CYP1A2*1F and GSTM1 Alleles Are Associated with Susceptibility to Porphyria Cutanea Tarda

Jeffrey K Wickliffe,Chul Lee,Robert J Desnick,James J Grady,Karl E Anderson,Gagan Sood,Sherif Z Abdel-Rahman,Csilla Kormos-Hallberg,Catherine M Rondelli

doi:10.2119/molmed.2010.00130

Abstract

Porphyria cutanea tarda (PCT) is a cutaneous porphyria with sporadic (type 1) and familial (type 2) subtypes, both resulting from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. Environmental and genetic factors are involved in the development of PCT, and genetic variants in the cytochrome P450 (CYP ) genes, CYP1A1 and CYP1A2, have been implicated. We investigated the association between PCT and variants in CYP1A1, CYP1A2 and CYP2E1, and the glutathione-S-transferase (GST ) genes, GSTM1 and GSTT1. PCT diagnosis was based on urinary or plasma porphyrin profiles. Patients were classified as type 1 or 2 PCT based on UROD mutation analysis. The CYP1A2*1F promoter A allele frequency was significantly higher (P < 0.022) and the A/A genotype frequency marginally higher in PCT patients overall (P < 0.057), with the A/A genotype significantly more common in type 1 PCT (P < 0.043). The presence of the wild-type GSTM1 allele also was associated significantly with PCT (P < 0.019). Neither hemochromatosis (HFE) mutations, tobacco smoking, hepatitis C and HIV infection, ethanol consumption, nor estrogen use were associated with these allelic variants. Age at onset was significantly lower in type 2 PCT patients (P < 0.001), as observed previously. Thus, positive associations between PCT and the CYP1A2*1F promoter A allele and A/A genotype and the wild-type GSTM1 allele indicates that these functional hepatic biotransformation enzymes are risk factors for the development of this disease.

Highlights

Porphyria cutanea tarda (PCT) is the most prevalent of the human porphyrias and results from the reduced activity (~20% of normal) of uroporphyrinogen decarboxylase (UROD) in the liver [1]
None of the cytochrome P450 (CYP) or GST variants we examined correlated with previously established susceptibility factors, namely HFE mutations, hepatitis C or HIV infection, estrogen or alcohol use or smoking, sample sizes became too small in these analyses to definitely exclude such associations
PCT is caused by the interaction of genetic and environmental factors which leads to the deficient activity of hepatic UROD, accumulation of highly carboxylated porphyrins and blistering cutaneous photosensitivity [1,2,7]

Summary

Introduction

Porphyria cutanea tarda (PCT) is the most prevalent of the human porphyrias and results from the reduced activity (~20% of normal) of uroporphyrinogen decarboxylase (UROD) in the liver [1]. Heterozygosity for a UROD mutation is not sufficient to cause PCT manifestations, but is a predisposing factor In both types 1 and 2 PCT, excess iron and multiple susceptibility factors contribute to the development of hepatic UROD deficiency. Outbreaks of PCT have occurred following exposure to halogenated polycyclic hydrocarbons such as hexachlorobenzene and tetrachlorodibenzo-p-dioxin [4,5,6]. These and related chemicals can cause hepatic UROD deficiency and uroporphyria in rodents, but it is not clear whether such exposures play a role in isolated cases of human PCT [7]

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Conclusion