PHARMACOGENETICS OF LOSARTAN IN MARFAN SYNDROME PATIENTS

Objective: Marfan syndrome is a genetic disorder affecting connective tissues due to a mutation in the fibrillin 1 gene (95%) than leads to upregulation of the transforming growth factor beta (TGF-β) family. The main cause of mortality in these patients is aortic dissection. Medications to lower blood pressure are used to decrease the aota wall stress. Losartan acts by lowering blood pressure and attenuating TGF-β-induced signaling; it is converted by hepatic cytochrome P450 enzymes to an active metabolite E3174. CYP2C9*2 or *3, CYP3A5*3 and CYP3A4*22 leading to losartan poor metabolism phenotypes. The objective of the present study was to assess the roles of the individual and combined effect of CYP2C9*2 and *3, CYP3A4*22 and CYP3A5*3 in Marfan normotensive patients treated with losartan to prevent cardiovascular complications. Design and method: Genomic DNA were isolated from peripheral blood cells. Genotypes were determined by Real-Time PCR using LightSNiP (TIB-MolBiol). Statistical analysis was conducted by R package “SNPassoc”. Results: The study enrolled 182 patients (93 males). The median age was 31yrs (range 2–71yrs). All patients received losartan (12.5 to 100 mg/day) on the base on the tolerability. CYPs *1 identifies reference allele. CYP2C9*2 allele is present in 42 (23.1%) patients in heterozygosis and in 5 (2.7%) in homozygosis. 26 (14.3%) patients carrying CYP2C9*3 allele in heterozygosis and 2 (1.1%) in homozygosis. CYP3A4 *22 are present in 21 (11.6%) and 2 (1.1%) of cases in heterozygosis and omozygosis, respectively. The heterozygosity and homozygosity status of CYP3A5*3 was observed in 25 (13.8%) and 156 (86.2%) patients, respectively. All variants are in Hardy-Weinberg equilibrium. No difference in tolerated dose of losartan was observed for all functional variants evaluated. Age and body weight were always considered as covariates in the multivariate regression since they resulted to significantly affect the daily dose of losartan. Conclusions: At present, there is insufficient evidence to support the use of genetic polymorphisms as predictors of the right dose of losartan in normotensive marfan patients. Further studies need to definitively exclude the pharmacogenetics prediction of losartan response in patients affected by the Marfan Syndrome.