Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Issue 2 (18th March 2015)

• Record Type: Journal Article
• Authors: McLaren, Christine E.; Emond, Mary J.; Subramaniam, V. Nathan; Phatak, Pradyumna D.; Barton, James C.; Adams, Paul C.; Goh, Justin B.; McDonald, Cameron J.; Powell, Lawrie W.; Gurrin, Lyle C.; Allen, Katrina J.; Nickerson, Deborah A.; Louie, Tin; Ramm, Grant A.; Anderson, Gregory J.; McLaren, Gordon D.
• Is Part Of: Hepatology. Volume 62:Issue 2(2015:Aug.)
• Page Start: 429
• Page End: 439
• Publication Date: 2015-03-18
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27711
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>To identify polymorphisms associated with variability of iron overload severity in <italic>HFE</italic>‐associated hemochromatosis, we performed exome sequencing of DNA from 35 male <italic>HFE</italic> 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 <italic>GNPAT</italic> gene showed the most significant association with severe iron overload (<italic>P</italic> = 3 × 10<sup>−6</sup>; <italic>P</italic> = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty‐two participants with severe iron overload had <italic>glyceronephosphate O‐acyltransferase</italic> (<italic>GNPAT</italic>) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of <italic>GNPAT</italic> deficiency, we performed small interfering RNA–based knockdown of <italic>GNPAT</italic> 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. <italic>Conclusion: GNPAT</italic> p.D519G is associated with a high‐iron phenotype in <italic>HFE</italic> C282Y homozygotes and may participate in hepcidin regulation. (H<sc>epatology</sc> 2015;62:429–439</p> </abstract>