Role of ABCB1 gene variants in the onset of Acute Intermittent Porphyria.

NANCIBEL ZÓSIMO MANRIQUE BOJÓRQUEZ; ROSSETTI, MARIA VICTORIA; MELITO, VIVIANA; ZUCCOLI JOHANNA; PAGNOTTA PRISCILA; PARERA, VICTORIA; BATLLE, ALCIRA; BUZALEH ANA MARIA

MILAN

Congreso; International Congress on Porphyrins and Porphyrias ICPP; 2019

International Congress on Porphyrins and Porphyrias ICPP

Acute Intermittent Porphyria (AIP) is a result of a partial and primary deficiency in Porphobilinogen deaminase (PBG-D), the third enzyme in the heme biosynthetic pathway. It is inherited with autosomal dominant character and clinical expression occurs after puberty. At the biochemical level, symptomatic individuals have increased levels of 5-aminolevulic acid and porphobilinogen in urine, responsible for acute signs. The AIP is the most common of the Acute Porphyrias and the first in frequency in the Argentine population (1:150000). The AIP can be triggered by the use of therapeutic drugs, so that genetic variants in cell detoxification could have an essential role in the manifestation of symptomatology.The glutathione-S-transferases (GST) are phase II enzymes involved in detoxification of reactive oxygen species, environmental carcinogens, metabolism of steroid hormones and metabolism of chemotherapeutic agents. Genetic polymorphisms that alter the activity of GST may affect the level of hormones and xenobiotics. Some polymorphisms in this gene are of clinical importance, among them: GSTT1 null, GSTM1 null and GSTP1 (rs1695, c.313 A>G). The aim was to analyze these polymorphisms in Control, latent AIP (lAIP) and symptomatic AIP (sAIP) patients by multiplex PCR (GSTM1 and GSTT1) and RFLP-PCR (GSTP1); in turn, compare with the results for PCT previously obtained in the laboratory.The homozygote deletion frequencies for GSTT1 null were: 8.3% (Control), 20.5%(sAIP), 6.1% (lAIP) and 10.5% (PCT). The null genotype frequencies forGSTM1 null were: 41.7% (Control), 51.3% (sAIP), 45.5% (lAIP) and 36.8% (PCT).Regarding the variants in GSTP1, the allelic frequencies for the non-wild type (G) variant were: 0.42 (Control), 0.47 (sAIP), 0.35 (lAIP) and 0.45 (PCT); the genotypic frequencies for said gene were: AA: 29.2%, AG: 58.3% and GG: 12.5% (Control); AA: 33.3%, AG: 38.5% and GG: 28.2% (sAIP); AA: 30%; AG: 70% and GG: 0% (lAIP); and AA: 25%, AG: 60% and GG: 15% (PCT).Risk alleles were calculated for the Control group and both AIP: 0: 45.5%, 1: 45.5%, 2: 9% and 3: 0% (Control); 0: 27%, 1: 46%, 2: 24.3% and 3: 2.7% (sAIP); and 0: 50%, 1: 50%, 2: 0% and 3: 0% (lAIP).In sAIP, the absence in homozygosis of the GSTT1 and GSTM1 genes is more represented and there is a higher prevalence of non-wild type genotype (GG) for the GSTP1 with respect to the remaining groups. A higher frequency of 2 and 3 risk alleles was observed for the sAIP group with respect to lAIP and Control, being the only group in which an individual with 3 risk alleles was detected (corresponds to a patient).These results suggest a possible implication of risk alleles considering GSTM1, GSTT1 and GSTP1 in the manifestation of symptoms in individuals with IAP.