Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants.

The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d-MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two-compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d-MPH plasma exposure.

Distribution of HLA-G extended haplotypes and one HLA-E polymorphism in a large-scale study of mother-child dyads with and without severe preeclampsia and eclampsia.

The etiological pathways and pathogenesis of preeclampsia have rendered difficult to disentangle. Accumulating evidence points toward a maladapted maternal immune system, which may involve aberrant placental expression of immunomodulatory human leukocyte antigen (HLA) class Ib molecules during pregnancy. Several studies have shown aberrant or reduced expression of HLA-G in the placenta and in maternal blood in cases of preeclampsia compared with controls. Unlike classical HLA class Ia loci, the nonclassical HLA-G has limited polymorphic variants. Most nucleotide variations are clustered in the 5'-upstream regulatory region (5'URR) and 3'-untranslated regulatory region (3'UTR) of HLA-G and reflect a stringent expressional control. Based on genotyping and full gene sequencing of HLA-G in a large number of cases and controls (n > 900), the present study, which to our knowledge is the largest and most comprehensive performed, investigated the association between the HLA-G 14-bp ins/del (rs66554220) and HLA-E polymorphisms in mother and newborn dyads from pregnancies complicated by severe preeclampsia/eclampsia and from uncomplicated pregnancies. Furthermore, results from extended HLA-G haplotyping in the newborns are presented in order to assess whether a combined contribution of nucleotide variations spanning the 5'URR, coding region, and 3'UTR of HLA-G describes the genetic association with severe preeclampsia more closely. In contrast to earlier findings, the HLA-G 14-bp ins/del polymorphism was not associated with severe preeclampsia. Furthermore, the polymorphism (rs1264457) defining the two nonsynonymous HLA-E alleles, HLA-E*01:01:xx:xx and HLA-E*01:03:xx:xx, were not associated with severe preeclampsia. Finally, no specific HLA-G haplotypes were significantly associated with increased risk of developing severe preeclampsia/eclampsia.

Potential role of the porcine superoxide dismutase 1 (SOD1) gene in pig reproduction.

In a recent study we confirmed that QTL regions on pig chromosomes 11, 13, and 15 are associated with reproduction traits in the pig. Within these regions the genetic variation was largest on chromosome 13. The QTL region on this chromosome was therefore studied further to identify genes known to contribute to litter size. The superoxide dismutase (SOD1) gene localized at around 200 Mb in the pig (Sscrofa10) was the most obvious candidate gene. In the present study, we have cloned and sequenced the porcine SOD1 gene. The SOD1 amino acid sequence is highly conserved between human, mouse, rat, and pig. Expression studies by quantitative PCR showed differential levels of the SOD1 transcript in all tissues investigated. Sequence comparison between sows with high and low estimated breeding value (EBV) for litter size, revealed a total of eight single nucleotide polymorphisms (SNPs) in the noncoding sequence and no SNPs in the coding region. One of the intronic SNPs was genotyped in 248 sows with high and low EBV for litter size. Allele frequency differed significantly between the two group of sows indicating that polymorphism in the chromosome 13 locus has an impact on litter size. The sows homozygous for the A/A genotype conceive three piglets more compared to the A/T genotype, making this SNP a possible marker for litter size. However, this genotype was negatively correlated with other important traits under selection in the Danish pig production.

Investigation of candidate regions influencing litter size in Danish Landrace sows.

Selection for increased litter size has been one of the main objectives in Danish pig breeding since 1992. This selection has led to an average increase of 0.30 piglets/litter per year for Landrace and Yorkshire sows, resulting in an average litter size of 15.3 piglets born alive in 2007, with an SD of 3.5 piglets. The objective of this study was to investigate differences in identity by state relationships and allele effects associated with litter size across 17 selected microsatellite marker positions on chromosomes 11, 13, and 15. For this purpose, 357 Danish Landrace sows with high and low EBV for litter size were genotyped. An assignment test showed that 91 and 90% of the sows could be assigned correctly to the group of sows representing high and low EBV, respectively, based on genotype information. Allele effects were estimated separately for each marker by using deregressed EBV and a linear model that include both a polygenic and an allele effect. The investigated region on chromosome 13 was found to have a greater average identity by state relationship compared with the other regions, indicating that selection has taken place in this region. This is supported by an increased average allele effect of microsatellite alleles in the region. In spite of the apparent increased historical selection pressure on chromosome 13, fairly large variation in allele effects was observed, indicating that the markers within the region may be used for marker-assisted selection. However, substantial variation in allele effects was observed for several markers on all 3 investigated chromosomes, indicating that selection should preferably be based on several markers.

A study of the occurrence of monochorionic and monozygotic twinning in the pig.

In humans as well as in most farm animals, monozygotic twins have been described. Nevertheless, only a few reports of twinning in the pig have been published. It has been suggested that monozygotic twins are formed during the first 14 days of pregnancy. This monozygotic twin study includes the investigation of porcine monochorionic embryos from 76 sows at days 26-29 post-insemination (p.i.), as well as an examination of 10 whole litters at days 21-22 p.i. In the former group, 29% of the sows carried monochorionic embryos. Based on DNA profiling using microsatellite markers, one monozygotic twin pair was found among these embryos. In the latter group, three monozygotic twin pairs were identified. Thus, it can be concluded that although the occurrence of monozygotic twins in pigs is a sporadic event, the fusion of extra-embryonic membranes is relatively common.