Pharmacogenomics: What is Next?

Pharmacogenomics is moving from a candidate gene strategy to large scale approaches. This is in line with the new paradigm of linking a trait to (a) pathway(s) rather than to single genes. In addition, breakthroughs in genomics offer a non-a priori assessment of implicated genes, expanding the possibilities in pharmacogenomics research. In this review, we discuss the pros and cons of new concepts in study design and on high throughput approaches to be implemented in the near future

Genetic, ethnic, and gender differences in the pharmacokinetics of antiretroviral agents

Variable antiretroviral therapy (ART) drug response likely reflects the combined influence of environment, underlying disease, concurrent drugs, and genetics. Gender exerts modest or negligible effects on ART disposition, and it is expected to have limited clinical implication, although it should be accounted for in large population studies. Ethnic denominations have, with the notable exception of efavirenz, no clear influence on ART disposition. Exploration of genetic factors might offer a better comprehension to the largely unpredictable and unresolved variability in ART concentrations and related toxicity or treatment outcome. Despite the negative perception of genetic research among the general public, this type of investigation is now widely accepted by concerned parties: patients, relatives, and study volunteer

Intereses, motivos y actitudes hacia el deporte en adolescentes : diferencias en función del nivel de práctica

El trabajo que se presenta forma parte de un estudio descriptivo más amplio en el que se analizan los hábitos, motivos, intereses y actitudes hacia el deporte en una muestra de adolescentes, estudiantes de 2º ciclo de E.S.O. Concretamente se analizan diferentes variables en función de la frecuencia e intensidad de la práctica deportiva en jóvenes practicantes. Se estudió una muestra representativa de la población mencionada compuesta por 1999 sujetos. El instrumento utilizado fue un cuestionario de elaboración propia y los resultados muestran que el nivel de práctica deportiva (bajo, medio, alto) establece diferencias en relación a motivos, actitudes y en definitiva patrones de actividad deportiva.The present analysis is part of a broader descriptive study that assess habits, motives, interests and attitudes toward sport practice in a sample of adolescents that study 2nd ESO. We analyse different variables in relation to frequency and levels of practice in young sport participants. We studied a representative sample of the population analysed (N=1999 subjects). We designed an instrument that includes the different variables. Results show that the level of sport practice (low, medium, high) implies significant differences in relation to motives attitudes and patterns of physical activity

Motius per a l’inici, manteniment i abandonament de la pràctica esportiva dels preadolescents de l’illa de Mallorca

Aquest article s’emmarca en una investigació més àmplia portada a terme amb nens i nenes d’entre 10 i 14 anys de l’illa de Mallorca sobre els hàbits de pràctica esportiva. De manera més precisa, en aquest treball s’analitzen quins són els motius d’inici, manteniment i/o abandonament de la pràctica esportiva entre el grup de població esmentat. Per dur-lo a terme es va fer una enquesta a 2.661 nens i nenes de Mallorca. La mostra es va obtenir a partir d’un mostratge polietàpic. L’instrument utilitzat és un qüestionari d’elaboració pròpia. Els resultats mostren que els amics són el principal motiu d’iniciació a la pràctica esportiva, amb un 33,6 % del total, i que els qui s’inicien i es mantenen en la pràctica esportiva ho fan principalment per diversió i lleure, amb un 37 %. Els estudis, amb un 33,6 % i l’avorriment, amb un 23,3 %, són els principals motius d’abandonament. Les diferències més significatives, pel que fa a gènere, recauen en el fet que les dones atorguen més importància al fet d’estar en forma que no pas els homes, els quals opten per la competició i els amics com a motius de pràctica. El gènere marca algunes diferències en relació amb l’hàbit de practicar esports en la preadolescència

Motivos para el inicio, mantenimiento y abandono de la práctica deportiva de los preadolescentes de la isla de Mallorca

El presente artículo se enmarca en una investigación más amplia llevada a cabo con niños y niñas de entre 10 y 14 años de la isla de Mallorca sobre los hábitos de práctica deportiva. De manera más precisa, en este trabajo se analizan cuáles son los motivos de inicio, mantenimiento y/o abandono de la práctica deportiva entre el grupo de población antes mencionado. Para ello se encuestaron a 2.661 niños y niñas de Mallorca. La muestra se obtuvo a partir de un muestreo polietápico. El instrumento utilizado es un cuestionario de elaboración propia. Los resultados muestran que los amigos son el principal motivo de iniciación a la práctica deportiva, con un 33,6 % del total, y que quienes se inician y mantienen en la práctica deportiva lo hacen principalmente por diversión y ocio, con un 37 %. Los estudios, con un 33,6 % y el aburrimiento, con un 23,3%, son los principales motivos de abandono. Las diferencias más significativas en cuanto a género recaen en que las mujeres otorgan más importancia al hecho de estar en forma que los hombres, quienes optan por la competición y los amigos como motivos de práctica. El género marca algunas diferencias en relación al hábito de practicar deportes en la preadolescencia

Gilbert Syndrome and the Development of Antiretroviral Therapy-Associated Hyperbilirubinemia

BackgroundUnconjugated hyperbilirubinemia results from Gilbert syndrome and from antiretroviral therapy (ART) containing protease inhibitors. An understanding of the interaction between genetic predisposition and ART may help to identify individuals at highest risk for developing jaundice MethodsWe quantified the contribution of UGT1A1*28 and ART to hyperbilirubinemia by longitudinally modeling 1386 total bilirubin levels in 96 human immunodeficiency virus (HIV)-infected individuals during a median of 6 years ResultsThe estimated average bilirubin level was 8.8 μmol/L (0.51 mg/dL). Atazanavir increased bilirubin levels by 15 μmol/L (0.87 mg/dL), and indinavir increased bilirubin levels by 8 μmol/L (0.46 mg/dL). Ritonavir, lopinavir, saquinavir, and nelfinavir had no or minimal effect on bilirubin levels. Homozygous UGT1A1*28 increased bilirubin levels by 5.2 μmol/L (0.3 mg/dL). As a consequence, 67% of individuals homozygous for UGT1A1*28 and receiving atazanavir or indinavir had ⩾2 episodes of hyperbilirubinemia in the jaundice range (>43 μmol/L [>2.5 mg/dL]), versus 7% of those with the common allele and not receiving either of those protease inhibitors (P<.001). Efavirenz resulted in decreased bilirubin levels, which is consistent with the induction of UDP-glucuronosyltransferase 1A1 ConclusionsGenotyping for UGT1A1*28 before initiation of ART would identify HIV-infected individuals at risk for hyperbilirubinemia and decrease episodes of jaundic

The HCP5 Single-Nucleotide Polymorphism: A Simple Screening Tool for Prediction of Hypersensitivity Reaction to Abacavir

The HLA-B*5701 allele is predictive of hypersensitivity reaction to abacavir, a response herein termed "ABC-HSR.” This study of 1103 individuals infected with human immunodeficiency virus assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), rs2395029, in relation to ABC-HSR. In populations with European ancestry, rs2395029 is in linkage disequilibrium with HLA-B*5701. The HCP5SNP was present in all 98 HLA-B*5701—positive individuals and was absent in 999 of 1005 HLA-B*5701—negative individuals. rs2395029 was overrepresented in 25 individuals with clinically likely ABC-HSR, compared with its frequency in 175 ABC-tolerant individuals (80% vs. 2%, respectively; P < .0001). Therefore, HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not availabl

Modeling the Influence of APOC3, APOE and TNF Polymorphisms on the Risk of Antiretroviral Therapy-Associated Lipid Disorders

BackgroundSingle-nucleotide polymorphisms in genes involved in lipoprotein and adipocyte metabolism may explain why dyslipidemia and lipoatrophy occur in some but not all antiretroviral therapy (ART)-treated individuals MethodsWe evaluated the contribution of APOC3 −482C→T, −455T→C, and 3238C→G; ɛ2 and ɛ4 alleles of APOE; and TNF −238G→A to dyslipidemia and lipoatrophy by longitudinally modeling >2600 lipid determinations and 2328 lipoatrophy assessments in 329 ART-treated patients during a median follow-up period of 3.4 years ResultsIn human immunodeficiency virus (HIV)-infected individuals, the effects of variant alleles of APOE on plasma cholesterol and triglyceride levels and of APOC3 on plasma triglyceride levels were comparable to those reported in the general population. However, when treated with ritonavir, individuals with unfavorable genotypes of APOC3 or APOE were at risk of extreme hypertriglyceridemia. They had median plasma triglyceride levels of 7.33 mmol/L, compared with 3.08 mmol/L in the absence of ART. The net effect of the APOE*APOC3*ritonavir interaction was an increase in plasma triglyceride levels of 2.23 mmol/L. No association between TNF −238G→A and lipoatrophy was observed ConclusionsVariant alleles of APOE and APOC3 contribute to an unfavorable lipid profile in patients with HIV. Interactions between genotypes and ART can lead to severe hyperlipidemia. Genetic analysis may identify patients at high risk for severe ritonavir-associated hypertriglyceridemi

Impact of Single Nucleotide Polymorphisms and of Clinical Risk Factors on New-Onset Diabetes Mellitus in HIV-Infected Individuals

Background.Metabolic complications, including cardiovascular events and diabetes mellitus (DM), are a major long-term concern in human immunodeficienc virus (HIV)-infected individuals. Recent genome-wide association studies have reliably associated multiple single nucleotide polymorphisms (SNPs) to DM in the general population. Methods.We evaluated the contribution of 22 SNPs identifie in genome-wide association studies and of longitudinally measured clinical factors to DM. We genotyped all 94 white participants in the Swiss HIV Cohort Study who developed DM from 1 January 1999 through 31 August 2009 and 550 participants without DM. Analyses were based on 6054 person-years of follow-up and 13,922 measurements of plasma glucose. Results.The contribution to DM risk explained by SNPs (14% of DM variability) was larger than the contribution to DM risk explained by current or cumulative exposure to different antiretroviral therapy combinations (3% of DM variability). Participants with the most unfavorable genetic score (representing 12% and 19% of the study population, respectively, when applying 2 different genetic scores) had incidence rate ratios for DM of 3.80 (95% confidenc interval [CI], 2.05-7.06) and 2.74 (95% CI, 1.53-4.88), respectively, compared with participants with a favorable genetic score. However, addition of genetic data to clinical risk factors that included body mass index only slightly improved DM prediction. Conclusions.In white HIV-infected persons treated with antiretroviral therapy, the DM effect of genetic variants was larger than the potential toxic effects of antiretroviral therapy. SNPs contributed significantl to DM risk, but their addition to a clinical model improved DM prediction only slightly, similar to studies in the general populatio