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ABSTRACTIntroduction: Several studies suggested a possible association between certain polymorphisms in the N-acetyl-transferase 2(NAT2) gene (which encodes a very important enzyme involved in xenobiotic metabolism) and the risk for Parkinson’s disease (PD). As the results of studies on this issue are controversial, we conducted a systematic review and a meta-analysis of eligible studies on this putative association.Areas covered: The authors revised the relationship between NAT2polymorphisms and the risk of developing PD using several databases, and performed a meta-analysis using the software Meta-Disc1.1.1. In addition heterogeneity between studies was analyzed. A description of studies regarding gene-gene interactions and gene-environmental interactions involving NAT2polymorphisms is also made.Expert opinion: Despite several recent meta-analyses showing an association between several polymorphisms in genes related with detoxification mechanisms such as cytochromeP4502D6 (CYP2D6), and glutathione transferases M1and T1(GSTM1, and GSTT1), data on NAT2gene polymorphisms obtained from the current meta-analysis do not support a major association with PD risk, except in Asian populations. However, data from many studies are incomplete and therefore insufficient data exists to draw definitive conclusions. Several studies suggesting gene-gene and gene-environmental factors involving NAT2gene in PD risk await confirmation.

Several single-nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase(COMT) gene have been associated with the risk of developing Parkinson’s disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on PD risk related with COMTSNPs (mainly rs4680). We also reviewed the possible relationship of COMTSNPs with clinical, neuropharmacological, neurochemical, and neuroimaging features of PD.

A recent genome-wide association study and other replication studies have suggested that the rs3794087 single nucleotide polymorphism in the solute carrier family 1 – glial affinity glutamate transporter-member 2 (SLC1A2) gene is associated with an increased risk for essential tremor (ET), and a replication study in an Asian cohort has shown a decreased risk for ET associated with the rs3794087T allele. We tried to replicate this association in a White Spanish population.

Advances in sequencing technologies, such as next-generation sequencing (NGS), represent an opportunity to perform genetic testing in a clinical scenario. In this study, we developed and tested a method for the detection of mutations in the large BRCA1and BRCA2tumor suppressor genes, using long-range PCR (LR-PCR) and NGS, in samples from individuals with a personal and/or family history of breast and/or ovarian cancer. Eleven LR-PCR fragments, between 3000 and 15,300 bp, containing all coding exons and flanking splice junctions of BRCA1and BRCA2, were obtained from DNA samples of five individuals carrying mutations in either BRCA1or BRCA2. Libraries for NGS were prepared using an enzymatic (Nextera technology) method. We analyzed five individual samples in parallel by NGS and obtained complete coverage of all LR-PCR fragments, with an average coding sequence depth for each nucleotide of 30 reads, running from ×7 (in exon 22 of BRCA1) to ×150. We detected and confirmed 100% of the mutations that predispose to the risk of cancer, together with other genomic variations in BRCA1and BRCA2. Our approach demonstrates that genomic LR-PCR, together with NGS, using the GS Junior 454 System platform, is an effective method for patient sample analysis of BRCA1and BRCA2genes. In addition, this method could be performed in regular molecular genetics laboratories.

Information on CYP2B6allele frequencies and detrimental genotypes in mixed human populations is scarce. The aim of this study was to analyze the frequencies and haplotypes of nonsynonymous CYP2B6single nucleotide polymorphisms (SNPs) in a Colombian population.

Some clinical and experimental data suggest a possible role of -aminobutyrate (GABA)-ergic mechanisms in the pathophysiology of essential tremor (ET). We studied the allelic and genotype frequencies of the single nucleotide polymorphisms, such as GABRA4-L26M(Leu26Met, rs2229940), GABRE-S102A(Ser26Ala, rs1139916), and GABRQ-I478F(Ile26Phe, rs3810651), in 200 patients with familial ET and 250 healthy controls using TaqMan genotyping. GABRA4-L26M, GABRE-S102A, and GABRQ-I478Fgenotype and allelic frequencies did not differ significantly between patients with ET and controls, and were unrelated to the age at onset of tremor or sex. The GABRQ-478Fallele seemed to be related to improvement of tremor with ethanol use among men (odds ratio=2.32, 95 confidence interval=0.26–4.3, P=0.007, Pc=0.021). The results of this study suggest that the single nucleotide polymorphisms studied in the GABRA4, GABRE, and GABRQgenes are not related to the risk for familial ET.

The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of all cytochrome P450– mediated drug biotransformations. In this study we investigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (substrate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetidine, ranitidine, and the novel H2-receptor antagonist ebrotidine in human liver microsomes. The inhibitory effect of the drugs on the enzymes activities were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine >>> ranitidine. The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive. To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazolam in 8 healthy volunteers. Midazolam biodisposition was significantly reduced when administered together with cimetidine (P < .05), whereas no significant inhibition was observed with ebrotidine or ranitidine compared with placebo. Psychomotor performance analysis revealed no significant effect of the observed reduction on midazolam biodisposition. We concluded that patients who are receiving treatment with drugs metabolized through CYP3A may experience enhanced drug effects as a result of pharmacokinetic interaction when treated concomitantly with cimetidine. In contrast, the effect of ranitidine or ebrotidine on CYP3A activity in vivo seems to have little clinical significance.

The polymorphic human cytochrome P450 2A6 (CYP2A6) metabolises a number of drugs, activates a variety of precarcinogens and constitutes the major nicotine C‐oxidase. A relationship between CYP2A6genotype and smoking habits, as well as incidence of lung cancer, has been proposed. Two defective alleles have hitherto been identified, one of which is very common in Asian populations. Among Caucasians, an additional defective and frequently distributed allele (CYP2A6*3) has been suggested to play a protective role against nicotine addiction and cigarette consumption. Here, we have re‐evaluated the genotyping method used for the CYP2A6*3allele and found that a gene conversion in the 3′ flanking region of 30–40% of CYP2A6*1alleles results in genotype misclassification. In fact, no true CYP2A6*3alleles were found among 100 Spaniards and 96 Chinese subjects. In one Spanish poor metaboliser of the CYP2A6 probe drug coumarin, we found two novel defective alleles. One, CYP2A6*5, encoded an unstable enzyme having a G479L substitution and the other was found to carry a novel type of CYP2A6gene deletion (CYP2A6*4D). The results imply the presence of numerous defective as well as active CYP2A6alleles as a consequence of CYP2A6/CYP2A7gene conversion events. We conclude that molecular epidemiological studies concerning CYP2A6 require validated genotyping methods for accurate detection of all known defective CYP2A6alleles.