Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Use of fluorous silica gel to separate fluorous thiol quenching derivatives in solution-phase parallel synthesis

A general fluorous thiol quenching method is introduced. Excess α-bromoketones or benzyl bromides in parallel N-alkylation reactions are quenched with a fluorous thiol (C6F13CH2CH2SH). The resulting fluorous derivatives can be separated from the reaction mixture by a solid phase extraction on fluorous silica gel. © 2002 Elsevier Science Ltd. All rights reserved

Is motherhood a discriminatory factor in women’s career?

Dissertação de Mestrado apresentada no ISPA – Instituto Universitário para obtenção de grau de Mestre na especialidade de Psicologia Social e das OrganizaçõesO objetivo do presente estudo é perceber se as mulheres com filhos são alvo de maior discriminação no que diz respeito à sua progressão de carreira, considerando que na atualidade o tema da igualdade de género é foco de especial atenção. Adotando uma metodologia do tipo quasi-experimental, com um design 2x2 fatorial, foram apresentados 4 candidatos (mulher sem filhos, mulher com filhos, homem sem filhos e homem com filhos) aos 136 participantes deste estudo. Cada participante avaliou um destes candidatos focando-se nas suas perceções e se o recomendaria para a promoção interna. Os resultados demonstraram que não existem diferenças significativas quanto à Recomendação para a progressão. No entanto, em relação às impressões, o candidato “homem sem filhos” foi percecionado como tendo menor focus na Vida Pessoal, enquanto todos os candidatos eram percecionados como tendo o mesmo nível de focus no Trabalho. Em conclusão, as mulheres com filhos são consideradas tão válidas como os homens para uma promoção interna, diferenciando-se destes somente na perceção de que o seu focus na Vida Pessoal é mais elevado, se bem que de forma significativa apenas quando ambos não têm filhos.The objective of the present study is to understand if women with children are targeted of greater discrimination regarding their career progression, considering that at the present the gender equality is a “hot-topic”. Using a quasi-experimental methodology with a 2x2 factorial design, 4 candidates were presented (woman without children, woman with children, man without children and man with children) to the 136 participants of this study. Each participant evaluated one of these candidates focusing on the perceived impressions and if they would recommend the candidate for an internal promotion. The results showed that there are no significant differences regarding the recommendation for career progression. However, regarding impressions, the “man without children” candidate was perceived as having the lowest focus on personal life, while all candidates were perceived as having similar focus at work. In conclusion, women with children are considered as valid as men for internal promotion, differing from men only in the perception that their focus on personal life is higher, although only significantly when both have no children

Failure to detect association between polymorphisms of the sodium channel gene SCN1A and febrile seizures in Chinese patients with epilepsy

A recent study in Caucasians found an association between the single nucleotide polymorphism (SNP) of SCN1A, IVS5N +5 G>A (rs3812718), and febrile seizures (FS). We examined whether this and other tagging SNPs of SCN1A were associated with an increased risk of FS in Han Chinese. A total of 728 Han Chinese patients with focal epilepsy were recruited: 97 had a history of FS (58% male, mean age 35 ± 12 years) and 631 did not (50% male, mean age 40 ± 15 years). Genotyping was performed for IVS5N +5 G>A and seven other tagging SNPs selected from the HapMap database. Genotyping was also performed in 848 ethnically matched population controls (50% male, mean age 37 ± 17 years). There was no statistically significant difference in either allele or genotype frequency of any of the SNPs studied between epilepsy patients with and without FS, and between epilepsy patients with FS and controls. The results do not suggest that SCN1A SNPs are susceptibility factors for FS in Han Chinese. © 2010 International League Against Epilepsy.link_to_subscribed_fulltex

Association of epilepsy with voltage gated sodium channel gene polymorphisms in Han Chinese

Abstract no. 1.321link_to_OA_fulltextThe 63rd Annual Meeting of the American Epilepsy Society, Boston, MA., 4-8 December 2009

The Anticonvulsant Triheptanoin Shows Anaplerotic Activity in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice

This journal suppl. entitled: Special Issue: 30th International Epilepsy Congress, Montreal, Canada, 23-27 June 2013Late Breaking Abstracts: LBP1090PURPOSE: High frequency action potentials are mediated by voltage-gated sodium channels, composed of one large a subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the CNS. Since mutations of these can cause certain genetic epilepsy syndromes, we investigated whether polymorphisms in these genes may affect epilepsy risk in general. METHOD: Epilepsy patients and control subjects from Hong Kong and Kuala Lumpur were matched in age, sex and ethnicity. Epilepsy was broadly classified based on ILAE criteria. Blood was withdrawn for DNA extraction. Using Haploview, we tagged the five genes with 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. Polymorphisms were genotyped by Sequenom Mass Array. RESULTS: The study included 1529 epilepsy patients (mean+/-SD age: 35 +/- 16 years) and 1935 control subjects (34 +/- 16 years) from four ethnic groups or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong (the latter comprising 54% of patients and 44% of controls). Of patients, 19% were idiopathic, 42% symptomatic, and 40% cryptogenic. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A, odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotypes GG vs. AA (p = 0.003). The association was consistent across ethnicities. Allele G is known to affect splicing and to speed recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed LD with rs2082366 (r2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated with epilepsy in Indians (OR = 0.56, p = 0.005). SCN2B rs602594 was associated with idiopathic epilepsy (OR = 0.62, p = 0.002). CONCLUSION: Common genetic variants in neuronal sodium channel genes are associated with the risk of epilepsy.link_to_OA_fulltex