Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood-Brain Barrier and Assess Target Site Disposition.

The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood-brain barrier (BBB) permeability evaluation tools are needed to explore drugs' ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution. We aimed to qualify a PBPK platform model to be used as a tool to predict CNS concentrations when significant transporter activity is absent and human data are sparse or unavailable. Data from the literature on the plasma and CNS of rats and humans regarding acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam were collected. Human BBB permeability values were extrapolated from rats using inter-species differences in BBB surface area. The percentage of predicted AUC and Cmax within the 1.25-fold criterion was 85% and 100% for rats and humans, respectively, with an overall GMFE of <1.25 in all cases. This work demonstrated the successful application of the PBPK platform for predicting human CNS concentrations of drugs passively crossing the BBB. Future applications include the selection of promising CNS drug candidates and the evaluation of new posologies for existing drugs.

The Mediterranean Sea as a barrier to gene flow: evidence from variation in and around the F7 and F12 genomic regions.

BACKGROUND: The Mediterranean has a long history of interactions among different peoples. In this study, we investigate the genetic relationships among thirteen population samples from the broader Mediterranean region together with three other groups from the Ivory Coast and Bolivia with a particular focus on the genetic structure between North Africa and South Europe. Analyses were carried out on a diverse set of neutral and functional polymorphisms located in and around the coagulation factor VII and XII genomic regions (F7 and F12). RESULTS: Principal component analysis revealed a significant clustering of the Mediterranean samples into North African and South European groups consistent with the results from the hierarchical AMOVA, which showed a low but significant differentiation between groups from the two shores. For the same range of geographic distances, populations from each side of the Mediterranean were found to differ genetically more than populations within the same side. To further investigate this differentiation, we carried out haplotype analyses, which provided partial evidence that sub-Saharan gene flow was higher towards North Africa than South Europe. CONCLUSIONS: As there is no consensus between the two genomic regions regarding gene flow through the Sahara, it is hard to reach a solid conclusion about its role in the differentiation between the two Mediterranean shores and more data are necessary to reach a definite conclusion. However our data suggest that the Mediterranean Sea was at least partially a barrier to gene flow between the two shores.

Population relationships in the Mediterranean revealed by autosomal genetic data (Alu and Alu/STR compound systems).

The variation of 18 Alu polymorphisms and 3 linked STRs was determined in 1,831 individuals from 15 Mediterranean populations to analyze the relationships between human groups in this geographical region and provide a complementary perspective to information from studies based on uniparental markers. Patterns of population diversity revealed by the two kinds of markers examined were different from one another, likely in relation to their different mutation rates. Therefore, while the Alu biallelic variation underlies general heterogeneity throughout the whole Mediterranean region, the combined use of Alu and STR points to a considerable genetic differentiation between the two Mediterranean shores, presumably strengthened by a considerable sub-Saharan African genetic contribution in North Africa (around 13% calculated from Alu markers). Gene flow analysis confirms the permeability of the Sahara to human passage along with the existence of trans-Mediterranean interchanges. Two specific Alu/STR combinations-CD4 110(-) and DM 107(-)-detected in all North African samples, the Iberian Peninsula, Greece, Turkey, and some Mediterranean islands suggest an ancient genetic background of current Mediterranean peoples.

Androgen receptor CAG and GGC polymorphisms in Mediterraneans: repeat dynamics and population relationships.

Microsatellite variation (CAG and GGC repeats) of the androgen receptor (AR) gene shows remarkable differences among African and non-African populations. In vitro studies have demonstrated an inverse relationship between the length of both microsatellites and AR activity. This fact may explain the observed association of the AR gene with prostate cancer and the strong ethnic differences in the incidence of this cancer. CAG and GGC genetic variation has been tested in a large set of populations from the Ivory Coast as well as 12 Mediterranean samples whose variation is described for the first time. The pattern of frequencies observed in the Ivory Coast agrees with data previously reported for other Sub-Saharan populations. Concerning the Mediterranean variation, Sardinian samples are characterised by low genetic diversities, and Egyptian Siwa Berbers by a particular pattern of GGC frequencies. High and Middle Atlas Moroccan Berbers are the most closely related to the Sub-Saharan variation. For both the CAG and GGC repeats, the Ivory Coast and some Moroccan samples exhibit high frequencies of low size alleles (CAG under 18 repeats, and GGC under 15 repeats) that have been associated with prostate cancer.

Alu polymorphisms in Jerba Island population (Tunisia): comparative study in Arab and Berber groups.

Jerba Island represents an interesting area because four distinct ethnic groups have been cohabiting there until now: Arabs, Berbers, dark-skinned people of sub-Saharan origin and Jews. Religious and cultural differences seem to have constituted an obstacle to their intermixing. Our aim is to provide further information on the genetic structure of the Arab and Berber groups for whom previous data based on haploid markers confirmed their reproductive isolation. Five polymorphic Alu markers (HS 4.69, Sb 19.3, TPA-25, ACE and APO-A1) were analysed in a sample of 43 Arabs and 48 Berbers of Jerba. The genetic relationships among these groups and several populations from North Africa, sub-Saharan Africa and Europe were analysed using genetic distances based on allele frequencies. The results showed a homogeneous distribution of Alu insertions in the two geographically close groups, reflecting ancient relationships between them. This study also revealed that Arabs from Jerba present close genetic distances to other North African populations, whilst Berbers of Jerba occupy an intermediate position among Mediterranean populations.

E65 K polymorphism in KCNMB1 gene is not associated with ischaemic heart disease in Spanish patients.

Hypertension is a main risk factor for atherosclerosis through vascular wall hyperplasia. A recent study reported a new polymorphism (E65 K) in the beta(1) subunit (KCNMB1) gene of the Ca(2+)-dependent potassium channel with a protective effect against the severity of diastolic hypertension, but further data have lead to conflicting results. In order to ascertain the involvement of the E65 K variant in cardiovascular system regulation, the potential association between this mutation and ischaemic heart disease was assessed through a family-based association study (n=302 individuals). Transmission disequilibrium analysis failed to detect any association between this polymorphism and ischaemic heart disease. Although a minor effect cannot be discarded, sample analytical power and negative results do not support a major role for E65 K polymorphism in atherogenic pathologies.

Angiotensin I converting enzyme polymorphism effects in patients with normal pressure hydrocephalus syndrome before and after surgery.

Previous reports have suggested an association between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE), cardiovascular disease, and cognitive performance. Normal pressure hydrocephalus (NPH) is considered to be an example of reversible dementia although the clinical improvement after shunting varies from subject to subject. An association has been suggested between vascular risk factors and the development of NPH. The ACE plays a major role in vascular pathology and physiology. In the present study we investigated the distribution of an ACE gene insertion/deletion polymorphism in 112 patients diagnosed with NPH and in 124 controls. We also evaluated the role of this genetic polymorphism in cognitive functioning before and following surgery in a subgroup of 72 patients. No differences in genetic or allele distributions were found between patients and healthy subjects, but among patients, carriers of D/D or D/I genotypes obtained less cognitive benefit following shunt surgery, especially on measures of memory and frontal function. Our data support previous findings in other conditions indicating that possession of at least one D allele is associated with poorer cognitive performance.

Poorer cognitive performance in humans with mild cognitive impairment carrying the T variant of the Glu/Asp NOS3 polymorphism.

Mild cognitive impairment (MCI) is a transitional state between normal aging and Alzheimer's disease (AD) and is a high-risk condition for dementia. The endothelial nitric oxide synthase (NOS3) gene encodes endothelial NOS, an enzyme that regulates the production of the vasodilatory nitric oxide associated with the cerebral small vessel pathology observed in early AD. We studied the distribution of genotype and allele frequencies of the NOS3 Glu/Asp polymorphism in a sample of 62 MCI subjects and 136 controls. Though no association between NOS3 gene variation and MCI status was observed, MCI cases carrying the Asp variant (T+) performed worse in the Mini-Mental State Examination, Wechsler Memory Scale (Revised) long-term visual memory and the phonetic verbal fluency tests. These results suggest that the T allele is a genetic risk factor for cognitive impairment in the elderly.

Patterns of phenotypic covariation and correlation in modern humans as viewed from morphological integration.

Proportionality of phenotypic and genetic distance is of crucial importance to adequately focus on population history and structure, and it depends on the proportionality of genetic and phenotypic covariance. Constancy of phenotypic covariances is unlikely without constancy of genetic covariation if the latter is a substantial component of the former. If phenotypic patterns are found to be relatively stable, the most probable explanation is that genetic covariance matrices are also stable. Factors like morphological integration account for such stability. Morphological integration can be studied by analyzing the relationships among morphological traits. We present here a comparison of phenotypic correlation and covariance structure among worldwide human populations. Correlation and covariance matrices between 47 cranial traits were obtained for 28 populations, and compared with design matrices representing functional and developmental constraints. Among-population differences in patterns of correlation and covariation were tested for association with matrices of genetic distances (obtained after an examination of 10 Alu-insertions) and with Mahalanobis distances (computed after craniometrical traits). All matrix correlations were estimated by means of Mantel tests. Results indicate that correlation and covariance structure in our species is stable, and that among-group correlation/covariance similarity is not related to genetic or phenotypic distance. Conversely, genetic and morphological distance matrices were highly correlated. Correlation and covariation patterns were largely associated with functional and developmental factors, which probably account for the stability of covariance patterns.

Molecular variation in endothelial nitric oxide synthase gene (eNOS) in western Mediterranean populations.

Endothelial nitric oxide synthase (eNOS or NOS3) is the main responsible for nitric oxide (NO) production in vascular system and different polymorphisms have been identified in epidemiological studies. Trying to test the eNOS genetic variation in general populations we studied the 27-bp VNTR in intron 4 and G894T substitution in exon 7 markers in 6 Western Mediterranean populations (3 from Iberian Peninsula, 1 from North Africa, and 2 from Sardinia) and a sample from Ivory Coast. The VNTR frequencies in Western Mediterranean and Ivory Coast fit well into the ranges previously described for Europeans and Sub-Saharans respectively, and a typical African allele has been detected in polymorphic frequencies in the Berber sample. The G894T substitution presents the highest frequencies described for the T allele in the North Mediterranean populations. Linkage disequilibrium is present between both markers in all populations except in the Ivory Coast sample. The variation found for these polymorphisms indicates that they may be a useful tool for population studies even at microgeographical level.

Alu insertions in the Iberian Peninsula and north west Africa--genetic boundaries or melting pot?

The Western Mediterranean Basin joins a set of ethnically different populations as Iberians and Basques in the North shore and Berbers and Arab-speakers in the South one. In spite of this differentiation, they have maintained historical contacts since ancient times. The existence of a possible common genetic background (specially for Berbers and Iberians) together with the genetic impact of the Islamic occupation of the Iberian Peninsula during 7 centuries are some of the intriguing anthropological questions that have been studied in this area using several classical and DNA markers. The aim of this work is to present the results on a survey of polymorphic Alu elements in 10 human populations of the Western Mediterranean. Recent Alu subfamilies include a significant number of polymorphic Alu insertions in humans. The polymorphic Alu elements are neutral genetic markers of identical descent with known ancestral states. This fact turns Alu insertions into useful markers for the study of human population genetics. A total number of 14 Alu insertions were analyzed in 5 Iberian populations, 3 Berber groups from North-Western Africa, an Arab-speaker population from Morocco and a sub-Saharan ethnic group from Ivory Coast. The results of this study allow the genetic characterization of Berber populations, which show a certain degree of differentiation from Arab-speaking groups of the same geographic area. Furthermore, a closer genetic distance between South Spain and Moroccan Berbers as compared with other Spanish samples supports a major genetic influx consistent with some (but not all) previous genetic studies on populations from the two shores of the Gibraltar Straits.

Molecular variation at functional genes and the history of human populations--data on candidate genes for cardiovascular risk in the Mediterranean.

A screening of 22 DNA polymorphisms has been performed in western Mediterranean populations (Iberian Peninsula, Morocco, and Central Mediterranean Islands). The analyzed markers correspond to polymorphic sites in several candidate genes for cardiovascular disease including apolipopoteins and their receptors (APOA1, APOB, APOE, APOC1, APOC2, LPA, and LDLR), genes implied in the hemostasis regulation (Factor VII, alpha and beta-fibrinogen, alpha and beta platelet-integrin, tissue plasminogen activator, and plasminogen activator inhibitor-1), and the angiotensin converting enzyme gene. The results are presented of a partial analysis carried out in following population samples: 6 from the Iberian Peninsula, 2 from Morocco, and 3 from Central Islands. The degree of inter-population diversity was significant and consistent with data from other kind of genetic polymorphisms. The apportionment of the allele frequency variance supported a geographic structure into three main regions: Central Mediterranean Islands, the Iberia Peninsula and North Africa. The genetic distance pattern is compatible with a south-to-north North African influence in the Iberian Peninsula and a remarkable gene flow from sub-Saharan Africa into Morocco. Epidemiologically, North Africa is characterized by high frequencies of LPA PNR alleles with high number of repeats (protective for cardiovascular risk) and high frequencies of the APOE*E4 allele (risk factor) as compared with European populations.