Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload

Mclaren, C.E., Emond, M.J., Subramaniam, V.N., Phatak, P.D., Barton, J.C., Adams, P.C., Goh, J.B., Mcdonald, C.J., Powell, L.W., Gurrin, L.C., Allen, K.J., Nickerson, D.A., Louie, T., Ramm, G.A., Anderson, G.J., & Mclaren, G.D. (2015) Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatology, 62(2), pp. 429-439.

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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 x10-6; 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. (Hepatology 2015;62:429-439

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ID Code: 99751
Item Type: Journal Article
Refereed: Yes
Keywords: acyltransferase; ferritin; glyceronephosphate o acyltransferase; hepcidin; messenger RNA; small interfering RNA; unclassified drug; acyltransferase; ferritin; glycerone-phosphate O-acyltransferase; HFE protein, human; HLA antigen class 1; membrane protein; small interfering RNA, adult; alcohol consumption; Article; Australia; Canada; clinical article; controlled study; disease severity; DNA sequence; exome; ferritin blood level; gene; gene expression; genetic association; genetic code; genetic variability; hemochromatosis; hetero, Acyltransferases; Alleles; Analysis of Variance; Blotting, Western; Case-Control Studies; Exome; Ferritins; Genetic Variation; Hemochromatosis; Hep G2 Cells; Histocompatibility Antigens Class I; Homozygote; Humans; Iron Overload; Liver Cirrhosis; Male; Membrane Proteins; Phenotype; Point Mutation; Real-Time Polym, Small Interfering; Sequence Analysis, Protein; Severity of Illness Index
DOI: 10.1002/hep.27711
ISSN: 1527-3350
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright © 2015 by the American Association for the Study of Liver Diseases
Deposited On: 12 Oct 2016 02:53
Last Modified: 14 Oct 2016 03:48

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