Journal
BLOOD
Volume 133, Issue 17, Pages 1888-1898Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-10-879585
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Funding
- National Institutes of Health Clinical and Translational Science Award
- National Center for Research Resources grant [1UL1RR025011]
- National Center for Advancing Translational Sciences [9U54TR000021, UL1TR000427]
- National Natural Science Foundation of China [31521003, 81770066]
- 111 Project [B13016]
- Marshfield Clinic Research Institute [SCH10218]
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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.
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