http://repub.eur.nl/res/aut/2760/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/16954/ 2009-08-01T00:00:00Z OBJECTIVES: The active metabolite of mycophenolate mofetil (MMF), mycophenolic acid, inhibits the activity of the target enzyme inosine monophosphate dehydrogenase (IMPDH). The aim of this study was to correlate eight different single nucleotide polymorphisms of the IMPDH type II gene to the activity of the IMPDH enzyme to explain between-patient differences in IMPDH activity. METHODS AND RESULTS: In a prospective study, we measured IMPDH activity, mycophenolic acid plasma concentrations, and eight polymorphisms of IMPDH type II in de novo kidney transplant recipients, 6 days posttransplantation while on MMF treatment. Polymorphisms in the IMPDH type II gene were only observed for the IMPDH type II 3757T>C (rs11706052) single nucleotide polymorphism. Ten of 101 patients (10%) were heterozygous and two of 101 patients (2%) homozygous for IMPDH type II 3757T>C. The allele frequency was 6.9%. The IMPDH activity over 12h (AUCact) was 49% higher for patients with an IMPDH type II 3757C variant [n=12 vs. n=68; 336 (95% confidence interval: 216-521) vs. 227 (95% confidence interval: 198-260)hμmol/s/mol adenosine monophosphate; P=0.04]. The IMPDH activity measured before transplantation (Actpre-Tx) was not significantly different between IMPDH type II 3757TT wild-type and variant carrier patients (P=0.99). CONCLUSION: We report that the IMPDH type II 3757T>C polymorphism is associated with an increased IMPDH activity in MMF-treated renal transplant patients. This polymorphism explains 8.0% of the interpatient variability in IMPDH activity. http://repub.eur.nl/res/pub/5910/ 2002-10-15T00:00:00Z A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.