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.
Background: Agricultural employment is one of the most dangerous occupations in the United States. Workers' compensation coverage requirements for agricultural work vary from state to state, and experience modifier rates (E-mods) affecting insurance premiums sometimes vary drastically across state lines and according to claim severities and farm sizes. We proposed to develop an interactive software application that would educate farmers on the impact of employee time loss on annual E-mod factor change specific to their geographic location and farm size. Methods: We conducted a comparative analysis of workers' compensation formulations, including E-mods among Upper Midwestern states. We performed sensitivity analysis of the formulas to claim amount and payroll to highlight differences related to claim severity and to farm size. Results: The state to state variation and remarkable complexity of these formulas was confirmed. E-Mod factors are shown to increase substantially across states with both claim size and payroll, though are found to be similar across Wisconsin and Minnesota which were examined in detail. Conclusions: The findings confirm that creating a nationally applicable interactive educational software tool for farmers and ranchers to view hypothetical rate changes by inputting on-farm injury scenarios represents a significant challenge and that educational outreach coupled with the use of commercial software, especially as less costly options become available, may serve the role of minimizing misunderstandings by current producers as may other informational sources.
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