Wellcome Trust Centre for Human Genetics

About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.

The role of atopic sensitization in flexural eczema: Findings from the International Study of Asthma and Allergies in Childhood Phase Two

Abstract: Background The association between allergic sensitization and eczema has been debated for years. Objective We sought to determine and compare the strength of the association between allergen skin sensitization and eczema in both developing and industrialized countries. Methods Twenty-eight thousand five hundred ninety-one randomly selected 8- to 12-year-old schoolchildren in 20 countries were physically examined for flexural eczema and received skin prick testing to Dermatophagoides pteronyssinus , Dermatophagoides farinae , cat hair, Alternaria tenuis , mixed tree and grass pollen, and allergens of local relevance. Results The age- and sex-adjusted odds ratios (ORs) for a positive association between flexural eczema and atopy ranged between 0.74 (95% CI, 0.31-1.81) and 4.53 (95% CI, 1.72-11.93), with a significantly stronger association in affluent compared with nonaffluent countries (combined age- and sex-adjusted OR affluent = 2.69 [95% CI, 2.31-3.13] and OR nonaffluent = 1.17 [95% CI, 0.81-1.70]). The combined population attributable fraction for atopy in flexural eczema was 27.9% for affluent and 1.2% for nonaffluent-country centers. Correlating gross national per-capita income with either ORs or population attributable fractions for atopy in flexural eczema confirmed a highly significant positive association ( P = .006 and P Conclusions The association between atopy and flexural eczema is weak and more variable than previously suggested, and the strength of this association is positively linked to gross national income.

Localization of the Netherton Syndrome Gene to Chromosome 5q32, by Linkage Analysis and Homozygosity Mapping

Abstract: Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Iα, the α subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor β2, and the diastrophic dysplasia sulfate–transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.

Progress in defining the molecular basis of type 2 diabetes mellitus through susceptibility-gene identification

Abstract: The rapid increase in the prevalence of type 2 diabetes (T2D) represents a major challenge for health care delivery worldwide. Identification of genes influencing individual susceptibility to disease offers a route to better understanding of the molecular mechanisms underlying pathogenesis, a necessary prerequisite for the rational development of improved preventative and therapeutic methods. The past decade has seen substantial success in identifying genes responsible for monogenic forms of diabetes (notably, maturity-onset diabetes of the young), and, in patients presenting with early-onset diabetes, a precise molecular diagnosis is an increasingly important element of optimal clinical care. Progress in gene identification for more common, multifactorial forms of type 2 diabetes has been slower, but there is now compelling evidence that common variants in the PPARG, KCNJ11 and CAPN10 genes influence T2D-susceptibility, and positional cloning efforts within replicated regions of linkage promise to deliver additional components of inherited susceptibility. The challenge in the years to come will be to understand how T2D risk is influenced by the interaction of these variants with each other and with pertinent environmental factors encountered during gestation, childhood and adulthood; and to establish how best to apply this understanding to provide individuals with clinically-useful diagnostic, prognostic and therapeutic information.

Cell Specific eQTL Analysis without Sorting Cells.

Abstract: The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.

Epigenetic regulation by histone demethylases in hypoxia

Abstract: The response to hypoxia is primarily mediated by the hypoxia-inducible transcription factor (HIF). Levels of HIF are regulated by the oxygen-sensing HIF hydroxylases, members of the 2-oxoglutarate (2OG) dependent oxygenase family. JmjC-domain containing histone lysine demethylases (JmjC-KDMs), also members of the 2OG oxygenase family, are key epigenetic regulators that modulate the methylation levels of histone tails. Kinetic studies of the JmjC-KDMs indicate they could also act in an oxygen-sensitive manner. This may have important implications for epigenetic regulation in hypoxia. In this review we examine evidence that the levels and activity of JmjC-KDMs are sensitive to oxygen availability, and consider how this may influence their roles in early development and hypoxic disease states including cancer and cardiovascular disease.