Study on the Role of ABCB1 and Glutathione S-transferase Gene Variants in the Association of Porphyria Cutanea Tarda and Human Immunodeficiency Virus Infection
2021
Porphyrias are a group of metabolic disorders due to alterations in heme biosynthesis. Porphyria Cutanea Tarda (PCT) is a hepatic cutaneous Porphyria resulting from an acquired or inherited deficiency of Uroporphyrinogen decarboxylase. Triggering factors are involved in the onset of this disease. In Argentina, PCT is strongly associated to infection with human immunodeficiency virus (HIV); however, whether the onset of this disease is associated with HIV infection and/or the antiretroviral therapy has not been determined. Our investigation was focused to study the involvement of genetic variants in the development of Porphyrias. In this work, the aim was to evaluate the role of ABCB1 and GST genetic variants in the association between PCT and HIV. This article summarized the main reports about the role of drug metabolism in the onset of PCT, in particular those related with cytochrome P-450 gene variants. Moreover, we extensively described our results about the involvement of ABCB1 transporter and Glutathione S-transferases (GSTs) variants in the association PCT-HIV. We centered our investigation on the ABCB1 gene variants: Exon 12 (rs1128503, NM_000927.5: c.1236C>T), exon 21 (rs2032582, NM_000927.5: and c.2677G>T/A) and exon 26 (rs1045642, NM_000927.5: and c.3435C>T), that affect drug efflux. The genotypification of GSTT1 null, GSTM1 null and GSTP1 (rs1695, NM_000852.4: and c.313A>G), gene variants that alter activity, modifying xenobiotics levels was also analyzed. The high frequency of c.3435C>T (PCT and PCT-HIV) and c.1236C>T (PCT) suggested that the onset of PCT was not specifically related to HIV infection or antiretroviral therapy for these variants. c.2677G>T/A frequencies in the PCT-HIV patients were higher compared with the other groups, suggesting that a mechanism involving antiretroviral therapy had a role in this association. PCT-HIV patients also had a high frequency of GSTT1 null and low frequency for GSTM1 null variants; thus, the genetic basis for PCT onset may involve a combination between the absence of GSTT1 and the presence of GSTM1. When the gene variants studied were analyzed in a whole, PCT-HIV patients had more risk alleles than Controls, PCT or HIV groups. In conclusion, genes encoding for proteins involved in the flow and metabolism of xenobiotics may influence the PCT-HIV association, providing novel insights into the molecular basis of the association between PCT and HIV.
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