Reply

Our work was supported, in part, by grant 1R24DK093433‐01 from the National Institute of Diabetes and Digestive and Kidney Diseases, grant P30 CA‐62203 from the National Cancer Institute, and funds from the Department of Veterans Affairs. This work was also supported, in part, by a Project Grant (APP1031325) from the National Health and Medical Research Council (NHMRC) of Australia (to V.N.S.). V.N.S., G.A.R., and G.J.A. are supported by Senior Research Fellowships from the NHMRC of Australia. Potential conflict of interest: Dr. Phatak consults for Novartis and Nektar. Dr. Adams received a grant from Gilead. Author names in bold designate shared co‐first authorship. We read with interest the report by Hsiao et al. that Taiwanese women not selected for iron phenotypes, who were hetero‐ or homozygous for the glyceronephosphate O‐acyltransferase (GNPAT) p.D519G (rs11558492) polymorphism, had higher serum iron levels than GNPAT wild‐type subjects. Women with GNPAT p.D519G also had higher levels of serum iron and transferrin saturation (TS) after a test dose of oral iron. Response to oral iron was not significantly different in Taiwanese women with or without TMPRSS6 rs855791, a polymorphism associated with reduced activity of the enzyme, matriptase‐2, an inhibitor of hepcidin transcription.1 Moreover, the association of GNPAT p.D519G with baseline serum iron levels was independent of TMPRSS6 rs855791, age, and amount of menstrual blood loss. In our exome sequencing study, GNPAT p.D519G was also associated with high‐iron phenotypes in Caucasian men with HFE p.C282Y homozygosity.2 The important results of Hsiao et al. provide further support for a role of GNPAT in the regulation of iron metabolism in a population in which HFE p.C282Y is rare. The allele frequency of GNPAT p.D519G in the Taiwanese cohort was 12%, similar to that in the general population of the 1000 Genomes Project (14%). Thus, GNPAT p.D519G is a relatively common determinant of the higher baseline serum iron levels and response of serum iron/TS measures to oral iron among Taiwanese women. In nonanemic young Caucasian women with hypoferritinemia, test doses of oral iron ≥60 mg increased circulating hepcidin levels and decreased fractional iron absorption on the subsequent day.3 Taken together, these observations suggest that GNPAT p.D519G alters hepcidin regulation and iron absorption in response to oral iron, although this is unproven. At present, there are no published observations of the possible effects of GNPAT p.D519G on hepcidin expression or iron absorption in Caucasian women with or without p.C282Y. In our article,2 we did not propose that GNPAT p.D519G is an “HFE modifier,” but rather that it is a modifier of iron status in HFE p.C282Y homozygotes. Hsiao et al. suggest that GNPAT p.D519G acts independently of HFE on hepcidin regulation, and their results indicated that the effect of the GNPAT p.D519G allele does not involve interaction with matriptase‐2. However, their observations do not exclude a possible interaction of GNPAT p.D519G with wild‐type HFE protein or any other upstream regulator of hepcidin transcription. We observed that small interfering RNA–mediated knockdown of GNPAT in HepG2/C3A cells markedly reduced HAMP messenger RNA expression, but had no demonstrable effect on the BMP/SMAD pathway.3 Thus, taken together, our results and those of Hsiao et al. are consistent with the possibilities that GNPAT p.D519G either affects a gene or genes upstream of HAMP or alters hepcidin expression directly. Elucidating GNPAT's putative role in regulating hepcidin requires further study.

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