Systems genetic analysis of multivariate response to iron deficiency in mice

Lina Yin, Erica L. Unger, Leslie C. Jellen, Christopher J. Earley, Richard P. Allen, Ann Tomaszewicz, James C. Fleet, Byron Jones

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The aim of this study was to identify genes that influence iron regulation under varying dietary iron availability. Male and female mice from 20+ BXD recombinant inbred strains were fed iron-poor or iron-adequate diets from weaning until 4 mo of age. At death, the spleen, liver, and blood were harvested for the measurement of hemoglobin, hematocrit, total iron binding capacity, transferrin saturation, and liver, spleen and plasma iron concentration. For each measure and diet, we found large, strainrelated variability. A principal-components analysis (PCA) was performed on the strain means for the seven parameters under each dietary condition for each sex, followed by quantitative trait loci (QTL) analysis on the factors. Compared with the iron-adequate diet, iron deficiency altered the factor structure of the principal components. QTL analysis, combined with PosMed (a candidate gene searching system) published gene expression data and literature citations, identified seven candidate genes, Ptprd, Mdm1, Picalm, lip1, Tcerg1, Skp2, and Frzb based on PCA factor, diet, and sex. Expression of each of these is cis-regulated, significantly correlated with the corresponding PCA factor, and previously reported to regulate iron, directly or indirectly. We propose that polymorphisms in multiple genes underlie individual differences in iron regulation, especially in response to dietary iron challenge. This research shows that iron management is a highly complex trait, influenced by multiple genes. Systems genetics analysis of iron homeostasis holds promise for developing new methods for prevention and treatment of iron deficiency anemia and related diseases.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume302
Issue number11
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

Fingerprint

Multivariate Analysis
Iron
Principal Component Analysis
Dietary Iron
Diet
Genes
Quantitative Trait Loci
Spleen
Sex Factors
Iron-Deficiency Anemias
Liver
Transferrin
Weaning
Hematocrit
Individuality
Statistical Factor Analysis
Hemoglobins
Homeostasis
Gene Expression
Research

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

Systems genetic analysis of multivariate response to iron deficiency in mice. / Yin, Lina; Unger, Erica L.; Jellen, Leslie C.; Earley, Christopher J.; Allen, Richard P.; Tomaszewicz, Ann; Fleet, James C.; Jones, Byron.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 302, No. 11, 01.06.2012.

Research output: Contribution to journalArticle

Yin, Lina ; Unger, Erica L. ; Jellen, Leslie C. ; Earley, Christopher J. ; Allen, Richard P. ; Tomaszewicz, Ann ; Fleet, James C. ; Jones, Byron. / Systems genetic analysis of multivariate response to iron deficiency in mice. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2012 ; Vol. 302, No. 11.
@article{3c910789a97942fda540b346b4119dee,
title = "Systems genetic analysis of multivariate response to iron deficiency in mice",
abstract = "The aim of this study was to identify genes that influence iron regulation under varying dietary iron availability. Male and female mice from 20+ BXD recombinant inbred strains were fed iron-poor or iron-adequate diets from weaning until 4 mo of age. At death, the spleen, liver, and blood were harvested for the measurement of hemoglobin, hematocrit, total iron binding capacity, transferrin saturation, and liver, spleen and plasma iron concentration. For each measure and diet, we found large, strainrelated variability. A principal-components analysis (PCA) was performed on the strain means for the seven parameters under each dietary condition for each sex, followed by quantitative trait loci (QTL) analysis on the factors. Compared with the iron-adequate diet, iron deficiency altered the factor structure of the principal components. QTL analysis, combined with PosMed (a candidate gene searching system) published gene expression data and literature citations, identified seven candidate genes, Ptprd, Mdm1, Picalm, lip1, Tcerg1, Skp2, and Frzb based on PCA factor, diet, and sex. Expression of each of these is cis-regulated, significantly correlated with the corresponding PCA factor, and previously reported to regulate iron, directly or indirectly. We propose that polymorphisms in multiple genes underlie individual differences in iron regulation, especially in response to dietary iron challenge. This research shows that iron management is a highly complex trait, influenced by multiple genes. Systems genetics analysis of iron homeostasis holds promise for developing new methods for prevention and treatment of iron deficiency anemia and related diseases.",
author = "Lina Yin and Unger, {Erica L.} and Jellen, {Leslie C.} and Earley, {Christopher J.} and Allen, {Richard P.} and Ann Tomaszewicz and Fleet, {James C.} and Byron Jones",
year = "2012",
month = "6",
day = "1",
doi = "10.1152/ajpregu.00634.2011",
language = "English (US)",
volume = "302",
journal = "American Journal of Physiology",
issn = "0363-6119",
publisher = "American Physiological Society",
number = "11",

}

TY - JOUR

T1 - Systems genetic analysis of multivariate response to iron deficiency in mice

AU - Yin, Lina

AU - Unger, Erica L.

AU - Jellen, Leslie C.

AU - Earley, Christopher J.

AU - Allen, Richard P.

AU - Tomaszewicz, Ann

AU - Fleet, James C.

AU - Jones, Byron

PY - 2012/6/1

Y1 - 2012/6/1

N2 - The aim of this study was to identify genes that influence iron regulation under varying dietary iron availability. Male and female mice from 20+ BXD recombinant inbred strains were fed iron-poor or iron-adequate diets from weaning until 4 mo of age. At death, the spleen, liver, and blood were harvested for the measurement of hemoglobin, hematocrit, total iron binding capacity, transferrin saturation, and liver, spleen and plasma iron concentration. For each measure and diet, we found large, strainrelated variability. A principal-components analysis (PCA) was performed on the strain means for the seven parameters under each dietary condition for each sex, followed by quantitative trait loci (QTL) analysis on the factors. Compared with the iron-adequate diet, iron deficiency altered the factor structure of the principal components. QTL analysis, combined with PosMed (a candidate gene searching system) published gene expression data and literature citations, identified seven candidate genes, Ptprd, Mdm1, Picalm, lip1, Tcerg1, Skp2, and Frzb based on PCA factor, diet, and sex. Expression of each of these is cis-regulated, significantly correlated with the corresponding PCA factor, and previously reported to regulate iron, directly or indirectly. We propose that polymorphisms in multiple genes underlie individual differences in iron regulation, especially in response to dietary iron challenge. This research shows that iron management is a highly complex trait, influenced by multiple genes. Systems genetics analysis of iron homeostasis holds promise for developing new methods for prevention and treatment of iron deficiency anemia and related diseases.

AB - The aim of this study was to identify genes that influence iron regulation under varying dietary iron availability. Male and female mice from 20+ BXD recombinant inbred strains were fed iron-poor or iron-adequate diets from weaning until 4 mo of age. At death, the spleen, liver, and blood were harvested for the measurement of hemoglobin, hematocrit, total iron binding capacity, transferrin saturation, and liver, spleen and plasma iron concentration. For each measure and diet, we found large, strainrelated variability. A principal-components analysis (PCA) was performed on the strain means for the seven parameters under each dietary condition for each sex, followed by quantitative trait loci (QTL) analysis on the factors. Compared with the iron-adequate diet, iron deficiency altered the factor structure of the principal components. QTL analysis, combined with PosMed (a candidate gene searching system) published gene expression data and literature citations, identified seven candidate genes, Ptprd, Mdm1, Picalm, lip1, Tcerg1, Skp2, and Frzb based on PCA factor, diet, and sex. Expression of each of these is cis-regulated, significantly correlated with the corresponding PCA factor, and previously reported to regulate iron, directly or indirectly. We propose that polymorphisms in multiple genes underlie individual differences in iron regulation, especially in response to dietary iron challenge. This research shows that iron management is a highly complex trait, influenced by multiple genes. Systems genetics analysis of iron homeostasis holds promise for developing new methods for prevention and treatment of iron deficiency anemia and related diseases.

UR - http://www.scopus.com/inward/record.url?scp=84861913783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861913783&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.00634.2011

DO - 10.1152/ajpregu.00634.2011

M3 - Article

VL - 302

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6119

IS - 11

ER -