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.

Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.

Abstract: Background Genetic factors may affect the susceptibility to tuberculosis, but no specific genes governing susceptibility have been identified. In mice, natural resistance to infection with some mycobacteria is influenced by the gene for natural-resistance–associated macrophage protein 1 (Nramp1 ), but the role of the human homologue of this gene, NRAMP1, in tuberculosis is unknown. We typed polymorphisms in NRAMP1 in a case–control study of tuberculosis in the Gambia, West Africa. Methods Sequence-specific oligonucleotide hybridization and microsatellite analysis were used to type NRAMP1 polymorphisms in 410 adults (mean age, 34.7 years) with smear-positive pulmonary tuberculosis and 417 ethnically matched, healthy controls. Patients with human immunodeficiency virus infection were excluded. Results Four NRAMP1 polymorphisms were each significantly associated with tuberculosis. Subjects who were heterozygous for two NRAMP1 polymorphisms in intron 4 and the 3' untranslated region of the gene were particula...

Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future

Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.

Abstract: To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants.