Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload.
Pubmed ID: 25605615
Pubmed Central ID: PMC4508230
Journal: Hepatology (Baltimore, Md.)
Publication Date: 08/01/2015
Affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA.
MeSH Terms: Humans, Male, Case-Control Studies, Alleles, Homozygote, Severity of Illness Index, Analysis of Variance, Blotting, Western, Phenotype, Real-Time Polymerase Chain Reaction, RNA, Small Interfering, Genetic Variation, Exome, Ferritins, Hemochromatosis, Acyltransferases, Hep G2 Cells, Histocompatibility Antigens Class I, Iron Overload, Liver Cirrhosis, Membrane Proteins, Point Mutation, Sequence Analysis, Protein, Hemochromatosis Protein
Grants: P30 CA062203, R24 DK093433, R24 DK099846, UL1 TR001414
Authors: McLaren CE, McLaren GD, Emond MJ, Subramaniam VN, Phatak PD, Barton JC, Adams PC, Goh JB, McDonald CJ, Powell LW, Gurrin LC, Allen KJ, Nickerson DA, Louie T, Ramm GA, Anderson GJ
Cite As: McLaren CE, Emond MJ, Subramaniam VN, Phatak PD, Barton JC, Adams PC, Goh JB, McDonald CJ, Powell LW, Gurrin LC, Allen KJ, Nickerson DA, Louie T, Ramm GA, Anderson GJ, McLaren GD. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatology 2015 Aug;62(2):429-39. Epub 2015 Mar 18.
UNLABELLED: To identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22; cases) or with normal or mildly increased iron stores (n = 13; controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single-nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (P = 3 × 10(-6) ; P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty-two participants with severe iron overload had glyceronephosphate O-acyltransferase (GNPAT) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA-based knockdown of GNPAT in the human liver-derived cell line, HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the messenger RNA encoding the iron-regulatory hormone, hepcidin. CONCLUSION: GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation.