The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda

RESEARCH ARTICLE The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda Colin P. Farrell 1 , Jessica R. Overbey 2 , Hetanshi Naik 3 , Danielle Nance 1 , Gordon D. McLaren 4,5 , Christine E. McLaren 6 , Luming Zhou 7 , Robert J. Desnick 3 , Charles J. Parker 1 , John D. Phillips 1 * a11111 OPEN ACCESS Citation: Farrell CP, Overbey JR, Naik H, Nance D, McLaren GD, McLaren CE, et al. (2016) The D519G Polymorphism of Glyceronephosphate O- Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda. PLoS ONE 11(9): e0163322. doi:10.1371/journal.pone.0163322 Editor: Fanis Missirlis, CINVESTAV-IPN, MEXICO Received: March 22, 2016 Accepted: September 7, 2016 Published: September 23, 2016 Copyright: © 2016 Farrell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: These data have been deposited in the dbSNP database (http://www.ncbi. nlm.nih.gov/SNP/) and are publicly available upon the next dbSNP Build (B149). Once the dbSNP Build occurs, the authors will post the accession number for these data as a comment on the published article. In the meantime, SNP typing data for this study can also be obtained by contacting the corresponding author, John Phillips, at John.phillips@hsc.utah.edu. 1 Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 2 Population Health Science and Policy, Mt. Sinai School of Medicine, New York City, New York, United States of America, 3 Genetics and Genomics Sciences, Mt. Sinai School of Medicine, New York City, New York, United States of America, 4 Veterans Affairs, Long Beach Healthcare System, Long Beach, California, United States of America, 5 Medicine, Division of Hematology/Oncology, University of California Irvine, Irvine, California, United States of America, 6 Epidemiology, University of California Irvine, Irvine, California, United States of America, 7 Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America * john.phillips@hsc.utah.edu Abstract Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homo- zygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damag- ing URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT. Conclusion: GNPAT D519G is a risk factor for fPCT, but not for sPCT. Funding: This work was supported by NIH grants DK020503 and DK090257 to JDP and DK093433 to GDM. The Porphyrias Consortium PLOS ONE | DOI:10.1371/journal.pone.0163322 September 23, 2016