Exome-wide rare variant analysis in familial essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. METHODS: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. RESULTS: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. CONCLUSIONS: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

The potential of LINGO-1 as a therapeutic target for essential tremor.

INTRODUCTION: LINGO-1 is a negative regulator of neuronal survival, oligodendrocyte differentiation and axonal outgrowth and regeneration, because it interacts with diverse growth factor receptors blocking or inhibiting their action. Consistent findings obtained in vitro and in animal models suggest that anti-LINGO-1 therapy may be useful in neurodegenerative disorders such as multiple sclerosis (MS), Parkinson's disease or essential tremor (ET). Moreover, genetic and pathological evidence provide a robust link between LINGO-1 and ET. AREAS COVERED: In this review, we present an overview of current knowledge on findings linking LINGO-1 and ET, with a special focus on genetic linkage, we include an overview of LINGO1 gene variations according to the 1000 genomes catalog, and we identify potential gene areas where common changes occur because, as well as the risk developing ET, LINGO1 genetic changes may influence the response to anti-LINGO-1 therapy. EXPERT OPINION: The goal of anti-LINGO-1 therapy in neurodegenerative diseases is to ease the brakes of neuronal growth and recovery. An anti-LINGO-1 antibody is under clinical trials for MS patients. Before planning trials with ET patients, refinement on the genetic link between LINGO1 and ET, and a detailed genetic and phenotypic assessment of ET patients to be enrolled, should be carried out.

Variability in histamine receptor genes HRH1, HRH2 and HRH4 in patients with hypersensitivity to NSAIDs.

AIM: Histamine plays an important role in the pathogenesis of allergic diseases. Genetic variations in histamine receptors (HRH) may influence the expression of allergic diseases. This study analyzes the association between HRH variants and NSAID hypersensitivity reactions. PATIENTS & METHODS: The authors analyzed copy number variations (CNVs) and common functional SNPs in genes HRH1, HRH2 and HRH4 in 442 unrelated patients with hypersensitivity to NSAIDs and in 414 healthy unrelated controls. RESULTS: The authors identified, both in patients and control subjects, individuals carrying CNVs in HRH genes. The most common genotype corresponded to two copies of each gene, but carriers of one or three copies of HRH1 (5% of individuals), HRH2 (1.1%) and HRH4 genes (0.9%) were also identified. CONCLUSION: For the first time, we describe CNVs in human HRH genes. Neither common functional SNPs in HRH genes nor CNVs influenced the risk of developing hypersensitivity to NSAIDs.

Assessment of nonsteroidal anti-inflammatory drug-induced hepatotoxicity.

INTRODUCTION: Liver toxicity related to NSAIDs is of outstanding importance because of the wide use of these drugs. NSAIDs are responsible for roughly 10% of the total of cases of drug-induced hepatotoxicity. The assessment of NSAID-induced hepatotoxicity, presently based on clinical and analytical biomarkers, is critical for early diagnosis and immediate withdrawal of the causing drug. AREAS COVERED: The review presents an overview of current knowledge of the assessments of NSAID-induced hepatotoxicity with emphasis on the causative drugs, the NSAID-specific mechanisms involved, and a summary of genetic and non-genetic risk factors. Additionally, the authors discuss genetic factors which show NSAID-specific risk, namely CYP2C, UGT2B7, GSTM1 and GSTT1, as well as HLA alleles. The paper includes a list of the NSAID 'usual suspects' that cause hepatotoxicity based on the integrated information of drug-induced hepatotoxicity databases. EXPERT OPINION: The ultimate goal of this research is pre-prescription testing. Unfortunately, genetic testing, alone, is not sufficient to predict NSAID-induced hepatotoxicity. The development of genetic biomarkers capable of identifying at-risk individuals will not be complete until we develop the ability to fully characterize patients' phenomes and the phenome-genome interaction in patients with NSAID-induced hepatotoxicity. Additionally, a characterization of the metabolic profile of the causative drug in patients with NSAID-induced hepatotoxicity would add crucial information which is presently disregarded in most studies. The full development of robust biomarkers will require the combination of several disciplines including causal statistics, phenomics, genomics, transcriptomics and metabonomics.

Polimorfismos genéticos y su influencia en la efectividad del tratamiento quimioterapéutico de pacientes leucémicos / Genetic polymorphisms and its influence in chemotherapeutic treatment of leukemic patients

En Chile la incidencia de leucemia es de 4.2/100.000 adultos al año. Dentro de ellas, 2,8/100.000 son leucemias agudas y 1,4/100.000 son leucemias crónicas. La quimioterapia para el cáncer ha progresado desde su introducción a la práctica clínica y constituye una modalidad terapéutica muy útil en las leucemias. Sin embargo, su uso se ve limitado por la imposibilidad de predecir la respuesta individual, por lo que la elección de la terapia suele ser en base a criterios médicos y de las guías clínicas establecidas. Esta variación inter-individual en la respuesta a un fármaco antineoplásico puede deberse a factores farmacocinéticos y/o farmacodinámicos, relacionados con otros factores genético-metabólicos, que se traducen en variantes polimórficas de las enzimas encargadas de la biotransformación de estos fármacos o receptores. Al respecto, se estima que la genética da cuenta entre un 20 a un 95 por ciento de la variabilidad en la respuesta terapéutica y toxicológica. De todas las drogas conocidas involucradas en reacciones adversas un 80 por ciento son metabolizadas por estas enzimas. Este artículo pretende dar una visión general acerca de la respuesta potencial de los pacientes sometidos a los protocolos quimioterapéuticos establecidos en Chile para las leucemias de acuerdo a sus perfiles genéticos en las enzimas de biotransformación involucradas.

In Chile, the incidence of leukemia is 4.2/100.000 adults a year. Among them, 2.8/100.000 is acute leukemia and 1.4/100.000 chronic leukemia. The chemotherapy for cancer has been improved through the years in clinical practice and it constitutes a very useful therapeutic option in leukemia. However, its use is limited due to uncertain response; therefore, the pharmacotherapy choice is mainly empiric. In this sense the inter-individual differences in response to antineoplastic drugs could be due to pharmacokinetic factors (affecting absorption, distribution, metabolism and excretion) or pharmacodinamics (affecting receptors or another pharmacological target). It is estimated that genetics accounts for 20 to 95 percent of variability in therapeutics and toxicological response to drugs, which are mainly metabolized through polymorphic biotransformation enzymes (80 percent). Therefore, the present review gives a comprehensive study of the probable response of patients to established leukemia chemotherapy treatment in Chile according their genetic profiles on involved metabolizing enzymes.

Genetic variability of histamine receptors in patients with Parkinson's disease.

BACKGROUND: Changes in the density and expression of histamine receptors (HRH) have been detected in Parkinson's disease (PD) patients, and HRH antagonists bring about improvements in motor and other symptoms, thus suggesting that HRH play a role in the clinical response of PD patients. This study is aimed to analyse polymorphic variations of HRH in patients with PD. METHODS: Leukocytary DNA from 195 PD patients and a control group of 231 unrelated healthy individuals was studied for the nonsynonymous HRH1Leu449Ser and the promoter HRH2G-1018A polymorphisms by using amplification-restriction analyses. RESULTS: The HRH1Leu449Ser amino acid substitution was identified in two women with late-onset PD whereas it was not observed among healthy subjects. The HRH2G-1018A polymorphism was observed with allele frequencies = 3.59 (95% CI = 1.74-5.44) and 5.0 (95% CI = 3.00-6.96) for patients with PD and healthy controls, respectively. These frequencies were independent of gender and age of onset of the disease. Multiple comparison analyses revealed that differences were not statistically significant. CONCLUSION: These results indicate that the polymorphisms analyzed are not a major risk factor for PD, although the HRH1Leu449Ser amino acid substitution might be related to PD.

Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans.

INTRODUCTION: Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. This study aimed to elucidate the influence of several GST polymorphisms on colorectal and gastric cancer risk. PATIENTS AND METHODS: GST mu1 (GSTM1), theta1 (GSTT1), pi1 (GSTP1), alpha1 (GSTA1) and mu3 (GSTM3) genotypes were determined in 144 colorectal cancer patients, 98 gastric cancer patients and 329 healthy control individuals. RESULTS: Colorectal cancer: the risk is greater for carriers of the GSTM1 null genotype (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.25-2.91), for carriers of the GSTT1 null genotype (OR = 3.62, 95% CI = 2.34-5.62), and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 4.98, 95% CI = 2.77-9.00). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.31, 95% CI = 0.09-0.88). Among carriers of the GSTP1 Ile/Ile genotype, smoking increases the risk compared with nonsmoking (OR = 2.35, 95% CI = 1.11-4.99). Gastric cancer: the risk is greater for carriers of the GSTT1 null genotype (OR = 2.58, 95% CI = 1.53-4.36) and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 3.32, 95% CI = 1.62-6.77). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.20, 95% CI = 0.02-0.86). DISCUSSION: The GSTT1 null genotype, particularly if it is associated with the GSTM1 null genotype, greatly increases the risk for colorectal and gastric cancers. The GSTP1 104 Val/Val genotype may protect from both malignant tumors. CONCLUSION: This study indicates that GST polymorphisms, in particular the GSTM1/GSTT1 double-null haplotype, can be considered low-penetrance genes for gastrointestinal cancer.

Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8.

INTRODUCTION: We have previously shown that human colorectal cancer tissue is able to inactivate the anticancer drug paclitaxel through cytochrome P450 (CYP)2C8 and CYP3A4 metabolisms. The aim of this study was to evaluate whether changes in the expression levels of genes coding for such enzymes are related to anticancer drug resistance after long-term exposure to the drug. METHODS: Human colorectal cancer cells (Caco-2) that are sensitive to paclitaxel were exposed to increasing concentrations of the drug from 0-250 nM during one year, in order to select paclitaxel-resistant cells. Subsequently, we compared the sensitivity to paclitaxel and the extent of expression of the CYP2C8, CYP3A4 and CYP3A5 genes in original and resistant cells. RESULTS: Resistant cancer cells displayed a 246-fold increased lethal dose (LD)50 to paclitaxel (p < 0.004) as compared with original cancer cells. A 4.4-fold (p = 0.005) enhancement of CYP2C8 expression and a 5.6-fold (p = 0.001) increase of multidrug resistance (MDR)1 expression was observed in resistant cells exposed to paclitaxel. When paclitaxel was removed from the culture medium, CYP2C8, but not MDR1 expression, reverted to basal levels and the resistance to paclitaxel decreased 3.2-fold (p = 0.005). No major changes in the expression levels of CYP3A4 and CYP3A5 were observed. CONCLUSIONS: Caco-2 cells are capable of increasing the expression levels of CYP2C8 as a response to long-term exposure to paclitaxel. This study provides evidence for a mechanism of acquired resistance to anticancer therapy based on the induction of anticancer-metabolizing enzymes.