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

Christine E McLaren, Mary J Emond, V Nathan Subramaniam, Pradyumna D Phatak, James C Barton, Paul C Adams, Justin B Goh, Cameron J McDonald, Lawrie W Powell, Lyle C Gurrin, Katrina J Allen, Deborah A Nickerson, Tin Louie, Grant A Ramm, Gregory J Anderson, Gordon D McLaren

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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. (Hepatology 2015).
    Original languageEnglish
    JournalHepatology (Baltimore, Md.)
    Volume62
    Issue number2
    DOIs
    Publication statusPublished - 20 Jan 2015

    Keywords

    • HepG2/C3A
    • hemochromatosis
    • hepatic iron concentration
    • hepcidin
    • iron overload

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