Implications of MDR1 polymorphisms in the development of Porphyria Cutanea Tarda in HIV infected individuals

ZUCCOLI JOHANNA; PAGNOTTA PRISCILA; BUZALEH ANA MARÍA; MELITO VIVIANA

Bordeaux

Congreso; INTERNATIONAL CONGRESS ON PORPHYRINS AND PORPHYRIAS 2017 (ICPP); 2017

Porphyria Cutanea Tarda (PCT), the most common Porphyria in Argentina, has a prevalence of 1:25,000. Although the clinical manifestation of PCT is frequently associated with different precipitating agents, mainly hepatotoxic drugs and hepatothropic virus infection, many biological variables could also be involved in its triggering, like genetic polymorphisms of Phase I or Phase II drug metabolism enzymes or transporters like the multidrug resistance gene (MDR1).In our country, a high incidence (17%) of HIV infection in PCT patients is found. However, since almost all the HIV infected patients with PCT had additional risk factors for Porphyria manifestation, it is still unclear if HIV infection is actually a precipitating factor for PCT. Despite this, there have been many reports that mentioned PCT triggering after or during the therapy with antiretroviral drugs, even in the absence of another precipitating agent. The multi-drug resistance (MDR) protein is a transmembrane glycoprotein with a molecular weight of 170 kDa. It is one of the ATP-dependent transporters encoded by MDR1 gene. A number of polymorphisms in the MDR1 gene can alter drug absorption, distribution and elimination. MDR1 actively pumps out of the cell xenobiotics such as antiretroviral drugs, protease and integrase inhibitors. Over 50 single nucleotide polymorphisms (SNPs) with high incidence in Caucasians were found to be of clinical importance. The most relevant among them are: exon 26 (c.3435 C>T), 21 (c.2677G>T/A) and 12 (c.1236 C>T), Previously the frequency of SNP in exon 26, 12 and 21 in control, PCT and PCT-HIV groups were investigated. Conclusions:Identification of polymorphisms of clinical importance and high incidence in Caucasians in exons 26, 12 and 21 of MDR1 gene was carried out in a non Porphyric HIV population.Analyzing allelic paired haplotypes, it was observed that the combination C3435T-G2677T/A was significantly elevated in the HIV-PCT cohort suggesting a probably role as a risk haplotype for the manifestation of PCT in these patients associated with the antirretroviral therapy used. Moreover, the allelic pair C3435T?C1236T was significatily high in PCT group no undergoing antirretroviral therapy, but exposed to another triggering factors.Results showed, with different profiles, the existence of a high prevalence of the polymorphic T allele in exons 26, 12 and 21 in both PCT groups, suggesting a possible relation of PgP expression and/or activity with PCT onset mediated by different triggering factors.Individuals with HIV infection are a susceptible group to develop Porphyria. Considering that antirretroviral drugs are substrates of MDR1 pump, the results here presented for the polymorphic allele in HIV and PCT-HIV could be a possible explanation for the high incidence of PCT in HIV caucasian population in Argentina (1:350) compared with the prevalence of PCT in our country (1:20.000).The early diagnosis of PCT is always relevant in order to begin the treatment and avoid porphyrins accumulation, responsibles of cutaneous injuries taking into account that these lesions are a potential source of virus propagation. So, to investigate MDR1 genotypes is of great importance for future medicine to apply an effective and personalized therapy, specially for risk groups like HIV population.