High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor

Abstract

Background: Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress. Although AIP penetrance is traditionally considered to be around 10–20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations. Genetic susceptibility factors underlying penetrance are still unknown. Drug-metabolizing cytochrome P450 enzymes (CYP) are polymorphic haem-dependent proteins which play a role in haem demand, so they might modulate the occurrence of AIP attacks. Our aim was to determine the prevalence and penetrance of AIP in our population and analyse the main hepatic CYP genes to assess their association with acute attacks. For this, CYP2C9*2, *3; CYP2C19*2; CYP2D6*4, *5; CYP3A4*1B and CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBS founder mutation c.669_698del30. Results: AIP penetrance was 52%, and prevalence was estimated as 17.7 cases/million inhabitants. The frequency of defective CYP2D6 alleles was 3.5 times higher in LAIP than in MAIP. MAIP was less frequent among CYP2D6*4 and *5 carriers (p < 0.05). The urine porphobilinogen (PBG)-to-creatinine ratio was lower in these individuals, although it was associated with a lower prevalence of attacks (p < 0.05) rather than with the CYP2D6 genotype.Conclusions: AIP prevalence in our region is almost 3 times higher than that estimated for the rest of Spain. The penetrance was high, and similar to other founder mutation AIP populations. This is very relevant for genetic counselling and effective health care. CYP2D6*4 and *5 alleles may be protective factors for acute attacks, and CYP2D6 may constitute a penetrance-modifying gene. Further studies are needed to confirm these findings, which would allow a further progress in clinical risk profile assessment based on the CYP genotype, leading to predictive personalized medicine for each AIP carrier in the future. Keywords: Acute intermittent porphyria, Founder mutation, Penetrance, CYP2D6, Susceptibility factor, Acute attacks, Personalized medicine, Genomic medicine

Nuestro objetivo en este trabajo fue determinar la prevalencia y penetrancia de porfiria aguda intermitente (AIP) en nuestra población y analizar los principales genes hepáticos de CYP para evaluar su asociación con ataques agudos de porfiria. Para ello, CYP2C9*2, *3; CYP2C19*2; CYP2D6*4, *5; Se genotiparon los alelos defectuosos CYP3A4*1B y CYP3A5*3 en cincuenta portadores de AIP de la Región de Murcia, una población española con una alta frecuencia de la mutación fundadora de HMBS c.669_698del30. La prevalencia de PAI en nuestra región es casi 3 veces mayor que la estimada para el resto de España. La penetrancia fue alta y similar a la de otras poblaciones de AIP con mutación fundadora. Esto es muy relevante para el asesoramiento genético y la atención sanitaria eficaz. Los alelos CYP2D6*4 y *5 pueden ser factores protectores para los ataques agudos, y CYP2D6 puede constituir un gen modificador de la penetrancia. Se necesitan más estudios para confirmar estos hallazgos, lo que permitiría seguir avanzando en la evaluación del perfil de riesgo clínico basado en el genotipo CYP, lo que conduciría a una medicina predictiva personalizada para cada portador de AIP en el futuro.