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2015 DEPARTMENT OF MEDICINE RESEARCH DAY Title of Poster: Dietary Iron and Genetic Variation Alter Metallostasis in Mice Presenter: Brie Fuqua Division: Cardiology ☐Faculty ☐Fellow ☐Resident ☒Post-doc Research Fellow ☐Graduate Student ☐Medical Student ☐Other Principal Investigator/Mentor: Aldons Lusis Co-Investigators: Chris D. Vulpe, Kathryn E. Page, Stela McLachlan, Hiro Irimagawa, David W. Killilea, Brian W. Parks, Simon T. Hui, Richard Davis, Hannah Qi, Zhiqiang Zhou, Eleazar Eskin Thematic Poster Category: Genetic Diseases, Gene-Environment Interactions, Gene Therapy Abstract Introduction: The great diversity in genetic disorders of iron metabolism in man, rodents, and other vertebrates suggests that multiple genes can contribute to the susceptibility to iron deficiency and to the severity of iron overload. Several studies have shown differences in iron homeostasis between inbred strains of mice. However, the variation in genetically attributed iron phenotypes cannot be fully explained by the set of genes currently known to be involved in iron metabolism. Association studies in humans and mice have identified new genomic loci associated with iron metabolism; however, causal genes in these loci are not known. To achieve increased resolution of the associated loci, we are collecting iron-related phenotype data from 110 different mouse strains that make up the Hybrid Mouse Diversity Panel (HMDP). We will associate genetic variants with iron phenotypes to identify novel genetic loci and identify causal genes involved in iron metabolism. Here we report preliminary phenotype data from a subset of strains from the HMDP panel. Methods: Male mice from six inbred mouse strains (A/J, AKR/J, BALB/cJ, C57BL/6J, C3H/HeJ, DBA/2J) were fed low (5 ppm), high (20000ppm), and sufficient (50ppm) iron diets for six weeks starting at 4 weeks of age. We assessed the levels of iron, calcium, copper, magnesium, manganese, and zinc in the heart, kidney, liver, pancreas, and spleen from each mouse using inductively coupled plasma atomic emission spectroscopy. The metal content was expressed as micrograms per gram dry weight of tissue. Means values for all metal-tissue-diet combinations for each mouse strain were compared by one-way ANOVA. Where a significant departure from homogeneity of variance was present we report Welch’s F. Results: In all six strains, most tissue iron levels, especially in the liver, increased with increasing dietary iron content, as expected. On the high iron diet, significant variation in tissue iron levels was observed between at least two mouse strains for all tissues examined. On the low and iron sufficient diets, variation between strains reached significance in the heart, liver, and spleen. The differences in the degree of change in iron levels between different tissues from mice on the different iron diets show how tissues respond differently to changes in dietary iron. The variation in other elemental profiles indicates multiple metal homeostasis differences between the strains. Conclusions: This study highlights the population diversity in the ability to handle iron stress (deficiency or overload), emphasizes the role of iron regulation in metallostasis, and indicates that genetic variation in this population plays an important role in maintaining metal homeostasis. The significant phenotype variation between these strains shows promise for the genetic mapping of these traits.
