• Mclaren, Christine
• Emond, Mary
• Phatak, Pradyumna
• Adams, Paul
• Goh, Justin
• Other, And
• Mcdonald, Cameron
• Powell, Lawrie
• Gurrin, Lyle
• Barton, James

Abstract

To identify polymorphisms associated with variability of iron overload severity in <em>HFE</em>-associated hemochromatosis, we performed exome sequencing of DNA from 35 male <em>HFE</em> 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 <em>GNPAT</em> gene showed the most significant association with severe iron overload (<em>P</em>=3 x10^-6; <em>P</em>=0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty-two participants with severe iron overload had <em>glyceronephosphate O-acyltransferase</em> (<em>GNPAT</em>) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of <em>GNPAT</em> deficiency, we performed small interfering RNA based knockdown of <em>GNPAT</em> 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.<em>Conclusion: GNPAT</em> p.D519G is associated with a high-iron phenotype in <em>HFE</em> C282Y homozygotes and may participate in hepcidin regulation. (H<span class="smallCaps">epatology</span> 2015;62:429-439

Topics

• impedance spectroscopy
• iron
• alcohol