Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels

The genetic determinants of variation in iron status are actively sought, but remain incompletely understood. Meta-analysis of two genome-wide association (GWA) studies and replication in three independent cohorts was performed to identify genetic loci associated in the general population with serum levels of iron and markers of iron status, including transferrin, ferritin, soluble transferrin receptor (sTfR) and sTfR-ferritin index. We identified and replicated a novel association of a common variant in the type-2 transferrin receptor (TFR2) gene with iron levels, with effect sizes highly consistent across samples. In addition, we identified and replicated an association between the HFE locus and ferritin and confirmed previously reported associations with the TF, TMPRSS6 and HFE genes. The five replicated variants were tested for association with expression levels of the corresponding genes in a publicly available data set of human liver samples, and nominally statistically significant expression differences by genotype were observed for all genes, although only rs3811647 in the TF gene survived the Bonferroni correction for multiple testing. In addition, we measured for the first time the effects of the common variant in TMPRSS6, rs4820268, on hepcidin mRNA in peripheral blood (n = 83 individuals) and on hepcidin levels in urine (n = 529) and observed an association in the same direction, though only borderline significant. These functional findings require confirmation in further studies with larger sample sizes, but they suggest that common variants in TMPRSS6 could modify the hepcidin-iron feedback loop in clinically unaffected individuals, thus making them more susceptible to imbalances of iron homeostasis.     

Linkage and association analyses of type 2 diabetes/impaired glucose metabolism and adiponectin serum levels in Japanese Americans from Hawaii

Type 2 diabetes is a common disorder associated with obesity. Lower plasma levels of adiponectin were associated with type 2 diabetes. Candidate regions on chromosomes 1 ( approximately 70 cM) and 14 ( approximately 30 cM) were evaluated for replication of suggestive linkage results for type 2 diabetes/impaired glucose homeostasis in an independent sample of Japanese Americans. Replication of independent linkage evidence for serum levels of adiponectin on chromosome 14 was also evaluated. We investigated 529 subjects from 175 sibships who were originally part of the Honolulu Heart Program. Analyses included nonparametric linkage and association using SAGE (Statistical Analysis for Genetic Epidemiology) and FBAT (family-based test of association) programs and Monte Carlo simulation of Fisher's exact test in SAS. For type 2 diabetes/impaired glucose metabolism, nominal linkage evidence (P < 0.02) followed-up by genotypic association (P = 0.016) was found with marker D14S297 at 31.8 cM; linkage analyses using only diabetes phenotype were also nominally significant at this marker (P < 0.02). Nominal evidence for genotypic association to adiponectin serum level phenotype (P = 0.04) was found with the marker D14S1032 at 23.2 cM. The present study was limited by relatively small sample size. Nevertheless, these results corroborate earlier studies, suggesting that further research is warranted in the candidate region approximately 30 cM on chromosome 14.     

Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats

Chondroitin sulfate proteoglycans (CSPGs) are upregulated in the central nervous system following injury. Chondroitin sulfate glycosaminoglycan (CS GAG) side chains substituted on this family of molecules contribute to the limited functional recovery following injury by restricting axonal growth and synaptic plasticity. In the current study, the effects of degrading CS GAGs with Chondroitinase ABC (Ch'ase ABC) in the injured spinal cords of adult cats were assessed. Three groups were evaluated for 5 months following T10 hemisections: lesion-only, lesion+control, and lesion+Ch'ase ABC. Intraspinal control and Ch'ase ABC treatments to the lesion site began immediately after injury and continued every other day, for a total of 15 treatments, using an injectable port system. Delivery and in vivo cleavage were verified anatomically in a subset of cats across the treatment period. Recovery of skilled locomotion (ladder, peg, and beam) was significantly accelerated, on average, by >3 weeks in Ch'ase ABC-treated cats compared to controls. Ch'ase ABC-treated cats also showed greater recovery of specific skilled locomotor features including intralimb movement patterns and significantly greater paw placement onto pegs. Although recovery of basic locomotion (bipedal treadmill and overground) was not accelerated, intralimb movement patterns were more normal in the Ch'ase ABC-treated cats. Qualitative assessment of serotonergic immunoreactivity also suggested that Ch'ase ABC treatment enhanced plasticity. Finally, analyses using fluorophore-assisted carbohydrate electrophoresis (FACE) indicate CS GAG content is similar in cat and human. These findings show, for the first time, that intraspinal cleavage of CS GAGs can enhance recovery of function following spinal cord injury in large animals with sophisticated motor behaviors and axonal growth requirements similar to those encountered in humans.     

A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubule-stabilizing activities

We discovered a thalidomide analogue [5-hydroxy-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33)] with antiproliferative activity against nine cancer cell lines in vitro. Flow cytometric analyses showed that the compound caused G2-M arrest, which occurred mainly at the mitotic phase. In addition, immunofluorescence microscopy and in vitro tubulin polymerization studies showed that 5HPP-33 has antimicrotubule activity with a paclitaxel-like mode of action. It is effective against four different paclitaxel-resistant cell lines. Thus, 5HPP-33 represents a potential antitumor agent.