Qatar Biomedical Research Institute QBRI

Doha, Qatar

Qatar Biomedical Research Institute QBRI

Doha, Qatar
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Falchi M.,Imperial College London | El-Sayed Moustafa J.S.,Imperial College London | Takousis P.,Imperial College London | Pesce F.,Imperial College London | And 78 more authors.
Nature Genetics | Year: 2014

Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10-14) and serum enzyme levels (P < 2.20 × 10-16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy =-0.15 (0.02) kg/m 2; P = 6.93 × 10-10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10-10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. © 2014 Nature America, Inc. All rights reserved.

Kilshaw S.,University College London | Al Raisi T.,Hamad Medical Corporation | Alshaban F.,Qatar Biomedical Research Institute QBRI
Anthropology and Medicine | Year: 2015

This paper considers how the globalized discourse of genetic risk in cousin marriage is shaped, informed and taken up in local moral worlds within the context of Qatar. This paper investigates the way Qataris are negotiating the discourse on genetics and risk. It is based on data from ongoing ethnographic research in Qatar and contributes to anthropological knowledge about this understudied country. Participants were ambivalent about genetic risks and often pointed to other theories of causation in relation to illness and disability. The discourse on genetic risk associated with marrying in the family was familiar, but for some participants the benefits of close marriage outweighed potential risks. Furthermore, the introduction of mandatory pre-marital screening gave participants confidence that risks were monitored and minimized. © 2015 © 2015 Taylor & Francis.

Bonnefond A.,French National Center for Scientific Research | Bonnefond A.,Lille University | Bonnefond A.,European Genomic Institute for Diabetes EGID | Skrobek B.,French National Center for Scientific Research | And 29 more authors.
Nature Genetics | Year: 2013

Large chromosomal clonal mosaic events (CMEs) have been suggested to be linked to aging and to predict cancer. Type 2 diabetes (T2D) has been conceptualized as an accelerated-aging disease and is associated with higher prevalence of cancers. Here we aimed to assess the association between T2D and CME occurrence in blood. We evaluated the presence of CMEs in 7,659 individuals (including 2,208 with T2D) using DNA arrays. A significant association between CME occurrence and T2D was found (odds ratio (OR) = 5.3; P = 5.1 × 10 -5) and was stronger when we only considered non-obese individuals with T2D (OR = 5.6; P = 4.9 × 10 -5). Notably, CME carriers with T2D had higher prevalence of vascular complications than non-carriers with T2D (71.4% versus 37.1%, respectively; P = 7.7 × 10 -4). In CME carriers, we found an increase in the percentage of abnormal cells over 6 years (P = 8.60 × 10 -3). In conclusion, given the increased risk of cancer in CME carriers, our results may have profound clinical implications in patients with severe T2D. © 2013 Nature America, Inc. All rights reserved.

Saeed S.,Imperial College London | Bonnefond A.,European Genomic Institute for Diabetes EGID | Bonnefond A.,French National Center for Scientific Research | Bonnefond A.,Lille University | And 20 more authors.
Obesity | Year: 2014

Objective Mutations in leptin receptor gene (LEPR) result in early onset extreme adiposity. However, their prevalence in different populations is not known. Indeed, LEPR screening by gold standard Sanger sequencing has been limited by its large size and the cost. One-step PCR-based targeted enrichment could be an option for rapid and cost effective molecular diagnosis of monogenic forms of obesity. Methods The study is based on 39 unrelated severely obese Pakistani children, previously shown to be negative for leptin (LEP) and melanocortin 4 receptor (MC4R) gene mutations, from an initial cohort of 62 probands. Patient samples were analyzed by microdroplet PCR-enrichment (RainDance technologies) targeting coding exons of 26 obesity-associated genes combined with next generation sequencing. Hormone levels were analyzed by ELISA. Results The analysis revealed two novel homozygous LEPR mutations, an essential splice site mutation in exon 15 (c.2396-1 G>T), and a nonsense mutation in exon 10 (c.1675 G>A). Both probands had high leptin levels and were phenotypically indistinguishable from age-matched leptin-deficient subjects from the same population. Conclusions The two subjects carrying homozygous LEPR mutations, reported here for the first time in the Pakistani population, constitute 3% of the whole cohort of severely obese children (compared to 17% for LEP and 3% for MC4R). Copyright © 2013 The Obesity Society.

Dikiy I.,New York Medical College | Dikiy I.,City University of New York | Fauvet B.,Ecole Polytechnique Federale de Lausanne | Fauvet B.,University of Lausanne | And 9 more authors.
ACS Chemical Biology | Year: 2016

Alpha-synuclein is a presynaptic protein of poorly understood function that is linked to both genetic and sporadic forms of Parkinson's disease. We have proposed that alpha-synuclein may function specifically at synaptic vesicles docked at the plasma membrane, and that the broken-helix state of the protein, comprising two antiparallel membrane-bound helices connected by a nonhelical linker, may target the protein to such docked vesicles by spanning between the vesicle and the plasma membrane. Here, we demonstrate that phosphorylation of alpha-synuclein at tyrosine 39, carried out by c-Abl in vivo, may facilitate interconversion of synuclein from the vesicle-bound extended-helix state to the broken-helix state. Specifically, in the presence of lipid vesicles, Y39 phosphorylation leads to decreased binding of a region corresponding to helix-2 of the broken-helix state, potentially freeing this region of the protein to interact with other membrane surfaces. This effect is largely recapitulated by the phosphomimetic mutation Y39E, and expression of this mutant in yeast results in decreased membrane localization. Intriguingly, the effects of Y39 phosphorylation on membrane binding closely resemble those of the recently reported disease linked mutation G51D. These findings suggest that Y39 phosphorylation could modulate functional aspects of alpha-synuclein and perhaps influence pathological aggregation of the protein as well. © 2016 American Chemical Society.

Chini V.P.,Qatar Biomedical Research Institute QBRI
Clinica Chimica Acta | Year: 2015

miRNAs are small non-coding RNAs that regulate gene expression. They have significant role in the regulation of cardiovascular function and conditions, such as Heart Failure (HF), as demonstrated by studies of miRNA expression profiling in myocardial tissue. The importance of the use of miRNAs as biomarkers in HF was enhanced when found that they exist extracellularly, with remarkable stability and there are indications that their expression levels reflect the cell response in cardiovascular conditions including Heart Failure. Advances in technology and bioinformatics broaden the field of applications of miRNAs in HF. The introduction of new platforms, such as Next Generation Sequencing, enabled the discovery of novel miRNAs that might be utilized as Heart Failure biomarkers for diagnostic and prognostic purposes and with potential applications in targeted therapeutics. © 2014 Elsevier B.V.

Landeck N.,Lund University | Hall H.,Lund University | Hall H.,McGill University | Ardah M.T.,United Arab Emirates University | And 5 more authors.
Molecular Neurodegeneration | Year: 2016

Background: Alpha-synuclein (asyn) has been shown to play an important role in the neuropathology of Parkinson's disease (PD). In the diseased brain, classic intraneuronal inclusions called Lewy bodies contain abnormal formations of asyn protein which is mostly phosphorylated at serine 129 (pS129 asyn). This suggests that post-translational modifications may play a role in the pathogenic process. To date, several uniplex assays have been developed in order to quantify asyn not only in the brain but also in cerebrospinal fluid and blood samples in order to correlate asyn levels to disease severity and progression. Notably, only four assays have been established to measure pS129 asyn specifically and none provide simultaneous readout of the total and pS129 species. Therefore, we developed a sensitive high-throughput duplex assay quantifying total and pS129 human asyn (h-asyn) in the same well hence improving accuracy as well as saving time, consumables and samples. Results: Using our newly established duplex assay we measured total and pS129 h-asyn in vitro showing that polo-like kinase 2 (PLK2) can phosphorylate asyn up to 41 % in HEK293 cells and in vivo the same kinase phosphorylated h-asyn up to 17 % in rat ventral midbrain neurons. Interestingly, no increase in phosphorylation was observed when PLK2 and h-asyn were co-expressed in rat striatal neurons. Furthermore, using this assay we investigated h-asyn levels in brain tissue samples from patients with PD as well as PD dementia and found significant differences in pS129 h-asyn levels not only between disease tissue and healthy control samples but also between the two distinct disease states especially in hippocampal tissue samples. Conclusions: These results demonstrate that our duplex assay for simultaneous quantification is a useful tool to study h-asyn phosphorylation events in biospecimens and will be helpful in studies investigating the precise causative link between post-translational modification of h-asyn and PD pathology. © 2016 The Author(s).

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