When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR).

CONTEXT: A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations. OBJECTIVE: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR. SUBJECTS: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes. RESULTS: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes. CONCLUSIONS: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.

Therapeutic drug monitoring and metabolites profil analysis of antiviral drugs

The widespread use of combination antiretroviral therapy (ARVs) has considerably improved the prognosis of patients infected with HIV. Conversely, considerable advances have been recently realized for the therapy of hepatitis C infection with the recent advent of potent new anti-HCV drugs that allow an increasing rate HCV infection cure. Despite their overall efficacy, a significant number of patients do not achieve or maintain adequate clinical response, defined as an undetectable viral load for HIV, and a sustained virological response (or cure) in HCV infection. Treatment failure therefore still remains an important issue besides drugs toxicities and viral resistance which is not uncommon in a significant percentage of patients who do not reach adequate virological suppression. The reasons of variability in drug response are multifactorial and apart from viral genetics, other factors such as environmental factors, drug- drug interactions, and imperfect compliance may have profound impact on antiviral drugs' clinical response. The possibility of measuring plasma concentration of antiviral drugs enables to guide antiviral drug therapy and ensure optimal drug exposure. The overall objective of this research was to widen up the current knowledge on pharmacokinetic and pharmacogenetic factors that influence the clinical response and toxicity of current and newly approved antiretroviral and anti-HCV drugs. To that endeavour, analytical methods using liquid chromatography coupled with tandem mass spectrometry have been developed and validated for the precise and accurate measurement of new antiretroviral and anti-HCV drugs . These assays have been applied for the TDM of ARVs and anti-HCV in patients infected with either HIV or HCV respectively, and co-infected with HIV- HCV. A pharmacokinetic population model was developed to characterize inter and intra-patient variability of rilpivirine, the latest marketed Non Nucleoside Reverse transcriptase (NNRTI) Inhibitor of HIVand to identify genetic and non genetic covariates influencing rilpivirine exposure. None of the factors investigated so far showed however any influence of RPV clearance. Importantly, we have found that the standard daily dosage regimen (25 mg QD) proposed for rilpivirine results in concentrations below the proposed therapeutic target in about 40% of patients. In these conditions, virologie escape is a potential risk that remains to be further investigated, notably via the TDM approach that can be a useful tool to identify patients who are at risk for being exposed to less than optimal levels of rilpivirine in plasma. Besides the last generation NNRTI rilpivirine, we have studied efavirenz, the major NNRTI clinically used so far. Namely for efavirenz, we aimed at identifying a potential new marker of toxicity that may be incriminated for the neuropsychological sides effects and hence discontinuation of efavirenz therapy. To that endeavour, a comprehensive analysis of phase I and phase II metabolites profiles has been performed in plasma, CSF and in urine from patients under efavirenz therapy. We have found that phase II metabolites of EFV constitute the major species circulating in blood, sometimes exceeding the levels of the parent drug efavirenz. Moreover we have identified a new metabolite of efavirenz in humans, namely the 8-OH-EFV- sulfate which is present at high concentrations in all body compartments from patients under efavirenz therapy. These investigations may open the way to possible alternate phenotypic markers of efavirenz toxicity. Finally, the specific influence of P-glycoprotein on the cellular disposition of a series ARVs (NNRTIs and Pis] has been studies in in vitro cell systems using the siRNA silencing approach. -- Depuis l'introduction de la thérapie antirétrovirale (ARVs) la morbidité et la mortalité liées au VIH ont considérablement diminué. En parallèle le traitement contre le virus de l'hépatite C (VHC) a connu récemment d'énormes progrès avec l'arrivée de nouveaux médicaments puissants, ce qui a permis une augmentation considérable de la guérison de l'infection par le VHC. En dépit de l'efficacité de ces traitements antiviraux, les échecs thérapeutiques ainsi que les effets secondaires des traitements restent un problème important. Une réponse imparfaite ou la toxicité du traitement est certainement multifactorielle. Le suivi thérapeutique des médicaments [Therapeutic Drug Monitoring TDM) à travers la mesure des concentrations plasmatiques constitue une approche importante pour guider le traitement médicamenteux et de s'assurer que les patients sont exposés à des concentrations optimales des médicaments dans le sang, et puissent tirer tout le bénéfice potentiel du traitement. L'objectif global de cette thèse était d'étudier les facteurs pharmacocinétiques et pharmacogénétiques qui influencent l'exposition des médicaments antiviraux (ARVs et anti- VHC) récemment approuvés. A cet effet, des méthodes de quantification des concentrations plasmatiques des médicaments antirétroviraux, anti-VHC ainsi que pour certains métabolites ont été développées et validées en utilisant la Chromatographie liquide couplée à la spectrométrie de masse tandem. Ces méthodes ont été utilisées pour le TDM des ARVs et pour les agents anti-VHC chez les patients infectés par le VIH, et le VHC, respectivement, mais aussi chez les patients co-infectés par le VIH-VHC. Un modèle de pharmacocinétique de population a été développé pour caractériser la variabilité inter-et intra-patient du médicament rilpivirine, un inhibiteur non nucléosidique de la transcriptase de VIH et d'identifier les variables génétiques et non génétiques influençant l'exposition au médicament. Aucun des facteurs étudiés n'a montré d'influence notable sur la clairance de la rilpivirine. Toutefois, la concentration résiduelle extrapolée selon le modèle de pharmacocinétique de population qui a été développé, a montré qu'une grande proportion des patients présente des concentrations minimales inférieures à la cible thérapeutique proposée. Dans ce contexte, la relation entre les concentrations minimales et l'échappement virologique nécessite une surveillance étroite des taux sanguins des patients recevant de la rilpivirine. A cet effet, le suivi thérapeutique est un outil important pour l'identification des patients à risque soient sous-exposés à lai rilpivirine. Pour identifier de nouveaux marqueurs de la toxicité qui pourraient induire l'arrêt du traitement, le profil des métabolites de phase I et de phase II a été étudié dans différentes matrices [plasma, LCR et urine) provenant de patients recevant de l'efavirenz. Les métabolites de phase II, qui n'avaient à ce jour jamais été investigués, constituent les principales espèces présentes dans les matrices étudiées. Au cours de ces investigations, un nouveau métabolite 8- OH-EFV-sulfate a été identifié chez l'homme, et ce dernier est. présent à des concentrations importantes. L'influence de certains facteurs pharmacogénétique des patients sur le profil des métabolites a été étudiée et ouvre la voie à de possibles nouveaux marqueurs phénotypiques alternatifs qui pourraient possiblement mieux prédire la toxicité associée au traitement par l'efavirenz. Finalement, nous nous sommes intéressés à étudier dans un modèle in vitro certains facteurs, comme la P-glycoprotéine, qui influencent la disposition cellulaire de certains médicaments antirétroviraux, en utilisant l'approche par la technologie du siRNA permettant de bloquer sélectivement l'expression du gène de cette protéine d'efflux des médicaments. -- Depuis l'introduction de la thérapie antiretrovirale (ARVs] la morbidité et la mortalité liées au VIH ont considérablement diminué. En parallèle le traitement contre le virus de l'hépatite C (VHC) a connu récemment d'énormes progrès avec l'arrivée de nouveaux médicaments puissants, ce qui a permis une augmentation considérable de la guérison de l'infection par le VHC. En dépit de l'efficacité de ces traitements antiviraux, les échecs thérapeutiques ainsi que les effets secondaires des traitements restent un problème important. Il a pu être démontré que la concentration de médicament présente dans l'organisme est corrélée avec l'efficacité clinique pour la plupart des médicaments agissant contre le VIH et contre le VHC. Les médicaments antiviraux sont généralement donnés à une posologie fixe et standardisée, à tous les patients, il existe cependant une importante variabilité entre les concentrations sanguines mesurées chez les individus. Cette variabilité peut être expliquée par plusieurs facteurs démographiques, environnementaux ou génétiques. Dans ce contexte, le suivi des concentrations sanguines (ou Therapeutic Drug Monitoring, TDM) permet de contrôler que les patients soient exposés à des concentrations suffisantes (pour bloquer la réplication du virus dans l'organisme) et éviter des concentrations excessives, ce qui peut entraîner l'apparition d'intolérence au traitement. Le but de ce travail de thèse est d'améliorer la compréhension des facteurs pharmacologiques et génétiques qui peuvent influencer l'efficacité et/ou la toxicité des médicaments antiviraux, dans le but d'améliorer le suivi des patients. A cet effet, des méthodes de dosage très sensibles et ont été mises au point pour permettre de quantifier les médicaments antiviraux dans le sang et dans d'autres liquides biologiques. Ces méthodes de dosage sont maintenant utilisées d'une part dans le cadre de la prise en charge des patients en routine et d'autre part pour diverses études cliniques chez les patients infectés soit par le HIV, le HCV ou bien coinfectés par les deux virus. Une partie de ce travail a été consacrée à l'investigation des différents facteurs démographiques, génétiques et environnementaux qui pourraient l'influencer la réponse clinique à la rilpivirine, un nouveau médicament contre le VIH. Toutefois, parmi tous les facteurs étudiés à ce jour, aucun n'a permis d'expliquer la variabilité de l'exposition à la rilpivirine chez les patients. On a pu cependant observer qu'à la posologie standard recommandée, un pourcentage relativement élevé de patients pourrait présenter des concentrations inférieures à la concentration sanguine minimale actuellement proposée. Il est donc utile de surveiller étroitement les concentrations de rilpivirine chez les patients pour identifier sans délai ceux qui risquent d'être sous-exposés. Dans l'organisme, le médicament subit diverses transformations (métabolisme) par des enzymes, notamment dans le foie, il est transporté dans les cellules et tissus par des protéines qui modulent sa concentration au site de son action pharmacologique. A cet effet, différents composés (métabolites) produits dans l'organisme après l'administration d'efavirenz, un autre médicament anti-VIH, ont été étudiés. En conclusion, nous nous sommes intéressés à la fois aux facteurs pharmacologiques et génétiques des traitements antiviraux, une approche qui s'inscrit dans l'optique d'une stratégie globale de prise en charge du patient. Dans ce contexte, le suivi des concentrations sanguines de médicaments constitue une des facettes du domaine émergent de la Médecine Personnalisée qui vise à maximiser le bénéfice thérapeutique et le profil de tolérance des médicaments antiviraux

Socio-economic inequalities in reported depression in Spain : a decomposition approach

Recent evidence questions some conventional view on the existence of income-related inequalities in depression suggesting in turn that other determinants might be in place, such as activity status and educational attainment. Evidence of socio-economic inequalities is especially relevant in countries such as Spain that have a limited coverage of mental health care and are regionally heterogeneous. This paper aims at measuring and explaining the degree of socio-economic inequality in reported depression in Spain. We employ linear probability models to estimate the concentration index and its decomposition drawing from 2003 edition of the Spanish National Health Survey, the most recent representative health survey in Spain. Our findings point towards the existence of avoidable inequalities in the prevalence of reported depression. However, besides ¿pure income effects¿ explaining 37% of inequality, economic activity status (28%), education (15%) and demographics (15%) play also a key encompassing role. Although high income implies higher resources to invest and cure (mental) illness, environmental factors influencing in peoples perceived social status act as indirect path as explaining the prevalence of depression. Finally, we find evidence of a gender effect, gender social-economic inequality in income is mainly avoidable.

Generational effects on adult height in individual heterogeneity

As adult height is a well-established retrospective measure of health and standard of living, it is important to understand the factors that determine it. Among them, the influence of socio-environmental factors has been subjected to empirical scrutiny. This paper explores the influence of generational (or environmental) effects and individual and gender-specific heterogeneity on adult height. Our data set is from contemporary Spain, a country governed by an authoritarian regime between 1939 and 1977. First, we use normal position and quantile regression analysis to identify the determinants of self-reported adult height and to measure the influence of individual heterogeneity. Second, we use a Blinder-Oaxaca decomposition approach to explain the `gender height gap¿ and its distribution, so as to measure the influence on this gap of individual heterogeneity. Our findings suggest a significant increase in adult height in the generations that benefited from the country¿s economic liberalization in the 1950s, and especially those brought up after the transition to democracy in the 1970s. In contrast, distributional effects on height suggest that only in recent generations has ¿height increased more among the tallest¿. Although the mean gender height gap is 11 cm, generational effects and other controls such as individual capabilities explain on average roughly 5% of this difference, a figure that rises to 10% in the lowest 10% quantile.

Decomposing Cross-Country Gaps in Obesity and Overweight: Does the Social Environment Matter?

[cat] Una qüestió clau sobre la producció de salut relativament poc explorada es refereix a la influència dels factors socioeconòmics i mediambientals sobre el pes i l’obesitat. Aquesta problemàtica adquireix particular rellevància quan es comparen dos països Mediterranis com Itàlia i Espanya. És interessant adonar-se que l’obesitat a Espanya és 5 punts percentual més elevada al 2003 mentre que a l’any 1990 era aproximadament la mateixa en ambdós països. Aquesta article presenta una descomposició no lineal dels gaps o diferencials en taxes de sobrepès (índex de massa corporal – IMC- entre 25 i 29.9 9 kg/m2), obesitat classe 1 (IMC≥30 kg/m2) i classe 2 (IMC≥35 kg/m2) entre Espanya i Itàlia per gènere i grups d’edat. En explicar aquests gaps entre països aïllem les influències dels estils de vida, els efectes socioeconòmics i els mediambientals. Els nostres resultats indiquen que quan no es controla pels efectes mediambientals (efectes de grup o ‘peer effects’) els hàbits alimentaris i el nivell educatiu són els principals predictors del gaps totals entre països (36-52%), si bé aquests dos factors exerceixen un impacte diferenciat segons gènere i edat. Un tant paradoxalment, quan controlem pels efectes de grup aquests predictors perden la seva capacitat explicativa i els efectes de grup passen a explicar entre el 46-76% dels gaps en sobrepès i obesitat i mostren un patró creixent amb l’edat.

What trees tell us: dendrochronological and statistical analysis of the data

Trees are a great bank of data, named sometimes for this reason as the "silentwitnesses" of the past. Due to annual formation of rings, which is normally influenced directly by of climate parameters (generally changes in temperature and moisture or precipitation) and other environmental factors; these changes, occurred in the past, are"written" in the tree "archives" and can be "decoded" in order to interpret what hadhappened before, mainly applied for the past climate reconstruction.Using dendrochronological methods for obtaining samples of Pinus nigra fromthe Catalonian PrePirineous region, the cores of 15 trees with total time spine of about 100 - 250 years were analyzed for the tree ring width (TRW) patterns and had quite high correlation between them (0.71 ¿ 0.84), corresponding to a common behaviour for the environmental changes in their annual growth.After different trials with raw TRW data for standardization in order to take outthe negative exponential growth curve dependency, the best method of doubledetrending (power transformation and smoothing line of 32 years) were selected for obtaining the indexes for further analysis.Analyzing the cross-correlations between obtained tree ring width indexes andclimate data, significant correlations (p<0.05) were observed in some lags, as forexample, annual precipitation in lag -1 (previous year) had negative correlation with TRW growth in the Pallars region. Significant correlation coefficients are between 0.27- 0.51 (with positive or negative signs) for many cases; as for recent (but very short period) climate data of Seu d¿Urgell meteorological station, some significant correlation coefficients were observed, of the order of 0.9.These results confirm the hypothesis of using dendrochronological data as aclimate signal for further analysis, such as reconstruction of climate in the past orprediction in the future for the same locality.

Altitudinal variation in haemosporidian parasite distribution in great tit populations.

BACKGROUND: One of the major issues concerning disease ecology and conservation is knowledge of the factors that influence the distribution of parasites and consequently disease outbreaks. This study aimed to investigate avian haemosporidian composition and the distribution of these parasites in three altitudinally separated great tit (Parus major) populations in western Switzerland over a three-year period. The objectives were to determine the lineage diversity of parasites occuring across the study populations and to investigate whether altitudinal gradients govern the distribution of haemosporidian parasites by lineage. METHODS: In this study molecular approaches (PCR and sequencing) were used to detect avian blood parasites (Plasmodium sp., Haemoproteus sp. and Leucocytozoon sp.) in populations of adult great tits caught on their nests during three consecutive breeding seasons. RESULTS: High levels of parasite prevalence (88-96%) were found across all of the study populations with no significant altitude effect. Altitude did, however, govern the distribution of parasites belonging to different genera, with Plasmodium parasites being more prevalent at lower altitudes, Leucocytozoon parasites more at high altitude and Haemoproteus parasite prevalence increasing with altitude. A total of 27 haemosporidian parasite lineages were recorded across all study sites, with diversity showing a positive correlation to altitude. Parasites belonging to lineage SGS1 (P. relictum) and PARUS4 and PARUS19 (Leucocytozoon sp.) dominated lower altitudes. SW2 (P. polare) was the second most prevalent lineage of parasite detected overall and these parasites were responsible for 68% of infections at intermediate altitude, but were only documented at this one study site. CONCLUSIONS: Avian haemosporidian parasites are not homogeneously distributed across host populations, but differ by altitude. This difference is most probably brought about by environmental factors influencing vector prevalence and distribution. The high occurrence of co-infection by different genera of parasites might have pronounced effects on host fitness and should consequently be investigated more rigorously.

Genetics of normal and pathological sleep in humans.

The complexity of sleep-wake regulation, in addition to the many environmental influences, includes genetic predisposing factors, which begin to be discovered. Most of the current progress in the study of sleep genetics comes from animal models (dogs, mice, and drosophila). Multiple approaches using both animal models and different genetic techniques are needed to follow the segregation and ultimately to identify 'sleep genes' and molecular bases of sleep disorders. Recent progress in molecular genetics and the development of detailed human genome map have already led to the identification of genetic factors in several complex disorders. Only a few genes are known for which a mutation causes a sleep disorder. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental factors, gene-gene, and gene-environment interactions. We review here the current progress in the genetics of normal and pathological sleep and suggest a few future perspectives.

Life-course socioeconomic environment and health risk behaviours: a multilevel small-area analysis of young-old persons in an urban neighbourhood in Lausanne, Switzerland

With a life expectancy at the age of 65 of around 20 years, damaging health risk behaviours of young-old adults have become a target for preventive actions. Such risk factors necessitate an accurate understanding of the present and past socioeconomic conditions associated with health risk behaviours. The aim of our study is to assess the impact of certain life events as well as economic and environmental factors on health risk behaviours. We included 1309 participants of the Lausanne Cohort Lc65+ aged 65-70 years and employed logistic regression analyses, with individuals nested within areas. The results illustrate the influences of socioeconomic factors from childhood to young-old age. Life experiences in adulthood and economic resources in young-old age are both associated with unfavourable health behaviours. Neighbourhood is a modest determinant as well, particularly regarding alcohol consumption. Therefore, prevention against health risk behaviours should focus on population subgroups defined on the basis of their socioeconomic and living contexts.

Effects of common origin and common rearing environment on variance in ectoparasite load and phenotype of nestling Alpine swifts

Knowledge of the quantitative genetics of resistance to parasitism is key to appraise host evolutionary responses to parasite selection. Here, we studied effects of common origin (i.e. genetic and pre-hatching parental effects) and common rearing environment (i.e. post-hatching parental effects and other environment effects) on variance in ectoparasite load in nestling Alpine swifts (Apus melba). This colonial bird is intensely parasitized by blood sucking louse-flies that impair nestling development and survival. By cross-fostering half of the hatchlings between pairs of nests, we show strong significant effect of common rearing environment on variance (90.7% in 2002 and 90.9% in 2003) in the number of louse-flies per nestling and no significant effect of common origin on variance in the number of louse-flies per nestling. In contrast, significant effects of common origin were found for all the nestling morphological traits (i.e. body mass, wing length, tail length, fork length and sternum length) under investigation. Hence, our study suggests that genetic and pre-hatching parental effects play little role in the distribution of parasites among nestling Alpine swifts, and thus that nestlings have only limited scope for evolutionary responses against parasites. Our results highlight the need to take into consideration environmental factors, including the evolution of post-hatching parental effects such as nest sanitation, in our understanding of host-parasite relationships.

Pathogenèse de la dermatite atopique [Pathogenesis of atopic dermatitis]

Although atopic dermatitis (AD) is a very frequent disease in our society, it is still poorly understood. AD mainly results from a complex interaction between a cutaneous barrier dysfunction, a dysregulation of the immune system and environmental factors. Recent studies have highlighted new mutations in genes coding for skin proteins inducing AD. Furthermore, a new cytokine named TSLP was discovered. TSLP plays a major role in allergic inflammation and represents a big step further in the understanding of AD pathogenesis. However, there are still a lot of unknown factors in this disease, which are actually thouroughly investigated in numerous studies.

Human epidermal stem cell function is regulated by circadian oscillations.

Human skin copes with harmful environmental factors that are circadian in nature, yet how circadian rhythms modulate the function of human epidermal stem cells is mostly unknown. Here we show that in human epidermal stem cells and their differentiated counterparts, core clock genes peak in a successive and phased manner, establishing distinct temporal intervals during the 24 hr day period. Each of these successive clock waves is associated with a peak in the expression of subsets of transcripts that temporally segregate the predisposition of epidermal stem cells to respond to cues that regulate their proliferation or differentiation, such as TGFβ and calcium. Accordingly, circadian arrhythmia profoundly affects stem cell function in culture and in vivo. We hypothesize that this intricate mechanism ensures homeostasis by providing epidermal stem cells with environmentally relevant temporal functional cues during the course of the day and that its perturbation may contribute to aging and carcinogenesis.

Contribution of Topography and Incident Solar Radiation to Variation of Soil and Plant Litter at an Area with Heterogeneous Terrain

Natural processes that determine soil and plant litter properties are controlled by multiple factors. However, little attention has been given to distinguishing the effects of environmental factors from the effects of spatial structure of the area on the distribution of soil and litter properties in tropical ecosystems covering heterogeneous topographies. The aim of this study was to assess patterns of soil and litter variation in a tropical area that intercepts different levels of solar radiation throughout the year since its topography has slopes predominantly facing opposing geographic directions. Soil data (pH, C, N, P, H+Al, Ca, Mg, K, Al, Na, sand, and silt) and plant litter data (N, K, Ca, P, and Mg) were gathered together with the geographic coordinates (to model the spatial structure) of 40 sampling units established at two sites composed of slopes predominantly facing northwest and southeast (20 units each). Soil and litter chemical properties varied more among slopes within similar geographic orientations than between the slopes facing opposing directions. Both the incident solar radiation and the spatial structure of the area were relevant in explaining the patterns detected in variation of soil and plant litter. Individual contributions of incident solar radiation to explain the variation in the properties evaluated suggested that this and other environmental factors may play a particularly relevant role in determining soil and plant litter distribution in tropical areas with heterogeneous topography. Furthermore, this study corroborates that the spatial structure of the area also plays an important role in the distribution of soil and litter within this type of landscape, which appears to be consistent with the action of water movement mechanisms in such areas.

Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.

Idiopathic hypogonadotropic hypogonadism (IHH) is defined by absent or incomplete puberty and characterised biochemically by low levels of sex steroids, with low or inappropriately normal gonadotropin hormones. IHH is frequently accompanied by non-reproductive abnormalities, most commonly anosmia, which is present in 50-60% of cases and defines Kallmann syndrome. The understanding of IHH has undergone rapid evolution, both in respect of genetics and breadth of phenotype. Once considered in monogenic Mendelian terms, it is now more coherently understood as a complex genetic condition. Oligogenic and complex genetic-environmental interactions have now been identified, with physiological and environmental factors interacting in genetically susceptible individuals to alter the clinical course and phenotype. These potentially link IHH to ancient evolutionary pressures on the ancestral human genome.

Therapeutic drug monitoring in cancer - Are we missing a trick?

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.