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;62:429–439

We read with interest the report by Hsiao et al. that\ud Taiwanese women not selected for iron phenotypes,\ud who were hetero- or homozygous for the glycerone-\ud phosphate O-acyltransferase (GNPAT) p.D519G\ud (rs11558492) polymorphism, had higher serum iron\ud levels than GNPAT wild-type subjects. Women with\ud GNPAT p.D519G also had higher levels of serum iron\ud and transferrin saturation (TS) after a test dose of oral iron. Response to oral iron was not significantly differ-\ud ent in Taiwanese women with or without TMPRSS6\ud rs855791, a polymorphism associated with reduced\ud activity of the enzyme, matriptase-2, an inhibitor of\ud hepcidin transcription

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