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1.  Pharmacogenetics of tacrolimus: ready for clinical translation? 
Tacrolimus (Tac) exhibits an interindividual pharmacokinetic variability that affects the dose required to reach the target concentration in blood. Tac is metabolized by two enzymes of the cytochrome P450 family, CYP3A5 and CYP3A4. The effect of the CYP3A5 genotype on Tac bioavailability has been demonstrated, and the main determinant of this pharmacogenetic effect is a single-nucleotide polymorphism (SNP) in intron 3 of CYP3A5 (6986 A>G; SNP rs776746; also known as CYP3A5*3). The mean dose-adjusted blood Tac concentration was significantly higher among CYP3A5*3 homozygotes than that of carriers of the wild-type allele (CYP3A5*1). In a recent prospective study, a group of kidney transplant patients received a Tac dose either according to the CYP3A5 genotype (the adapted group) or according to the standard regimen (the control group). All patients received induction therapy with mycophenolate mofetil, corticosteroids, and either basiliximab or intravenous anti-thymocyte globulin. Patients in the adapted-dose group required 3–8 days (median 6 days) to reach the target range compared with 3–25 days (median 7 days) in the control group (P=0.001). The total number of dose modifications was also lower in the adapted-dose group. This study also suggested that the CYP3A5 genotype might contribute minimally to the reduction of early acute rejection. However, additional studies are necessary to determine whether the pharmacogenetic approach could help reduce the necessity for induction therapy and co-immunosuppressors.
PMCID: PMC4089617  PMID: 25028625
cytochromes P450; pharmacogenetics; pharmacokinetics; renal transplantation; tacrolimus
2.  Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia 
BMC Neurology  2010;10:89.
Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases.
We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype).
We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF.
In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.
PMCID: PMC2964648  PMID: 20932283
3.  A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction 
BMC Biology  2004;2:5.
Excessive proliferation of vascular smooth muscle cells and leukocytes within the artery wall is a major event in the development of atherosclerosis. The growth suppressor p27kip1 associates with several cyclin-dependent kinase/cyclin complexes, thereby abrogating their capacity to induce progression through the cell cycle. Recent studies have implicated p27kip1 in the control of neointimal hyperplasia. For instance, p27kip1 ablation in apolipoprotein-E-null mice enhanced arterial cell proliferation and accelerated atherogenesis induced by dietary cholesterol. Therefore, p27kip1 is a candidate gene to modify the risk of developing atherosclerosis and associated ischaemic events (i.e., myocardial infarction and stroke).
In this study we found three common single-nucleotide polymorphisms in the human p27kip1 gene (+326T>G [V109G], -79C>T, and -838C>A). The frequency of -838A carriers was significantly increased in myocardial infarction patients compared to healthy controls (odds ratio [OR] = 1.73, 95% confidence interval [95%CI] = 1.12–2.70). In addition, luciferase reporter constructs driven by the human p27kip1 gene promoter containing A at position -838 had decreased basal transcriptional activity when transiently transfected in Jurkat cells, compared with constructs bearing C in -838 (P = 0.04).
These data suggest that -838A is associated with reduced p27kip1 promoter activity and increased risk of myocardial infarction.
PMCID: PMC400507  PMID: 15061869
myocardial infarction; p27kip1; single-nucleotide polymorphisms

Results 1-3 (3)