A serum 25-hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intima-media thickness).

AIMS/HYPOTHESIS: The findings of studies investigating whether or not low serum 25-hydroxyvitamin D [25(OH)D] concentration promotes development of atherosclerosis have been contradictory. The present study employed a Mendelian randomisation approach and carotid artery intima-media thickness (cIMT), a surrogate marker of coronary artery disease, to address this question. METHODS: The multicentre, longitudinal Carotid Intima-Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE) cohort study, which enrolled individuals with at least three cardiovascular risk factors and no history or symptoms of cardiovascular disease, was used for the present investigation. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30. Six single nucleotide polymorphisms (SNPs) associated with serum 25(OH)D concentration in genome-wide association studies were identified and genotyped in 3,418 individuals, of whom 929 had type 2 diabetes. RESULTS: SNPs in the genes encoding vitamin D binding protein (GC; rs2282679 and rs7041) and 7-dehydrocholesterol reductase/NAD synthetase-1 (DHCR7; rs12785878 and rs3829251) were negatively associated with 25(OH)D levels. Effect sizes and significance of associations between SNPs and 25(OH)D levels differed between individuals with and without type 2 diabetes, although no significant interactions were observed. A SNP in DHCR7 interacted with type 2 diabetes to significantly influence progression of cIMT measures independent of 25(OH)D levels and established risk factors. Expression analysis demonstrated that this SNP modulates DHCR7 mRNA levels in aortic adventitia. CONCLUSIONS/INTERPRETATION: SNPs in GC and DHCR7 were associated with serum levels of 25(OH)D, but only rs3829251 (DHCR7) influenced progression of subclinical atherosclerosis, as measured by cIMT, in a manner dependent on type 2 diabetes status but independent of 25(OH)D levels.

MHC gene related effects on microglia and macrophages in experimental autoimmune encephalomyelitis determine the extent of axonal injury.

Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats is a chronic inflammatory demyelinating disease of the central nervous system (CNS) strongly mimicking multiple sclerosis (MS). We determined the involvement of macrophages and microglia in the lesions of MOG-EAE in relation to different major histocompatibility complex (MHC, RT1 in rat) haplotypes. We used intra-RT1 recombinant rat strains with recombinations between the RT1a and RT1u haplotypes on the disease permissive LEW non-MHC genome. Activated microglia and macrophages were identified morphologically and by expression of ED1 and allograft inhibitory factor-1 (AIF-1), and differentiated by their morphological phenotype. White matter lesions contained more macrophages and less microglia compared to grey matter lesions. Similarly active lesions were mainly infiltrated by macrophages, while microglia were abundant in inactive demyelinated plaques. In addition, we found a highly significant genetic association between a macrophage or microglia dominated lesional phenotype, which was independent from location and activity of the lesions. This was not only the case in demyelinating plaques of chronic EAE, but also in purely inflammatory lesions of acute passive transfer EAE. Rat strains with an u-haplotype in both the Class II and the telomeric non-classical Class I region revealed inflammatory and demyelinating lesions, which were dominated by activated microglia. The a-haplotype in any of these regions was associated with macrophage dominated lesions. A comparison of lesions, exactly matched for stages of demyelinating activity in these different rat strains, showed that in spite of a similar extent of demyelination, axonal injury was significantly less in microglia compared to macrophage dominated lesions. Thus, our studies document a genetic influence of the MHC-region on the relative contribution of macrophages versus microglia in the pathogenesis of EAE.

Measurement invariance of personality traits from a five-factor model perspective: multi-group confirmatory factor analyses of the HP5 inventory.

Associations between personality and health may be influenced by contextual factors varying across studied cohorts. Moreover, measurement bias related to contextual factors could also influence these associations. Gender and age have been discussed as important contextual factors when studying personality and health outcomes. An examination of measurement invariance across gender and age may therefore be warranted. In the present study, measurement invariance across age and gender was examined for a five-factor model of personality traits in which scales have been included to operationalise lower-order traits related to health-behaviour or health outcomes. Using multi-group confirmatory factor analysis on a population based cohort (n= 5700), all important parameters of the measurement model were found to be invariant. On the basis of this invariant model, hypotheses of mean differences across age and gender in personality traits were tested. These results were discussed in relation to meta-analyses on personality change and gender differences in personality.

Porcine diazepam-binding inhibitor is immunohistochemically colocalized with somatostatin in the D cells of human and porcine gastrointestinal tract and in pancreatic islet cells.

The cellular distribution of a novel porcine peptide, diazepam-binding inhibitor (DBI), was immunohistochemically mapped in the human and porcine gastrointestinal tract and pancreas. Using a rabbit antiserum, raised against porcine DBI, immunoreactive epithelial cells were found in the gastric antrum and duodenal mucosa and in the parenchymal cells of the islets of Langerhans of both species. The immunoreactivity could not be absorbed by high concentrations of insulin, somatostatin (SS-14, SS-28), glucagon, or pancreatic polypeptide but was abolished by porcine DBI. Using semithin, consecutive sections, the immunoreactive intestinal and islet cells were found to be identical to the somatostatin-producing D cells. Since it has been shown that porcine DBI interferes with the secretion of insulin, the peptide may act as a modulator of islet hormone release, possibly in a paracrine manner.