Identification of Polymorphic Gnpat As a Risk Factor for Porphyria Cutanea Tarda

Symptoms of porphyria cutanea tarda (PCT) resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y) that increases iron absorption by reducing hepcidin expression is a risk factor for PCT. These observations suggest that PCT is an iron dependent disease and that factors that affect iron homeostasis influence the risk of developing the PCT. Recently, a polymorphic variant (D519G) of GNPAT was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype [McLaren CE, et al. Hepatology Aug;62(2):429-39 2015]. Available evidence suggests that like HFE C282Y, GNPAT D519G increases iron absorption by reducing expression of hepcidin. Therefore, we investigated the prevalence GNPAT D519G in patients with PCT. The study population consisted of 247 patients with PCT. High-resolution DNA melting analysis and Taqman SNP assays were used to identify HFE (C282Y) and GNPAT (D519G) allelic variants, respectively and mutations in uroporphyrinogen decarboxylase (UROD) were identified by nucleotide sequencing. Patients with mutant UROD were categorized as familial PCT (F-PCT) (n=87, 36.0%) and those with wild-type UROD were categorized as sporadic PCT (S-PCT) (n=155, 64.0%). GNPAT D519G was significantly enriched in the patient population (prevalence 22.1%, p<0.001) compared to the general population (prevalence 13.6%) as was HFE C282Y (prevalence of 19.2% in the study population compared to 1.5% in the general population, p<0.001). The relative risk of GNPAT D519G was significantly increased in patients with F-PCT compared to those with S-PCT (odds ratio 1.81, CI 1.06-3.08) whereas the relative risk of HFE C282Y in the F-PCT was lower than in the S-PCT population (odds ratio 0.82, CI 0.46-1.47). Together, these observations suggest that GNPAT D519G, is more likely to require a cofactor (e. g., mutant UROD) to produce PCT whereas HFE C282Y functions as an independent PCT risk factor. This difference may be a consequence of the relative potency of GNPAT D519G (weak) and HFE C282Y (strong) with respect to effects on iron homeostasis. Our studies have identified a new risk factor (polymorphic GNPAT) for PCT that adds support for the involvement of aberrant iron metabolism in the pathobiology of PCT.