Smoking but not homozygosity for CYP1A2 g‐163A allelic variant leads to earlier disease onset in patients with sporadic porphyria cutanea tarda

Abstract

These authors contributed equally to this work. à These authors share senior authorship.Abstract: Porphyria cutanea tarda (PCT) results from decreased activity of hepatic uroporphyrinogen decarboxylase (UROD). Both sporadic and familial forms are characterised by typical cutaneous lesions triggered by genetic ⁄ environmental factors. Studies in rodents showed that cytochrome P4501A2 (CYP1A2) plays a central role in the synthesis of a competitive inhibitor of hepatic UROD, but there is little evidence in humans. The impact of smoking and CYP1A2 g-163C > A allelic variant upon first appearance of clinical signs was investigated in 102 patients (80 sporadic-PCT) and 150 healthy donors from Spain. We found an increase in the frequency of CYP1A2 g-163A allele in patients with PCT when compared with controls, although the more inducible A ⁄ A genotype had no effect on the onset age. In sporadic-PCT, smoking leads to earlier onset of clinically overt disease in moderate-to-heavy smokers ( ‡10 cigarettes ⁄ day). In conclusion, this study provides evidence that smoking hastens the onset of cutaneous symptoms in sporadic-PCT patients.

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

“…Matched, healthy, communitybased controls were used as the comparison population. The results confirm an association of PCT with the CYP1A2*1F promoter variant, specifically the "A" allele, as previously reported in Danish and Spanish patients, although not in French patients (17)(18)(19). Table 2 compares the CYP1A2*1F genotype and allele frequencies in patients and controls in this and the previous three studies.…”

“…This promoter variant was associated with PCT in two European studies, but not in a third (17)(18)(19). Variants in CYP1A1 have been associated with differences in metabolism of polycyclic aromatic hydrocarbons and steroid hormones (20)(21)(22)(23)(24).…”

“…Patients with well documented PCT and matched, communitybased controls were studied for eight variants in cytochrome P450 genes including: CYP1A1*2A, *2C and *4; CYP1A2*1E/*1K; *1K; *1F; rs2069522; CYP2E1*5 and for GSTM1 and GSTT1 deletion variants (denoted as GSTM1 null and GSTT1 null, respectively), which are known or suspected to have functional effects on their respective enzymatic activities (16,(28)(29)(30)(31)(32)(33). As noted, the CYP1A2*1F and CYP1A1*4 variants have been associated previously with PCT (17,18,25). Associations of these variants with known susceptibility factors, including use of alcohol, tobacco or estrogen, infections with hepatitis C virus or HIV, and UROD and HFE mutations as well as sex and age of onset, were studied.…”

Identification of CYP3A5 and CYP2B6 Polymorphisms in Porphyria Cutanea Tarda Associated to Human Immunodeficiency Virus

“…There are other genetic polymorphisms of Phase I or even of Phase II enzymes, or transporters like the multidrug resistance transporter gene (MDR1) [37], which can contribute to antiretroviral drug toxicities and response or even it is possible that the PCT-HIV association has more than one factor responsible for the onset of PCT symptoms. In a somehow similar study it was reported recently, in humans, the increased frequency of the CYP1A2-g-163A allele in s-PCT smoker patients, leading to the significant earlier onset of the clinical overt disease [38].…”

Frequency of CYP450 enzyme gene polymorphisms in the Greek population: review of the literature, original findings and clinical significance

“…In the Greek population, CYP2C19*2 allele frequency was estimated in a sample of 283 individuals at 13.1%, while CYP2C19*3 allele was absent from the studied population [10]. In this initial study, we estimated that the proportion of genotype-derived phenotypes was 2.1% for PMs, 21 of CYP2C19*17 allele, we re-genotyped the same population and re-assessed the frequency of EMs. Specifically, the novel CYP2C19*17 allele was found at a frequency as high as 19.6%, whereas 31.8% of the population carried at least one CYP2C19*17 allele (*1/*17 and *17/*17 genotypes) [11] (Table 1).…”