12 results on '"Rafferty I"'
Search Results
2. HERITABLE THROMBOPHILIC DEFECTS IN LEGG-PERTHES DISEASE
- Author
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Jobanputra, S., Rafferty, I., Knotts, L., Sherlock, D., and Chalmers, E. A.
- Published
- 2000
3. PULMONARY EMBOLISM ASSOCIATED WITH VARICELLA INFECTION
- Author
-
McColl, M. D., Chalmers, E. A., and Rafferty, I.
- Published
- 1998
4. A genome-wide association study identifies protein quantitative trait loci (pQTLs)
- Author
-
Luigi Ferrucci, J. Raphael Gibbs, Michael N. Weedon, Tamara B. Harris, Alison J. Hurst, William Henley, Annamaria Corsi, Vijay Panicker, Colin M. Dayan, Amanda J. Bennett, Nicole Washecka, Kara Stevens, Stefania Bandinelli, Jack M. Guralnik, Giuseppe Paolisso, Sampath Arepalli, Marjo-Riitta Järvelin, Ian Rafferty, Joyce van de Leemput, John R. B. Perry, Sonja W. Scholz, Mark I. McCarthy, Gregory J. Tranah, Hana Lango, Javier Simón-Sánchez, Rongling Li, Aimo Ruokonen, Andrew B. Singleton, Anne B. Newman, Timothy M. Frayling, Fulvio Lauretani, Dena G. Hernandez, Neil Rice, Anna Murray, David Melzer, Sajjad Rafiq, Angela Britton, Melzer, D., Perry, J., Hernandez, D., Corsi, A., Stevens, K., Rafferty, I., Murray, A., Gibbs, J., Paolisso, Giuseppe, Rafiq, S., SIMON SANCHEZ, J., Lango, H., Sholz, S., Weedon, M., Arepalli, S., Rice, N., Washecka, N., Hurst, A., Britton, A., Henley, W., VAN DE LEEMPUT, J., Li, R., Newman, A., Tranah, G., Harris, T., Panicker, V., Dayan, C., Bennet, A., Mccarthy, M., Ruokonen, A., Jarvelin, M., Guralnik, J., Bandinelli, S., Frayling, T., Singleton, A., and Ferrucci, L.
- Subjects
Male ,Cancer Research ,Transcription, Genetic ,Genetic Linkage ,Gene Dosage ,Genome-wide association study ,DISEASE ,0302 clinical medicine ,Biochemistry/Protein Chemistry ,Copy-number variation ,Genetics and Genomics/Genetics of Disease ,Genetics (clinical) ,Genetics & Heredity ,RISK ,Aged, 80 and over ,Genetics ,0303 health sciences ,BIRTH COHORT ,interleukin ,Genetics and Genomics/Functional Genomics ,Genetics and Genomics/Gene Expression ,Blood Proteins ,Genetics and Genomics/Physiogenomics ,Middle Aged ,CANCER ,Diabetes and Endocrinology ,InCHIANTI study ,030220 oncology & carcinogenesis ,MENDELIAN RANDOMIZATION ,Female ,Life Sciences & Biomedicine ,Biochemistry/Transcription and Translation ,Research Article ,Adult ,liver function markers ,lcsh:QH426-470 ,Genotype ,Cardiovascular Disorders ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Genetics and Genomics/Complex Traits ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genetic variation ,Humans ,YEAST ,Allele ,Molecular Biology ,QH426 ,POLYMORPHISMS ,Ecology, Evolution, Behavior and Systematics ,Aged ,030304 developmental biology ,0604 Genetics ,Science & Technology ,HUMAN GENE-EXPRESSION ,RECEPTOR ,Genome, Human ,Genetic Variation ,Molecular biology ,R1 ,COMMON VARIANT ,lcsh:Genetics ,Genetics and Genomics/Genome Projects ,Expression quantitative trait loci ,Liver function ,Developmental Biology ,Genome-Wide Association Study - Abstract
There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10−57), CCL4L1 (p = 3.9×10−21), IL18 (p = 6.8×10−13), LPA (p = 4.4×10−10), GGT1 (p = 1.5×10−7), SHBG (p = 3.1×10−7), CRP (p = 6.4×10−6) and IL1RN (p = 7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways., Author Summary One of the central dogmas of molecular genetics is that DNA is transcribed to RNA which is translated to protein and alterations to proteins can influence human diseases. Genome-wide association studies have recently revealed many new DNA variants that influence human diseases. To complement these efforts, several genome-wide studies have established that DNA variation influences mRNA expression levels. Loci influencing mRNA levels have been termed “eQTLs”. In this study we have performed the first genome-wide association study of the third piece in this jigsaw – the role of DNA variation in relation to protein levels, or “pQTLs”. We analysed 42 proteins measured in blood fractions from the InCHIANTI study. We identified eight cis effects including common variants in or near the IL6R, CCL4, IL18, LPA, GGT1, SHBG, CRP and IL1RN genes, all associated with blood levels of their respective protein products. Mechanisms implicated included altered transcription (GGT1) but also rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA) and variation in gene copy number (CCL4). Blood levels of many of these proteins are correlated with human diseases and the identification of “pQTLs” may in turn help our understanding of disease.
- Published
- 2008
5. Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series.
- Author
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van de Leemput J, Wavrant-De Vrièze F, Rafferty I, Bras JM, Giunti P, Fisher EM, Hardy JA, Singleton AB, and Houlden H
- Subjects
- Adolescent, Adult, Cohort Studies, Exons genetics, Female, Humans, Male, Middle Aged, Spinocerebellar Ataxias classification, Young Adult, Inositol 1,4,5-Trisphosphate Receptors genetics, Point Mutation genetics, Sequence Analysis, DNA methods, Spinocerebellar Ataxias genetics
- Abstract
Spinocerebellar ataxia type 15 and 16 (SCA15/16) are autosomal dominant cerebellar ataxias that are slowly progressive with a predominantly pure ataxia phenotype (ADCA III). The locus for SCA15 was first mapped to 3p24.2-3pter and subsequently full or partial deletions in the inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene were identified in several ADCA III families that segregated with the disease. A single missense coding variant has been described, but the pathogenicity of this change has not been proven. We sequenced the entire coding region and flanking regions of ITPR1 in unrelated ADCA III families (n = 38) that were negative for large deletions on whole genome arrays, and for which SCAs 1, 2, 3, 6, 7, 8, 11, 12, 14, 17 and the Friedreich's ataxia expansion were excluded in all probands. Mutation at SCA5, 10, and 27 was also excluded in some families. A number of coding and noncoding polymorphisms were identified but no ITPR1 mutations were found. The results indicate that point mutations in ITPR1 are at best a rare cause of ADCA III., (2010 Movement Disorder Society)
- Published
- 2010
- Full Text
- View/download PDF
6. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.
- Author
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Chiò A, Schymick JC, Restagno G, Scholz SW, Lombardo F, Lai SL, Mora G, Fung HC, Britton A, Arepalli S, Gibbs JR, Nalls M, Berger S, Kwee LC, Oddone EZ, Ding J, Crews C, Rafferty I, Washecka N, Hernandez D, Ferrucci L, Bandinelli S, Guralnik J, Macciardi F, Torri F, Lupoli S, Chanock SJ, Thomas G, Hunter DJ, Gieger C, Wichmann HE, Calvo A, Mutani R, Battistini S, Giannini F, Caponnetto C, Mancardi GL, La Bella V, Valentino F, Monsurrò MR, Tedeschi G, Marinou K, Sabatelli M, Conte A, Mandrioli J, Sola P, Salvi F, Bartolomei I, Siciliano G, Carlesi C, Orrell RW, Talbot K, Simmons Z, Connor J, Pioro EP, Dunkley T, Stephan DA, Kasperaviciute D, Fisher EM, Jabonka S, Sendtner M, Beck M, Bruijn L, Rothstein J, Schmidt S, Singleton A, Hardy J, and Traynor BJ
- Subjects
- Case-Control Studies, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Amyotrophic Lateral Sclerosis genetics
- Abstract
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
- Published
- 2009
- Full Text
- View/download PDF
7. A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20.
- Author
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Knight MA, Hernandez D, Diede SJ, Dauwerse HG, Rafferty I, van de Leemput J, Forrest SM, Gardner RJ, Storey E, van Ommen GJ, Tapscott SJ, Fischbeck KH, and Singleton AB
- Subjects
- Chromosome Mapping, Female, Genetic Linkage, Humans, Male, Multigene Family genetics, Oligonucleotide Array Sequence Analysis, Pedigree, Polymorphism, Single Nucleotide, Reverse Transcriptase Polymerase Chain Reaction, Chromosomes, Human, Pair 11 genetics, Gene Duplication, Spinocerebellar Ataxias classification, Spinocerebellar Ataxias genetics
- Abstract
Spinocerebellar ataxia type 20 (SCA20) has been linked to chromosome 11q12, but the underlying genetic defect has yet to be identified. We applied single-nucleotide polymorphism genotyping to detect structural alterations in the genomic DNA of patients with SCA20. We found a 260 kb duplication within the previously linked SCA20 region, which was confirmed by quantitative polymerase chain reaction and fiber fluorescence in situ hybridization, the latter also showing its direct orientation. The duplication spans 10 known and 2 unknown genes, and is present in all affected individuals in the single reported SCA20 pedigree. While the mechanism whereby this duplication may be pathogenic remains to be established, we speculate that the critical gene within the duplicated segment may be DAGLA, the product of which is normally present at the base of Purkinje cell dendritic spines and contributes to the modulation of parallel fiber-Purkinje cell synapses.
- Published
- 2008
- Full Text
- View/download PDF
8. A genome-wide association study identifies protein quantitative trait loci (pQTLs).
- Author
-
Melzer D, Perry JR, Hernandez D, Corsi AM, Stevens K, Rafferty I, Lauretani F, Murray A, Gibbs JR, Paolisso G, Rafiq S, Simon-Sanchez J, Lango H, Scholz S, Weedon MN, Arepalli S, Rice N, Washecka N, Hurst A, Britton A, Henley W, van de Leemput J, Li R, Newman AB, Tranah G, Harris T, Panicker V, Dayan C, Bennett A, McCarthy MI, Ruokonen A, Jarvelin MR, Guralnik J, Bandinelli S, Frayling TM, Singleton A, and Ferrucci L
- Subjects
- Adult, Aged, Aged, 80 and over, Blood Proteins metabolism, Female, Gene Dosage, Genetic Linkage, Genetic Variation, Genotype, Humans, Male, Middle Aged, Transcription, Genetic, Blood Proteins genetics, Genome, Human, Polymorphism, Single Nucleotide, Quantitative Trait Loci
- Abstract
There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2008
- Full Text
- View/download PDF
9. Genotype, haplotype and copy-number variation in worldwide human populations.
- Author
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Jakobsson M, Scholz SW, Scheet P, Gibbs JR, VanLiere JM, Fung HC, Szpiech ZA, Degnan JH, Wang K, Guerreiro R, Bras JM, Schymick JC, Hernandez DG, Traynor BJ, Simon-Sanchez J, Matarin M, Britton A, van de Leemput J, Rafferty I, Bucan M, Cann HM, Hardy JA, Rosenberg NA, and Singleton AB
- Subjects
- Africa, Alleles, Chromosomes, Human, Pair 2 genetics, Genetics, Population, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide genetics, Gene Dosage genetics, Genetic Variation genetics, Genome, Human genetics, Geography, Haplotypes genetics
- Abstract
Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected--including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas--the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations.
- Published
- 2008
- Full Text
- View/download PDF
10. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.
- Author
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van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR, Houlden H, Gwinn-Hardy K, Fung HC, Lin X, Hernandez D, Simon-Sanchez J, Wood NW, Giunti P, Rafferty I, Hardy J, Storey E, Gardner RJ, Forrest SM, Fisher EM, Russell JT, Cai H, and Singleton AB
- Subjects
- Animals, Base Sequence, Cell Line, Transformed, Female, Humans, Inositol 1,4,5-Trisphosphate Receptors deficiency, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Inositol 1,4,5-Trisphosphate Receptors genetics, Sequence Deletion, Spinocerebellar Ataxias genetics
- Abstract
We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Delta18/Delta18)), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5' part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies SCA15 in humans., Competing Interests: Competing interests. The authors have declared that no competing interests exist.
- Published
- 2007
- Full Text
- View/download PDF
11. Management of heparin allergy during pregnancy with danaparoid.
- Author
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Harrison SJ, Rafferty I, and McColl MD
- Subjects
- Adult, Cesarean Section, Chondroitin Sulfates administration & dosage, Chondroitin Sulfates analysis, Dermatan Sulfate administration & dosage, Dermatan Sulfate analysis, Drug Combinations, Enoxaparin therapeutic use, Factor V genetics, Factor Xa Inhibitors, Female, Gestational Age, Heparitin Sulfate administration & dosage, Heparitin Sulfate analysis, Heterozygote, Humans, Injections, Subcutaneous, Milk, Human chemistry, Mutation, Pregnancy, Chondroitin Sulfates therapeutic use, Dermatan Sulfate therapeutic use, Drug Hypersensitivity, Enoxaparin adverse effects, Heparitin Sulfate therapeutic use, Venous Thrombosis drug therapy
- Abstract
We report a patient who presented with a left proximal deep vein thrombosis at 25 + 5 weeks gestation. She developed a severe urticarial rash 3 weeks following initiation of therapy with Enoxaparin. The patient was heterozygous for the factor V Leiden mutation. She was treated with subcutaneous twice-daily danaparoid (Orgaran) for the remainder of the pregnancy, achieving anti-Xa levels in the therapeutic range 0.5-1.0 IU/ml. Delivery was at term by caesarean section 2 days after spontaneous rupture of membranes and failure to progress in labour. Danaparoid was withheld during this time. Danaparoid was restarted 3 h post delivery and the patient anticoagulated with warfarin in the post-partum period. There was no recurrence of thrombosis or bleeding events during therapy with danaparoid. No anti-Xa activity was demonstrated in breast milk.
- Published
- 2001
- Full Text
- View/download PDF
12. Factor V Leiden, prothrombin 20210G-->A and the MTHFR C677T mutations in childhood stroke.
- Author
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McColl MD, Chalmers EA, Thomas A, Sproul A, Healey C, Rafferty I, McWilliam R, and Eunson P
- Subjects
- Age Factors, Cerebrovascular Disorders physiopathology, Child, Child, Preschool, Humans, Infant, Risk Factors, Cerebrovascular Disorders genetics, Factor V genetics, Mutation, Prothrombin genetics
- Abstract
Ischaemic stroke is a rare occurrence in children and in a proportion of cases the aetiology remains unknown. We have investigated the role of thrombophilia in the aetiology of this condition. Of 50 cases identified at two centres, 37 were available for detailed haematological analysis. No cases were identified with deficiencies of antithrombin, protein C or protein S. One case had elevated IgG anticardiolipin antibodies at low titre. The prevalence of the prothrombin 20210 G-->A mutation, factor V Leiden (FVL) mutation and the C677T mutation in the MTHFR gene was compared in cases to that observed in random unselected cord blood controls. The odds ratio for stroke was not significantly increased in carriers of the prothrombin mutation (OR 1.2; 95% CI 0.1-10.7), FVL (OR 2.5; 95% CI 0.5-13.5), or the C677T mutation (OR 1.7; 95% CI 0.6-4.5). Our findings suggest that thrombophilia may not play a significant role in the aetiology of stroke in children, although a large prospective study is required to investigate this area further.
- Published
- 1999
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