Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis

Background

Schizophrenia is a highly heritable complex psychiatric disorder with an underlying pathophysiology that is still not well understood. Metaanalyses of schizophrenia linkage studies indicate numerous but rather large disease-associated genomic regions, whereas accumulating gene- and protein expression studies have indicated an equally large set of candidate genes that only partially overlap linkage genes. A thorough assessment, beyond the resolution of current GWA studies, of the disease risk conferred by the numerous schizophrenia candidate genes is a daunting and presently not feasible task. We undertook these challenges by using an established clinical paradigm, the estrogen hypothesis of schizophrenia, as the criterion to select candidates among the numerous genes experimentally implicated in schizophrenia. Bioinformatic tools were used to build and priorities the signaling networks implicated by the candidate genes resulting from the estrogen selection. We identified ten candidate genes using this approach that are all active in glucose metabolism and particularly in the glycolysis. Thus, we tested the hypothesis that variants of the glycolytic genes are associated with schizophrenia or at least with gender-associated aspects of the illness.

Results

We genotyped 185 SNPs in three independent case-control samples of Scandinavian origin (a total of 765 patients and 1274 control subjects). Variants of the mitogen-activated protein kinase 14 gene (MAPK14) and the phosphoenolpyruvate carboxykinase 1 (PCK1) and fructose-1,6-biphosphatase (FBP1) were nominal significantly associated with schizophrenia, and several haplotypes within enolase 2 gene (ENO2) consist of the same SNP allele having elevated risk of schizophrenia. Importantly, we find no evidence of stratification due to nationality or gender.

Conclusion

Several gene variants in the Glycolysis were associated with schizophrenia in three independent samples. However, the findings are weak and not resistant to correction for multiple testing, which may indicate that they are either spurious or may relate to a particular subtype or aspect of the illness.     

Characterization of recombinant plasminogen activator production by primate endothelial cells transduced with retroviral vectors

Retroviral vector-mediated expression of plasminogen activators (PAs) from endothelial cells (ECs) has been proposed as a potential therapeutic approach for intravascular thrombosis. To define the potential for gene transfer to increase fibrinolytic activity in a primate system, baboon ECs were transduced with retroviral vectors expressing wild-type and glycosylphosphatidylinositol-anchored urokinase, as well as wild-type and serpin-resistant tissue PA (t-PA). Expression of either t-PA or urokinase was increased by one log over baseline levels. There was no specific effect of either t-PA or urokinase overexpression on endogenous t-PA, urokinase, or PA inhibitor 1 (PAI-1) expression. Recombinant urokinase could be anchored to the cell surface at a level eight-fold above that of receptor-bound urokinase. The majority of secreted urokinase accumulated in conditioned medium as a free proenzyme, whereas both wild-type and serpin-resistant t-PA accumulated almost exclusively in complexes with PAI-1. In most but not all of the assays, the urokinase vectors conferred PA activity above that of the t-PA vectors. These data show that PA synthesis and activity are specifically increased subsequent to retroviral vector-mediated gene transfer in primate ECs. However, definition of an optimal PA vector will require in vivo experimentation.     

Hypoglycaemia and elevated urine ethylmalonic acid in a child homozygous for the short-chain acyl-CoA dehydrogenase 625G > A gene variation

The aim of this case report is to call attention to short-chain acyl-CoA dehydrogenase (SCAD) deficiency as a possible contributory factor to hypoglycaemia in childhood. We report on a previously healthy 14 mo-old Danish boy who presented with hypoglycaemia and metabolic acidosis after a few days of upper airway infection. After two days on a normal diet, he recovered clinically and biochemically. A thorough biochemical examination did not reveal the cause of the hypoglycaemia. However, the excretion of ethylmalonic acid in two morning urine samples was moderately increased, and hence the SCAD gene was screened for mutations. We found the child homozygous for the G > A SCAD gene variation at position 625.
Conclusion : In this patient, reduced function of the SCAD protein is reflected in the excretion of ethylmalonic acid, a marker of intracellular accumulation of butyryl-CoA and the cytotoxic butyric acid. Furthermore, gluconeogenesis might be compromised owing to lack of reducing equivalents from the oxidation of short-chain fatty acids in the fasting or stressed state, thus contributing to the predisposition for fasting hypoglycaemia.     

Is there any association between consanguinity and hearing loss

BACKGROUND: Hearing loss (HL) and its complications appear to be increasingly common in developing countries. Previous studies have supported the association between hearing loss and consanguinity. OBJECTIVE: The aim of the present study was to determine the frequency of hearing loss and its association with consanguinity among Qatari population. In addition, correlation between hearing loss and Rhesus (Rh) blood groups has been investigated. DESIGN: This is a cross-sectional study. SETTING: The study conducted at the Hamad General Hospital, Hamad Medical Corporation. SUBJECTS: Total sample of 2800 infants screened and 2277 subjects were eligible to be included in the study. METHODS: The neonatal screening for hearing loss was conducted from January 2003 to November 2003 among all the 2800 infants born during that period. Some of them were admitted to neonatal intensive care unit (NICU). The hearing loss was screened using otoacoustic emission (Garson Stadler Incorporation, GSI-70), auditory brain stem responses (ABR) and tympanogram. RESULTS: Out of 2277 infant screened, the prevalence of hearing loss was (119/2277) 5.2%. The prevalence of HL was more common in boys (2.7%) than in girls (2.5%). We did not find any statistical significance differences between genders with the respect of HL. Parental consanguinity was more common among HL cases compared with non-HL 60.5% versus 25.3% (p < 0.0001). Family history of hearing loss did not show any differences between the two groups. 4.2% versus 4.3%. Risk factors like caesarean section, prenatal smoking and prenatal high blood pressure did not show any significant differences between the two groups. However, admission to NICU is associated with increase prevalence of HL 8.4% versus 4.4% (p = 0.043). The present study revealed that strong correlation between hearing loss, consanguineous (r = 0.217, p < 0.01), father education level illiterate (r = 0.293, p < 0.01), mothers consanguineous (r = 0.206, p < 0.01), mothers educational level illiterate (r = 0.228, p < 0.01), mother blood group positive (r = 0.476, p < 0.01), family history of HL among first or second degree of relatives (r = 0.620, p < 0.01) and father hypertension (r = 0.570, p < 0.01). Furthermore, a significant correlation between hearing loss and Rh blood groups has been discovered. CONCLUSION: The present study was directed at determining the prevalence and risk factors of HL in the infant population of Qatar. The data revealed that parental consanguinity was more common among hearing loss cases. There is a strong correlation between hearing loss and baby's age.     

A novel phenotypic pattern in X-linked inheritance: craniofrontonasal syndrome maps to Xp22

Craniofrontonasal syndrome (CFNS, OMIM 304110) is a distinctive genetic disorder whose main clinical manifestations include coronal synostosis, widely spaced eyes, clefting of the nasal tip and various skeletal anomalies. CFNS originally was thought to be transmitted as an autosomal dominant trait, but recent studies suggest that it is X- linked dominant, whereby all daughters of males are affected, whereas none of their sons are affected. Here we report data confirming that CFNS is X-linked, mapping to a 13 cM interval in Xp22 with a maximum two-point lod score of 3.9 (theta = 0) at DXS8022 and a multipoint lod score of 5.08 at DXS1224. Detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder. CFNS represents the first multiple congenital anomaly syndrome with this unusual phenotypic pattern of X-linked inheritance.      

Protection against severe clinical manifestations of Plasmodium falciparum malaria among sickle cell trait subjects is due to modification of the release of cytokines and/or cytoadherence of infected erythrocytes to the host vascular beds

It is proposed that the surface ligands of Plasmodium falciparum infected HbAS erythrocytes, not like infected HbAA erythrocytes, are altered due to the sickling that soon takes place once a HbAS erythrocyte gets infected with P. falciparum parasite. This alteration modulates cytoadherence and/or binding of the sickled erythrocytes to the peripheral blood mononuclear cells (PBMCs). Both cytoadherence and binding to PBMCs are responsible for the pathogenesis of malaria. Therefore, subjects of the HbAS genotype experience mild symptoms of malaria. The hypothesis could be tested in vitro by comparing the binding of P. falciparum infected HbAS and HbAA erythrocytes to platelet-endothelial cell adhesion molecule-1 (CD31) and by comparing the levels of tumor necrosis factor (TNF) and interferon gamma (IFN-gamma) following in vitro stimulation of PBMCs by HbAS and HbAA infected erythrocytes.