted]
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0006-4971eISSN: 1528-0020DOI: 10.1182/blood-2018-10-879585Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6484389
- Format
- –
- Schlagworte
- Amino Acid Sequence, Case-Control Studies, Diploidy, Exome - genetics, Female, Fibroblast Growth Factor 6 - genetics, Fibroblast Growth Factor 6 - metabolism, Follow-Up Studies, Gene Expression Regulation, Genes, Recessive, Genetic Predisposition to Disease, Genome-Wide Association Study, Hemochromatosis - genetics, Hemochromatosis - pathology, Hepcidins - genetics, Hepcidins - metabolism, Humans, Iron - metabolism, Iron Overload - genetics, Iron Overload - pathology, Male, Middle Aged, Neoplasms - genetics, Neoplasms - pathology, Protein Interaction Maps, Red Cells, Iron, and Erythropoiesis, Scleroderma, Systemic - genetics, Scleroderma, Systemic - pathology, Sequence Homology