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


CONCLUSIONS
GNPAT D519G is a risk factor for fPCT, but not for sPCT.
Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Colin P
CP
Farrell
Population Health Science and Policy, Mt. Sinai School of Medicine, New York City, New York, United States of America.
Jessica R
JR
Overbey
Genetics and Genomics Sciences, Mt. Sinai School of Medicine, New York City, New York, United States of America.
Hetanshi
H
Naik
Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Danielle
D
Nance
Veterans Affairs, Long Beach Healthcare System, Long Beach, California, United States of America.|Medicine, Division of Hematology/Oncology, University of California Irvine, Irvine, California, United States of America.
Gordon D
GD
McLaren
Epidemiology, University of California Irvine, Irvine, California, United States of America.
Christine E
CE
McLaren
Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Luming
L
Zhou
Genetics and Genomics Sciences, Mt. Sinai School of Medicine, New York City, New York, United States of America.
Robert J
RJ
Desnick
Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Charles J
CJ
Parker
Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
John D
http://orcid.org/0000-0003-1567-1678
JD
Phillips
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