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Biomedical subjects

Jeremy Hull

Publications and source records attributed to Jeremy Hull.

10 recordsLinked to original sources
PubMed2006

Localization of a long-range cis-regulatory element of IL13 by allelic transcript ratio mapping.

It appears that, for many genes, the two alleles possessed by an individual may produce different amounts of transcript. When such allelic differences in transcription are observed for some individuals but not others, a plausible explanation is genetic variation in the cis-acting elements that regulate the gene in question. Here we describe a novel analytical approach that uses such observations, combined with genotyping data from the HapMap project, to define the genomic location of cis-acting regulatory elements. When applied to the human 5q31 chromosomal region, where complex regulatory mechanisms are known to exist, we demonstrate the sensitivity of this approach by locating a highly significant cis-regulatory element operating on IL13 at long range from a position 250 kb upstream from the gene (P = 2 x 10(-6)). As this method is unaffected by other sources of variation, such as environmental and trans-acting genetic factors, it provides a tractable approach for dissecting the complexities of genetic variation in gene regulation.

Alleles↗
PubMed2005

Genetic variation at the IL10 gene locus is associated with severity of respiratory syncytial virus bronchiolitis.

The intense airway inflammatory response associated with respiratory syncytial virus (RSV) infection may be an important determinant in the severity of the disease. Interleukin (IL)-10 is a key regulatory cytokine known to be secreted during this infection. We investigated the role that IL-10 plays in RSV disease by studying the effects that variation in the IL10 gene has on the outcome of the disease. Eight single nucleotide polymorphisms (SNPs) spanning the IL10 gene were selected, and haplotypes were constructed. SNPs that efficiently tagged these haplotypes were then typed in 580 infants with severe RSV bronchiolitis and in 580 control subjects. None of the SNPs or haplotypes was associated with RSV bronchiolitis. In a subgroup analysis, 2 SNPs (IL10-1117 and IL10-3585) were associated (odds ratio, 1.7; P=.004) with the need for mechanical ventilation. These data are consistent with the theory that IL10 plays a role in the severity of RSV infection in infants.

Bronchiolitis, Viral↗
PubMed2005

Accuracy of haplotype reconstruction from haplotype-tagging single-nucleotide polymorphisms.

Many investigators are now using haplotype-tagging single-nucleotide polymorphism (htSNPs) as a way of screening regions of the genome for association with disease. A common approach is to genotype htSNPs in a study population and to use this information to draw inferences about each individual's haplotypic makeup, including SNPs that were not directly genotyped. To test the validity of this approach, we simulated the exercise of typing htSNPs in a large sample of individuals and compared the true and inferred haplotypes. The accuracy of haplotype inference varied, depending on the method of selecting htSNPs, the linkage-disequilibrium structure of the region, and the amount of missing data. At the stage of selection of htSNPs, haplotype-block-based methods required a larger number of htSNPs than did unstructured methods but gave lower levels of error in haplotype inference, particularly when there was a significant amount of missing data. We present a Web-based utility that allows investigators to compare the likely error rates of different sets of htSNPs and to arrive at an economical set of htSNPs that provides acceptable levels of accuracy in haplotype inference.

Biometry↗
PubMed2004

Familial susceptibility to severe respiratory infection in early life.

Lower respiratory tract infections (LRTI) are common in the first year of life and are mostly caused by viruses. Severity of LRTI in infants is associated with early-life environmental factors. Genetic association studies also suggest a role of heredity in susceptibility to acute bronchiolitis. We designed a case control study to further investigate relative importance of familial influences in risk of LRTI in early childhood compared to environmental factors. From a hospital database, we selected 1,308 children (436 cases; 872 controls) living in Oxfordshire. Cases were children under age 5 years admitted to hospital with LRTI. Parental history and other exposures were recorded in cases and controls by postal questionnaire. Maternal history of asthma increased the risk of severe LRTI in the first year of life, independent of subsequent asthma in a child. History of maternal bronchiolitis also increased the risk of infant LRTI. These results further support the possibility that genetic factors play an important role in susceptibility to severe viral respiratory infections in early life, and suggest that this effect may be independent of subsequent childhood asthma.

Asthma↗
PubMed2003

Haplotype mapping of the bronchiolitis susceptibility locus near IL8.

Susceptibility to viral bronchiolitis, the commonest cause of infant admissions to hospital in the industrialised world, is associated with polymorphism at the IL8 locus. Here we map the genomic boundaries of the disease association by case-control analysis and TDT in 580 affected UK infants. Markers for association mapping were chosen after determining patterns of linkage disequilibrium across the surrounding region of chromosome 4q, a 550-kb segment containing nine genes, extending from AFP to PPBP. The region has three major clusters of high linkage disequilibrium and is notable for its low haplotypic diversity. We exclude adjacent chemokine genes as the cause of the association, and identify a disease-associated haplotype that spans a 250-kb region from AFM to IL8. In between these two genes there is only one structural feature of interest, a novel gene RASSF6, which is predicted to encode a Ras effector protein.

Base Sequence↗
PubMed2003

Variants of the chemokine receptor CCR5 are associated with severe bronchiolitis caused by respiratory syncytial virus.

Respiratory syncytial virus (RSV) bronchiolitis is characterized by intense inflammation of the airways, and high levels of proinflammatory cytokines and chemokines can be found in respiratory secretions of affected infants. Important among these chemokines are RANTES (regulated on activation, normal T cell-expressed and -secreted) and macrophage inflammatory-protein alpha, MIP-1alpha, both of which show correlation with severe RSV bronchiolitis. It is not clear whether high levels of these chemokines are important in disease pathogenesis, and this study addresses this question by studying genetic variants of their major receptor, CC chemokine receptor 5. Results from both a case-control and family-based genetic-association analysis show that the -2459G and -2554T variants are associated with severe RSV bronchiolitis (P=.01). It is proposed that these CCR5 variants influence the inflammatory response, and these data provide further evidence of the important role that host genetic variability plays in the determination of disease severity in RSV bronchiolitis.

Bronchiolitis, Viral↗
PubMed2002

IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria.

Interferon (IFN)-gamma is a critical mediator of immunity to malaria. This study explored the relationship between polymorphisms in the promoter region of the gene encoding IFN-gamma receptor 1 (IFNGR1) and susceptibility to malaria in African children. Four polymorphisms were found in the region between -1400 and +100 nt of the translational start site by sequencing, and analysis of 562 nuclear families revealed 6 haplotypes. Case-control analysis of 562 Gambian children with severe malaria and 569 umbilical cord blood samples (controls) showed that in Mandinka, the major Gambian ethnic group, heterozygotes for the IFNGR1-56 polymorphism were protected against cerebral malaria (odds ratio, 0.54; P=.016) and against death resulting from cerebral malaria (odds ratio, 0.22; P=.006). Analysis of a family study by transmission disequilibrium testing revealed a similar result. Further data are needed to validate this finding, but these results are reminiscent of those for other well-established heterozygote advantages, such as that associated with hemoglobin S.

Adult↗
PubMed2002

Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors.

Tumour necrosis factor-alpha (TNF) expression is increased in inflammatory bowel disease (IBD), and TNF maps to the IBD3 susceptibility locus. Transmission disequilibrium and case-control analyses, in two independent Caucasian cohorts, showed a novel association of the TNF(-857C) promoter polymorphism with IBD (overall P=0.001 in 587 IBD families). Further genetic associations of TNF(-857C) with IBD sub-phenotypes were seen for ulcerative colitis and for Crohn's disease, but only in patients not carrying common NOD2 mutations. The genetic data suggest a recessive model of inheritance, and we observed ex vivo lipopolysaccharide-stimulated whole-blood TNF production to be higher in healthy TNF(-857C) homozygotes. We show the transcription factor OCT1 binds TNF(-857T) but not TNF(-857C), and interacts in vitro and in vivo with the pro-inflammatory NF(-kappa)B transcription factor p65 subunit at an adjacent binding site. Detailed functional analyses of these interactions in gut macrophages, in addition to further genetic mapping of this gene-dense region, will be critical to understand the significance of the observed association of TNF(-857C) with IBD.

Animals↗
PubMed2002

Evolution of a polymorphic regulatory element in interferon-gamma through transposition and mutation.

Mammalian transposable elements have intrinsic regulatory elements that can activate neighboring genes, and it is speculated that they can also carry extrinsic transactivating DNA sequences to new genomic locations. We have identified a polymorphic segment of the human interferon-gamma promoter region where two adjacent binding sites for NF-kappaB and NFAT originated from the insertion of an Alu element approximately 22-34 MYA. Both binding sites lie outside the Alu consensus sequence but within the boundaries of the insertion, suggesting that this segment of DNA was comobilized when the Alu element moved from another part of the genome. Sequence comparisons and examination of DNA-protein interactions across nine different primate species indicate that the inserted sequence contained the intact NFAT binding site, whereas the ability to bind NF-kappaB evolved through a series of mutations after the insertion. These observations are consistent with the notion that retropseudogenes can comobilize intact regulatory sequences to new locations and thereby influence the evolution of gene regulatory networks; however, the extent to which such events have shaped the evolution of gene regulation remains unknown.

Alu Elements↗