Pharmacogenetic biomarkers of response in Crohn’s disease

Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment. Several studies have considered the possibility that these differences in response are caused by the genetic variability of patients. Many genes have been investigated as potential predictors of response to biological drugs, such as ADAM17, ATG16L1, EMSY, CASP9, CCNY, CNTN5, FASLG, FCGR, NOD2, PTGER4, IL13, IL1B, IL27, IL11, IL17F, TNF and TNFR genes. In this review, we will gather the information on influence of gene polymorphisms investigated to date on response to biological drugs in CD patients

ABCB1 gene polymorphisms and response to chemotherapy in breast cancer patients: a meta-analysis

The ABCB1 gene encodes the P-glycoprotein, an efflux pump for some antineoplastic agents which acts as a resistance mechanism to chemotherapy. Three SNPs (C3435T, C1236T and G2677T/A), are the most widely studied in ABCB1. The inconsistent conclusions about the association of these polymorphisms and the response to chemotherapy in breast cancer (BC) patients prompted us to conduct a meta-analysis. A total of nine (770 patients), five (566 patients) and three studies (367 patients) relating the ABCB1 C3435T, C1236T and G2677T/A polymorphisms respectively, were included. The main analysis revealed a lack of association between ABCB1 polymorphisms and response to chemotherapy in every genetic model: C3435T (dominant OR: 0.888; 95%CI: 0.558-1.413), C1236T (dominant OR: 1.968; 95%CI: 0.609-6.362) and G2677T/A (GG vs GT + GA + TT + TA + AA OR: 0.854; 95%CI: 0.418-1.744). Stratification by ethnicity, cancer type and response criteria did not change the pattern of results. The available evidence indicates that three polymorphisms within ABCB1; C3435T, C1236T and G2677T/A, cannot be considered a reliable predictor of response to chemotherapy in BC patients

Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer

Surgery is the standard treatment for early-stage NSCLC, and platinum-based chemotherapy remains as the treatment of choice for advanced-stage NSCLC patients with naïve EGFR status. However, overall 5-years relative survival rates are low. Interleukins (ILs) are crucial for processes associated with tumor development. In NSCLC, IL1B, IL6, IL12A, IL13 and IL16 gene polymorphisms may contribute to individual variation in terms of patient survival. The purpose of this study was to evaluate the association between IL gene polymorphisms and survival in NSCLC patients. A prospective cohorts study was performed, including 170 NSCLC patients (114 Stage IIIB-IV, 56 Stage I-IIIA). IL1B (C > T; rs1143634), IL1B (C > T; rs12621220), IL1B (C > G; rs1143623), IL1B (A > G; rs16944), IL1B (C > T; rs1143627), IL6 (C > G; rs1800795), IL12A (C > T; rs662959), IL13 (A > C; rs1881457) and IL16 (G > T; rs7170924) gene polymorphisms were analyzed by PCR Real-Time. Patients with IL16 rs7170924-GG genotype were in higher risk of death (p = 0.0139; HR = 1.82; CI95% = 1.13-2.94) Furthermore, carriers of the TT genotype for IL12A rs662959 presented higher risk of progression in the non-resected NSCLC patient subgroup (p = 0.0412; HR = 4.49; CI95% = 1.06-18.99). The rest of polymorphisms showed no effect of on outcomes. Our results suggest that IL16 rs7170924-GG and IL12A rs662959-TT genotypes predict higher risk of death and progression, respectively, in NSCLC patients. No influence of IL1B rs12621220, IL1B rs1143623, IL1B rs16944, IL1B rs1143627, IL6 rs1800795, IL13 rs1881457 on NSCLC clinical outcomes was found in our patients

IMPACT OF DNA REPAIR, FOLATE AND GLUTATHIONE GENE POLYMORPHISMS ON RISK OF NON-SMALL CELL LUNG CANCER

Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC. No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC

Diabetes-Related Neurological Implications and Pharmacogenomics

15 páginasDiabetes mellitus (DM) is the most commonly occurring cause of neuropathy around the world and is beginning to grow in countries where there is a risk of obesity. DM Type II, (T2DM) is a common age-related disease and is a major health concern, particularly in developed countries in Europe where the population is aging. T2DM is a chronic disease which is characterised by hyperglycemia, hyperinsulinemia and insulin resistance, together with the body’s inability to use glucose as energy. Such metabolic disorder produces a chronic inflammatory state, as well as changes in lipid metabolism leading to hypertriglyceridemia, thereby producing chronic deterioration of the organs and premature morbidity and mortality. The pathology’s effects increase cerebral damage, leading to the rapid onset of neurodegenerative diseases. Hyperglycemia causes oxidative stress in tissues which are susceptible to the complications involved in diabetes, including peripheral nerves. Other additional mechanisms include activation of polyol aldose reductase signalling accompanied by protein kinase C (PKC)-ß activation, poly(ADP ribose) polymerase activation, cyclooxygenase (COX) 2 activation, endothelial dysfunction, altered Na+/K+ ATPase pump function, dyslipidaemia and perturbation of calcium balance. All the forgoing has an impact on neuron activity, mitochondrial function, membrane permeability and endothelial function. These biochemical processes directly affect the neurons and endothelial tissue, thereby accelerating cerebral aging by means of peroxidation of the polyunsaturated fatty acids and thus injuring cell membrane integrity and inducing apoptosis in the glial cells. The Central Nervous System (CNS) includes two types de glial cells: microglia and macroglia (astrocytes, oligodendrocytes and radial cells which include Bergmann cells and Müller cells). Glial cells constitute more than 90% of the CNS cell population. Human studies have shown that some oral antidiabetic drugs can improve cognition in patients suffering mild cognitive impairment (MCI) and dementia [1, 2]. While it is still unclear whether diabetes management will reduce MCI and Alzheimer’s disease (AD), incidence, emerging evidence suggests that diabetes therapies may improve cognitive function. This review focuses three aspects: the clinical manifestation of diabetes regarding glial and neuronal cells, the association between neurodegeneration and diabetes and summarises some of the pharmacogenomic data obtained from studies of T2DM treatment, focusing on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly-prescribed oral anti-diabetic drugs (OADs).La diabetes mellitus (DM) es la causa más común de neuropatía en todo el mundo y está comenzando a crecer en países donde existe riesgo de obesidad. La DM tipo II (DM2) es una enfermedad común relacionada con la edad y es un problema de salud importante, particularmente en los países desarrollados de Europa, donde la población está envejeciendo. La DM2 es una enfermedad crónica que se caracteriza por hiperglucemia, hiperinsulinemia y resistencia a la insulina, junto con la incapacidad del organismo para utilizar la glucosa como energía. Tal trastorno metabólico produce un estado inflamatorio crónico, así como cambios en el metabolismo de los lípidos que conducen a la hipertrigliceridemia, produciendo así un deterioro crónico de los órganos y morbilidad y mortalidad prematuras. Los efectos de la patología aumentan el daño cerebral, lo que conduce a la rápida aparición de enfermedades neurodegenerativas. La hiperglucemia provoca estrés oxidativo en los tejidos que son susceptibles a las complicaciones implicadas en la diabetes, incluidos los nervios periféricos. Otros mecanismos adicionales incluyen la activación de la señalización de poliol aldosa reductasa acompañada de activación de proteína quinasa C (PKC) -ß, activación de poli (ADP ribosa) polimerasa, activación de ciclooxigenasa (COX) 2, disfunción endotelial, función alterada de la bomba de Na + / K + ATPasa, dislipidemia y perturbación del equilibrio del calcio. Todo lo anterior tiene un impacto en la actividad neuronal, la función mitocondrial, la permeabilidad de la membrana y la función endotelial. Estos procesos bioquímicos afectan directamente a las neuronas y al tejido endotelial, acelerando así el envejecimiento cerebral mediante la peroxidación de los ácidos grasos poliinsaturados y lesionando así la integridad de la membrana celular e induciendo la apoptosis en las células gliales. El Sistema Nervioso Central (SNC) incluye dos tipos de células gliales: microglia y macroglia (astrocitos, oligodendrocitos y células radiales que incluyen células de Bergmann y células de Müller). Las células gliales constituyen más del 90% de la población de células del SNC. Los estudios en humanos han demostrado que algunos fármacos antidiabéticos orales pueden mejorar la cognición en pacientes que sufren deterioro cognitivo leve (DCL) y demencia [1, 2]. Si bien aún no está claro si el manejo de la diabetes reducirá la incidencia de DCL y la enfermedad de Alzheimer (EA), la evidencia emergente sugiere que las terapias para la diabetes pueden mejorar la función cognitiva. Esta revisión se centra en tres aspectos: la manifestación clínica de la diabetes con respecto a las células gliales y neuronales, la asociación entre la neurodegeneración y la diabetes y resume algunos de los datos farmacogenómicos obtenidos de los estudios de tratamiento de la DM2