Penny Lympany - Academia.edu (original) (raw)

Papers by Penny Lympany

Research paper thumbnail of Chemokine gene polymorphisms in idiopathic anterior uveitis

Cytokine, 2006

The aim of this study was to determine whether there are any associations between single nucleoti... more The aim of this study was to determine whether there are any associations between single nucleotide polymorphisms of the chemokine genes IL-8, MCP-1, their corresponding receptors CXCR1 and CCR2 and disease outcome in patients with acute idiopathic anterior uveitis. 60 Caucasian patients with idiopathic acute recurrent anterior uveitis together with 120 healthy Caucasian control subjects were tested for the presence of 16 bi-allelic polymorphisms and HLA-B27 using polymerase chain reaction in association with sequence-specific primers with mismatches at the 3' end. The genetic data was then compared between patients and controls, and within the patient group itself for association with clinical disease outcome. As expected, the frequency of HLA-B27 was significantly higher in the patient group than the control group (63.33% versus 15.83%; Pearson's P<0.0001, Fisher's P<0.0001). In addition, the frequency of the T allele of MCP-1 63555 was found to be significantly higher in the control group when compared to the patient group (P=0.0160). This study describes an association between acute anterior uveitis and MCP-1 63555 polymorphisms where the T allele may be a protective marker against the disease.

Research paper thumbnail of Human Leukocyte Antigen-DRB1 Position 11 Residues Are a Common Protective Marker for Sarcoidosis

American Journal of Respiratory Cell and Molecular Biology, 2001

Genetic factors, in particular human leukocyte antigens (HLAs) are important determinants of susc... more Genetic factors, in particular human leukocyte antigens (HLAs) are important determinants of susceptibility to sarcoidosis, a chronic granulomatous disease of undetermined etiology. To clarify the role of HLA in sarcoidosis we determined HLA-DR and -DQ alleles in case-control samples from three European populations (United Kingdom, Czech, and Polish) and compared these results with those published for three additional populations (Italian, Japanese, and Scandinavian) to determine whether the HLA-DR and/or -DQ alleles act as ethnic-dependent, or ethnic-independent modifiers of disease risk. Although variations were apparent in the alleles associated with susceptibility, reductions in the frequency of alleles associated with protection were remarkably consistent in the six populations. Previously detected associations between single-nucleotide polymorphisms at the TAP2 locus and sarcoidosis were shown to be due to linkage disequilibrium with the HLA-DR locus. The protective HLA-DR alleles, which encode the DR1 and DR4 antigens, were found to share characteristic small hydrophobic residues at position 11, which were replaced by small hydrophilic residues in the remaining, nonprotective, HLA-DR alleles. This residue position is within a pocket of the HLA-DR complex antigen binding groove (designated P6), where it is the only variable amino acid and therefore determines the peptide binding preferences of this pocket. A highly significant reduction in the frequency of individuals carrying HLA-DR alleles with a hydrophobic residue at position 11 was observed in the sarcoidosis cases in the three populations we examined. This suggests this HLA-DR residue is an important protective marker in sarcoidosis.

Research paper thumbnail of The TGF-beta1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes

Diabetic Med, 2005

We hypothesize that transforming growth factor-beta (TGF-beta), a multifunctional growth factor w... more We hypothesize that transforming growth factor-beta (TGF-beta), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of diabetic nephropathy. Our aim was to examine three polymorphisms within the TGF-beta 1 gene, in codons 10, 25 and 263, for association with nephropathy in Type 1 diabetes. We conducted a large case-control study using cases with Type 1 diabetes and clinical nephropathy. Controls were Type 1 diabetic subjects who have been injecting insulin for at least 50 years and have extremely low risk of nephropathy. Genotyping was by polymerase chain reaction with sequence-specific primers. There was a significant difference in the frequency of the TGF-beta 1 codon 10 genotypes in the diabetic nephropathy group (n = 420) when compared with the controls (n = 410, P = 0.007). There were no significant differences when the frequencies of the TGF-beta1 codons 25 and 263 genotypes in the diabetic nephropathy group were compared with the control group. In our study the TGF-beta 1 codon 10 polymorphism is associated with nephropathy in Type 1 diabetes and variation in this gene may contribute to the genetic predisposition to this complication in Type 1 diabetes.

Research paper thumbnail of Polymorphisms of chemokine and chemokine receptor genes in idiopathic immune-mediated posterior segment uveitis

Mol Vis 13 388 396, Feb 1, 2007

Research paper thumbnail of TGF beta 1, TGF beta 2, TGF beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin induced lung fibrosis

American Journal Of Pathology

Transforming growth factor (TGF)-beta 1 may potentiate wound healing and fibrosis by stimulating ... more Transforming growth factor (TGF)-beta 1 may potentiate wound healing and fibrosis by stimulating fibroblast collagen deposition. TGF-beta 1 is implicated in the pathogenesis of pulmonary fibrosis, but the role of TGF-beta 2 and TGF-beta 3 remains unclear. We examined their effects on lung fibroblast procollagen metabolism in vitro and localized their gene expression during bleomycin-induced lung fibrosis using in situ hybridization with digoxigenin-labeled riboprobes. All three isoforms stimulated fibroblast procollagen production. TGF-beta 3 was the most potent and also reduced procollagen degradation. In normal mouse lung, TGF-beta 1 and TGF-beta 3 mRNA transcripts were abundant in bronchiolar epithelium. After bleomycin, TGF-beta 1 gene expression was maximally enhanced at 10 days, with the signal being predominant in macrophages. Signal was also enhanced in mesenchymal, pulmonary endothelial, and mesothelial cells. After 35 days, the pattern of TGF-beta 1 gene expression returne...

Research paper thumbnail of Genetic and environmental risk factors in beryllium sensitization and chronic beryllium disease

Research paper thumbnail of Transforming growth factor-beta1 polymorphisms in Korean patients with systemic sclerosis

Tissue Antigens, 2004

Transforming growth factor-b1 (TGF-b1) plays an important role in the pathogenesis of systemic sc... more Transforming growth factor-b1 (TGF-b1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate the role of TGF-b1 gene polymorphisms in SSc, we genotyped six biallelic polymorphic positions (position À988, À800, and À509; and codons 10, 25, and 263) in 61 Korean SSc patients and in 148 healthy controls, using polymerase chain reaction-sequence-specific primers. Genetic polymorphisms were found at position À509 and codon 10 in Koreans. The allele frequencies of C/T at position À509 were 0.59/0.41 in patients and 0.56/0.44 in controls. The allele frequencies of C/T at codon 10 were 0.40/0.60 in patients and 0.50/0.50 in controls. In conclusion, no skewed distribution of TGF-b1 gene polymorphisms was found in Korean patients with SSc.

Research paper thumbnail of Polymorphic analysis of the high-affinity tumor necrosis factor receptor 2

Tissue Antigens, 1999

The tumor necrosis factor receptor 2 (TNF-RII, CD120b, TNF-R p75/80) gene has recently been chara... more The tumor necrosis factor receptor 2 (TNF-RII, CD120b, TNF-R p75/80) gene has recently been characterised. It is located on chromosome 1p362 and consists of 10 exons and 9 introns A number of biallelic polymorphisms have been found in exons 4, 6, 9 and 10 based on differences between published sequences. In this study we have used polymerase chain reaction methodology in association with sequence-specific primers (PCR-SSP) incorporating mismatches at the 3' end to identify these polymorphisms. We were able to confirm the presence of a single biallelic polymorphism in exon 6 corresponding to a (T/G) at nucleotide 676 of TNF-RII mRNA (gb:M32315) which results in an amino acid change and three biallelic polymorphisms in exon 10 (in the3'UTR) corresponding to (A/G) at nucleotide 1663, (T/G) at nucleotide 1668 and a (C/T) at nucleotide 1690 of gb:M32315, whereas no polymorphisms were observed in exons 4 and 9. Here we report that in 192 unrelated UK Caucasian individuals the allele frequencies determined by direct counting were: 676-T (0.77), 1663-G (0.51), 1668-T (0.95), and 1690-T (0.64) and the calculated gene frequencies were; 676-T (0.52), 676-G (0.12); 1663-G (0.30), 1663-A (0.28); 1668-T (0.77), 1668-G (0.025); and 1690-T (0.40), 1690-C (0.20). Furthermore, the presence of an A allele at nucleotide position 1663 was found to be strongly associated with the presence of a C allele at nucleotide position 1690 and a G allele at nucleotide position 1668 whereas the presence of a G allele at position 1663 was associated with the absence of a C allele at nucleotide position 1690.

Research paper thumbnail of Rapid genotyping of transforming growth factor β 1 gene polymorphisms in a UK Caucasoid control population using the polymerase chain reaction and sequence-specific primers

Tissue Antigens, 1998

Transforming growth factor (TGF) PI is a growth factor which

Research paper thumbnail of The CR1 C5507G polymorphism is not involved in susceptibility to idiopathic pulmonary fibrosis in two European populations

Tissue Antigens, 2008

Idiopathic pulmonary fibrosis (IPF), a severe lung disease with unknown aetiology, is thought to ... more Idiopathic pulmonary fibrosis (IPF), a severe lung disease with unknown aetiology, is thought to have an important genetic component. Single nucleotide polymorphism, C5507G, of the complement receptor 1 (CR1) gene, which affects the number of CR1 molecules on erythrocytes, has been associated with susceptibility to IPF in a single European population. To replicate this finding, 53 Czech IPF patients with 203 Czech healthy control subjects and 70 English IPF patients with 149 English controls were investigated. In both populations, there were no significant differences in distribution of CR1 C5507G variants between IPF patients and their appropriate control groups. In conclusion, the association of the CR1 C5507G polymorphism with susceptibility to IPF was not reproducible in Czech and English populations.

Research paper thumbnail of Influence of MHC CLASS II in Susceptibility to Beryllium Sensitization and Chronic Beryllium Disease

The Journal of Immunology, 2003

A glutamic acid at residue 69(Glu 69 ) in the HLA-DPB1 gene (Glu 69 ) is associated with chronic ... more A glutamic acid at residue 69(Glu 69 ) in the HLA-DPB1 gene (Glu 69 ) is associated with chronic beryllium disease (CBD) and possibly beryllium sensitization (BeS). This study tested the hypothesis that MHC class II polymorphisms are important in susceptibility to BeS and CBD and that the Glu 69 variant is related to markers of disease severity. Genomic DNA was obtained from BeS (n ‫؍‬ 50), CBD (n ‫؍‬ 104), and beryllium-exposed nondiseased (Be-nondiseased) (n ‫؍‬ 125) subjects. HLA-DPB1, -DRB1, and -DQB1 genotypes were determined by (sequence-specific primers) PCR. Disease severity was assessed by pulmonary function and exercise testing. A higher frequency of the DPB1 Glu 69 gene was found in CBD and BeS compared with the Be-nondiseased subjects, with odds ratios of 10.1 for CBD vs Be-nondiseased and 9.5 for BeS vs Be-nondiseased. The majority of BeS and CBD subjects displayed non-0201 Glu 69 alleles. Glu 69 homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRB1*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRB1*13 and DQB1*06 were associated with CBD in the absence of Glu 69 . Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO 2 at rest, maximum workload on exercise testing, and a higher arterialalveolar gradient at rest, were associated with Glu 69 homozygosity. We conclude that DPB1 Glu69 is a marker of sensitization and not specific for disease. Glu 69 homozygosity acts as a functional marker associated with markers of CBD severity.

Research paper thumbnail of An HLA-associated nonresponsiveness to melittin: A components of bee venom+

Journal of Allergy and Clinical Immunology, 1990

Previous work has demonstrated a close association between certain histocompatibility antigens an... more Previous work has demonstrated a close association between certain histocompatibility antigens and the gene that controls the IgE response to certain ragweed allergens. For example, there is a 90% association between lgE production to the short ragweed allergen, Amb a V, and an HLA class ii allele. To assess whether these HLA linkages are specific for ragweed, we have investigated the association between HLA antigens and the capacity of individuals to mount a specific IgE response to melittin in patients with bee-venom allergy. Twenty-two subjects with bee-venom sensitivity, 22 healthy beekeepers without bee-venom allergy, and a normal population of 149 unselected individuals were studied. With serologic tissue typing and restriction fragment length polymorphism analysis, we have demonstrated a significant decrease in the HLA-DR4 and DQw3 alleles in subjects who are allergic to melittin compared to the control populations. There was also a negative association between the presence of HLA-DR4 and DQw3 alleles with the capacity of the individuals to mount an IgE response to phospholipase A2 (PLA2). The bee-venom sensitive subjects had a slightly lower titer of anti-PLA2 lgG when these subjects were compared to the bee-venom insensitive beekeepers. These results support the view that either HLA-DR or HLA-DQ has a protective role in controlling the lgE immune response. Lack of an lgE response to melittin or PLA, is unlikely to be due to a failure to recognize allergen. (J ALLERGY CLIN IMMUNOL 1990;86:160-70.)

Research paper thumbnail of An analysis with sequence-specific oligonucleotide probes of the association between aspirin-induced asthma and antigens of the HLA system

Journal of Allergy and Clinical Immunology, 1993

Background: Previous work has suggested that in addition to environmental influences, there is a ... more Background: Previous work has suggested that in addition to environmental influences, there is a genetic predisposition for the development of both asthma and atopy. A subset of asthmatic subjects who are intolerant to aspirin has been identified. A previous study has suggested that there is an association between aspirin sensitivity and HLA-DQw2.

Research paper thumbnail of Genetic analysis using DNA polymorphism of the linkage between chromosome 11q13 and atopy and bronchial hyperresponsiveness to methacholine

Journal of Allergy and Clinical Immunology, 1992

Previous studies have suggested that there is a genetic predisposition for the development of ast... more Previous studies have suggested that there is a genetic predisposition for the development of asthma and atopy. A recent study has also demonstrated that there is a striking link between chromosome I Iq and the IgE response underlying asthma and rhinitis. To assess the linkage between chromosome I1 q (region DI 1 S97) and atopy or bronchial hyperresporasiveness (BH ), we have studied nine families of two and, in many instances, three generations with the index case having asthma andlor atopy. With variable number of tandem repeat analysis with the probe, ph-MS.51, we have been unable to confirm a significant link between region DI IS97 of chromosome Ilq and either atopy or BH to methacholine. We have demonstrated that atopy and BH produce similar log of odds scores with linkage analysis at each recombination fraction from 0.001 to 0.5 with both Hinfl and Tag1 restriction digests and that the use of either a positive skin prick test or positive RAST as a definition of atopy does not significantly alter the log of odds score. (J ALLERGY CLIN IMMJNOL 1992;89:619-28.)

Research paper thumbnail of HLA-DPB POLYMORPHISMS: Glu 69 ASSOCIATION WITH SARCOIDOSIS

International Journal of Immunogenetics, 1996

Research paper thumbnail of Inhibitor kappa B-alpha (IκB-α) promoter polymorphisms in UK and Dutch sarcoidosis

Genes and Immunity, 2003

... For the identification of the polymorphism at position -826, we used the sequence-specific fo... more ... For the identification of the polymorphism at position -826, we used the sequence-specific forward primers 5'-TT ATG AAC ACA ATA GCT ACT CTG C and 5'-CTT ATG AAC ACA ATA GCT ACT CTG T and in haplotype combination with position -297 primers at a final ...

Research paper thumbnail of The source and role of RANTES in interstitial lung disease

European Respiratory Journal, 1997

The chemokine "regulated on activation, normal T-cell expressed and secreted" (RANTES) is a poten... more The chemokine "regulated on activation, normal T-cell expressed and secreted" (RANTES) is a potent eosinophil and lymphocyte attractant with particular preference for CD45RO+ T-cells and eosinophils. These cells accumulate in the lungs of patients with sarcoidosis and fibrosing alveolitis. The purpose of this study was to determine whether RANTES mediates the inflammatory cell influx in these diffuse lung diseases.

Research paper thumbnail of Mannose-binding lectin promoter and structural gene variants in sarcoidosis

European Journal of Clinical Investigation, 2000

Sarcoidosis is a chronic granulomatous disease of unknown aetiology. Studies have suggested that ... more Sarcoidosis is a chronic granulomatous disease of unknown aetiology. Studies have suggested that the causative agent may be an infectious micro-organism. The mannose binding lectin (MBL) is involved in innate immunity to a wide range of micro-organisms. Mutations in the promoter region and exon 1 of the MBL gene occur with high frequency and are associated with reduced serum levels of MBL and increased susceptibility to microbial diseases. This study investigated whether MBL variants predispose to sarcoidosis by increasing their susceptibility to micro-organisms. MBL gene promoter and exon 1 variants were detected by sequence specific primer polymerase chain reaction (SSP-PCR) in 167 UK Caucasian sarcoidosis patients and 164 control subjects. Severity of pulmonary disease outcome among patients was assessed by radiography after a minimum of 4 years from disease onset and classified as mild, moderate, and severe disease categories, accordingly. MBL variant frequencies were similar in patients and controls studied. Among sarcoidosis patients, the frequencies of variants were similar regardless of severity of disease outcome. The average patient ages at time of diagnosis were similar for all MBL genotypes. MBL gene variants do not appear to influence susceptibility to sarcoidosis, age of disease onset, or severity of disease.

Research paper thumbnail of The TGF-beta1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes

Diabetic Medicine, 2005

We hypothesize that transforming growth factor-beta (TGF-β), a multifunctional growth factor whic... more We hypothesize that transforming growth factor-beta (TGF-β), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of diabetic nephropathy. Our aim was to examine three polymorphisms within the TGF-β1 gene, in codons 10, 25 and 263, for association with nephropathy in Type 1 diabetes.

Research paper thumbnail of Chemokine gene polymorphisms in idiopathic anterior uveitis

Cytokine, 2006

The aim of this study was to determine whether there are any associations between single nucleoti... more The aim of this study was to determine whether there are any associations between single nucleotide polymorphisms of the chemokine genes IL-8, MCP-1, their corresponding receptors CXCR1 and CCR2 and disease outcome in patients with acute idiopathic anterior uveitis. 60 Caucasian patients with idiopathic acute recurrent anterior uveitis together with 120 healthy Caucasian control subjects were tested for the presence of 16 bi-allelic polymorphisms and HLA-B27 using polymerase chain reaction in association with sequence-specific primers with mismatches at the 3' end. The genetic data was then compared between patients and controls, and within the patient group itself for association with clinical disease outcome. As expected, the frequency of HLA-B27 was significantly higher in the patient group than the control group (63.33% versus 15.83%; Pearson's P<0.0001, Fisher's P<0.0001). In addition, the frequency of the T allele of MCP-1 63555 was found to be significantly higher in the control group when compared to the patient group (P=0.0160). This study describes an association between acute anterior uveitis and MCP-1 63555 polymorphisms where the T allele may be a protective marker against the disease.

Research paper thumbnail of Chemokine gene polymorphisms in idiopathic anterior uveitis

Cytokine, 2006

The aim of this study was to determine whether there are any associations between single nucleoti... more The aim of this study was to determine whether there are any associations between single nucleotide polymorphisms of the chemokine genes IL-8, MCP-1, their corresponding receptors CXCR1 and CCR2 and disease outcome in patients with acute idiopathic anterior uveitis. 60 Caucasian patients with idiopathic acute recurrent anterior uveitis together with 120 healthy Caucasian control subjects were tested for the presence of 16 bi-allelic polymorphisms and HLA-B27 using polymerase chain reaction in association with sequence-specific primers with mismatches at the 3' end. The genetic data was then compared between patients and controls, and within the patient group itself for association with clinical disease outcome. As expected, the frequency of HLA-B27 was significantly higher in the patient group than the control group (63.33% versus 15.83%; Pearson's P<0.0001, Fisher's P<0.0001). In addition, the frequency of the T allele of MCP-1 63555 was found to be significantly higher in the control group when compared to the patient group (P=0.0160). This study describes an association between acute anterior uveitis and MCP-1 63555 polymorphisms where the T allele may be a protective marker against the disease.

Research paper thumbnail of Human Leukocyte Antigen-DRB1 Position 11 Residues Are a Common Protective Marker for Sarcoidosis

American Journal of Respiratory Cell and Molecular Biology, 2001

Genetic factors, in particular human leukocyte antigens (HLAs) are important determinants of susc... more Genetic factors, in particular human leukocyte antigens (HLAs) are important determinants of susceptibility to sarcoidosis, a chronic granulomatous disease of undetermined etiology. To clarify the role of HLA in sarcoidosis we determined HLA-DR and -DQ alleles in case-control samples from three European populations (United Kingdom, Czech, and Polish) and compared these results with those published for three additional populations (Italian, Japanese, and Scandinavian) to determine whether the HLA-DR and/or -DQ alleles act as ethnic-dependent, or ethnic-independent modifiers of disease risk. Although variations were apparent in the alleles associated with susceptibility, reductions in the frequency of alleles associated with protection were remarkably consistent in the six populations. Previously detected associations between single-nucleotide polymorphisms at the TAP2 locus and sarcoidosis were shown to be due to linkage disequilibrium with the HLA-DR locus. The protective HLA-DR alleles, which encode the DR1 and DR4 antigens, were found to share characteristic small hydrophobic residues at position 11, which were replaced by small hydrophilic residues in the remaining, nonprotective, HLA-DR alleles. This residue position is within a pocket of the HLA-DR complex antigen binding groove (designated P6), where it is the only variable amino acid and therefore determines the peptide binding preferences of this pocket. A highly significant reduction in the frequency of individuals carrying HLA-DR alleles with a hydrophobic residue at position 11 was observed in the sarcoidosis cases in the three populations we examined. This suggests this HLA-DR residue is an important protective marker in sarcoidosis.

Research paper thumbnail of The TGF-beta1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes

Diabetic Med, 2005

We hypothesize that transforming growth factor-beta (TGF-beta), a multifunctional growth factor w... more We hypothesize that transforming growth factor-beta (TGF-beta), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of diabetic nephropathy. Our aim was to examine three polymorphisms within the TGF-beta 1 gene, in codons 10, 25 and 263, for association with nephropathy in Type 1 diabetes. We conducted a large case-control study using cases with Type 1 diabetes and clinical nephropathy. Controls were Type 1 diabetic subjects who have been injecting insulin for at least 50 years and have extremely low risk of nephropathy. Genotyping was by polymerase chain reaction with sequence-specific primers. There was a significant difference in the frequency of the TGF-beta 1 codon 10 genotypes in the diabetic nephropathy group (n = 420) when compared with the controls (n = 410, P = 0.007). There were no significant differences when the frequencies of the TGF-beta1 codons 25 and 263 genotypes in the diabetic nephropathy group were compared with the control group. In our study the TGF-beta 1 codon 10 polymorphism is associated with nephropathy in Type 1 diabetes and variation in this gene may contribute to the genetic predisposition to this complication in Type 1 diabetes.

Research paper thumbnail of Polymorphisms of chemokine and chemokine receptor genes in idiopathic immune-mediated posterior segment uveitis

Mol Vis 13 388 396, Feb 1, 2007

Research paper thumbnail of TGF beta 1, TGF beta 2, TGF beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin induced lung fibrosis

American Journal Of Pathology

Transforming growth factor (TGF)-beta 1 may potentiate wound healing and fibrosis by stimulating ... more Transforming growth factor (TGF)-beta 1 may potentiate wound healing and fibrosis by stimulating fibroblast collagen deposition. TGF-beta 1 is implicated in the pathogenesis of pulmonary fibrosis, but the role of TGF-beta 2 and TGF-beta 3 remains unclear. We examined their effects on lung fibroblast procollagen metabolism in vitro and localized their gene expression during bleomycin-induced lung fibrosis using in situ hybridization with digoxigenin-labeled riboprobes. All three isoforms stimulated fibroblast procollagen production. TGF-beta 3 was the most potent and also reduced procollagen degradation. In normal mouse lung, TGF-beta 1 and TGF-beta 3 mRNA transcripts were abundant in bronchiolar epithelium. After bleomycin, TGF-beta 1 gene expression was maximally enhanced at 10 days, with the signal being predominant in macrophages. Signal was also enhanced in mesenchymal, pulmonary endothelial, and mesothelial cells. After 35 days, the pattern of TGF-beta 1 gene expression returne...

Research paper thumbnail of Genetic and environmental risk factors in beryllium sensitization and chronic beryllium disease

Research paper thumbnail of Transforming growth factor-beta1 polymorphisms in Korean patients with systemic sclerosis

Tissue Antigens, 2004

Transforming growth factor-b1 (TGF-b1) plays an important role in the pathogenesis of systemic sc... more Transforming growth factor-b1 (TGF-b1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate the role of TGF-b1 gene polymorphisms in SSc, we genotyped six biallelic polymorphic positions (position À988, À800, and À509; and codons 10, 25, and 263) in 61 Korean SSc patients and in 148 healthy controls, using polymerase chain reaction-sequence-specific primers. Genetic polymorphisms were found at position À509 and codon 10 in Koreans. The allele frequencies of C/T at position À509 were 0.59/0.41 in patients and 0.56/0.44 in controls. The allele frequencies of C/T at codon 10 were 0.40/0.60 in patients and 0.50/0.50 in controls. In conclusion, no skewed distribution of TGF-b1 gene polymorphisms was found in Korean patients with SSc.

Research paper thumbnail of Polymorphic analysis of the high-affinity tumor necrosis factor receptor 2

Tissue Antigens, 1999

The tumor necrosis factor receptor 2 (TNF-RII, CD120b, TNF-R p75/80) gene has recently been chara... more The tumor necrosis factor receptor 2 (TNF-RII, CD120b, TNF-R p75/80) gene has recently been characterised. It is located on chromosome 1p362 and consists of 10 exons and 9 introns A number of biallelic polymorphisms have been found in exons 4, 6, 9 and 10 based on differences between published sequences. In this study we have used polymerase chain reaction methodology in association with sequence-specific primers (PCR-SSP) incorporating mismatches at the 3' end to identify these polymorphisms. We were able to confirm the presence of a single biallelic polymorphism in exon 6 corresponding to a (T/G) at nucleotide 676 of TNF-RII mRNA (gb:M32315) which results in an amino acid change and three biallelic polymorphisms in exon 10 (in the3'UTR) corresponding to (A/G) at nucleotide 1663, (T/G) at nucleotide 1668 and a (C/T) at nucleotide 1690 of gb:M32315, whereas no polymorphisms were observed in exons 4 and 9. Here we report that in 192 unrelated UK Caucasian individuals the allele frequencies determined by direct counting were: 676-T (0.77), 1663-G (0.51), 1668-T (0.95), and 1690-T (0.64) and the calculated gene frequencies were; 676-T (0.52), 676-G (0.12); 1663-G (0.30), 1663-A (0.28); 1668-T (0.77), 1668-G (0.025); and 1690-T (0.40), 1690-C (0.20). Furthermore, the presence of an A allele at nucleotide position 1663 was found to be strongly associated with the presence of a C allele at nucleotide position 1690 and a G allele at nucleotide position 1668 whereas the presence of a G allele at position 1663 was associated with the absence of a C allele at nucleotide position 1690.

Research paper thumbnail of Rapid genotyping of transforming growth factor β 1 gene polymorphisms in a UK Caucasoid control population using the polymerase chain reaction and sequence-specific primers

Tissue Antigens, 1998

Transforming growth factor (TGF) PI is a growth factor which

Research paper thumbnail of The CR1 C5507G polymorphism is not involved in susceptibility to idiopathic pulmonary fibrosis in two European populations

Tissue Antigens, 2008

Idiopathic pulmonary fibrosis (IPF), a severe lung disease with unknown aetiology, is thought to ... more Idiopathic pulmonary fibrosis (IPF), a severe lung disease with unknown aetiology, is thought to have an important genetic component. Single nucleotide polymorphism, C5507G, of the complement receptor 1 (CR1) gene, which affects the number of CR1 molecules on erythrocytes, has been associated with susceptibility to IPF in a single European population. To replicate this finding, 53 Czech IPF patients with 203 Czech healthy control subjects and 70 English IPF patients with 149 English controls were investigated. In both populations, there were no significant differences in distribution of CR1 C5507G variants between IPF patients and their appropriate control groups. In conclusion, the association of the CR1 C5507G polymorphism with susceptibility to IPF was not reproducible in Czech and English populations.

Research paper thumbnail of Influence of MHC CLASS II in Susceptibility to Beryllium Sensitization and Chronic Beryllium Disease

The Journal of Immunology, 2003

A glutamic acid at residue 69(Glu 69 ) in the HLA-DPB1 gene (Glu 69 ) is associated with chronic ... more A glutamic acid at residue 69(Glu 69 ) in the HLA-DPB1 gene (Glu 69 ) is associated with chronic beryllium disease (CBD) and possibly beryllium sensitization (BeS). This study tested the hypothesis that MHC class II polymorphisms are important in susceptibility to BeS and CBD and that the Glu 69 variant is related to markers of disease severity. Genomic DNA was obtained from BeS (n ‫؍‬ 50), CBD (n ‫؍‬ 104), and beryllium-exposed nondiseased (Be-nondiseased) (n ‫؍‬ 125) subjects. HLA-DPB1, -DRB1, and -DQB1 genotypes were determined by (sequence-specific primers) PCR. Disease severity was assessed by pulmonary function and exercise testing. A higher frequency of the DPB1 Glu 69 gene was found in CBD and BeS compared with the Be-nondiseased subjects, with odds ratios of 10.1 for CBD vs Be-nondiseased and 9.5 for BeS vs Be-nondiseased. The majority of BeS and CBD subjects displayed non-0201 Glu 69 alleles. Glu 69 homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRB1*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRB1*13 and DQB1*06 were associated with CBD in the absence of Glu 69 . Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO 2 at rest, maximum workload on exercise testing, and a higher arterialalveolar gradient at rest, were associated with Glu 69 homozygosity. We conclude that DPB1 Glu69 is a marker of sensitization and not specific for disease. Glu 69 homozygosity acts as a functional marker associated with markers of CBD severity.

Research paper thumbnail of An HLA-associated nonresponsiveness to melittin: A components of bee venom+

Journal of Allergy and Clinical Immunology, 1990

Previous work has demonstrated a close association between certain histocompatibility antigens an... more Previous work has demonstrated a close association between certain histocompatibility antigens and the gene that controls the IgE response to certain ragweed allergens. For example, there is a 90% association between lgE production to the short ragweed allergen, Amb a V, and an HLA class ii allele. To assess whether these HLA linkages are specific for ragweed, we have investigated the association between HLA antigens and the capacity of individuals to mount a specific IgE response to melittin in patients with bee-venom allergy. Twenty-two subjects with bee-venom sensitivity, 22 healthy beekeepers without bee-venom allergy, and a normal population of 149 unselected individuals were studied. With serologic tissue typing and restriction fragment length polymorphism analysis, we have demonstrated a significant decrease in the HLA-DR4 and DQw3 alleles in subjects who are allergic to melittin compared to the control populations. There was also a negative association between the presence of HLA-DR4 and DQw3 alleles with the capacity of the individuals to mount an IgE response to phospholipase A2 (PLA2). The bee-venom sensitive subjects had a slightly lower titer of anti-PLA2 lgG when these subjects were compared to the bee-venom insensitive beekeepers. These results support the view that either HLA-DR or HLA-DQ has a protective role in controlling the lgE immune response. Lack of an lgE response to melittin or PLA, is unlikely to be due to a failure to recognize allergen. (J ALLERGY CLIN IMMUNOL 1990;86:160-70.)

Research paper thumbnail of An analysis with sequence-specific oligonucleotide probes of the association between aspirin-induced asthma and antigens of the HLA system

Journal of Allergy and Clinical Immunology, 1993

Background: Previous work has suggested that in addition to environmental influences, there is a ... more Background: Previous work has suggested that in addition to environmental influences, there is a genetic predisposition for the development of both asthma and atopy. A subset of asthmatic subjects who are intolerant to aspirin has been identified. A previous study has suggested that there is an association between aspirin sensitivity and HLA-DQw2.

Research paper thumbnail of Genetic analysis using DNA polymorphism of the linkage between chromosome 11q13 and atopy and bronchial hyperresponsiveness to methacholine

Journal of Allergy and Clinical Immunology, 1992

Previous studies have suggested that there is a genetic predisposition for the development of ast... more Previous studies have suggested that there is a genetic predisposition for the development of asthma and atopy. A recent study has also demonstrated that there is a striking link between chromosome I Iq and the IgE response underlying asthma and rhinitis. To assess the linkage between chromosome I1 q (region DI 1 S97) and atopy or bronchial hyperresporasiveness (BH ), we have studied nine families of two and, in many instances, three generations with the index case having asthma andlor atopy. With variable number of tandem repeat analysis with the probe, ph-MS.51, we have been unable to confirm a significant link between region DI IS97 of chromosome Ilq and either atopy or BH to methacholine. We have demonstrated that atopy and BH produce similar log of odds scores with linkage analysis at each recombination fraction from 0.001 to 0.5 with both Hinfl and Tag1 restriction digests and that the use of either a positive skin prick test or positive RAST as a definition of atopy does not significantly alter the log of odds score. (J ALLERGY CLIN IMMJNOL 1992;89:619-28.)

Research paper thumbnail of HLA-DPB POLYMORPHISMS: Glu 69 ASSOCIATION WITH SARCOIDOSIS

International Journal of Immunogenetics, 1996

Research paper thumbnail of Inhibitor kappa B-alpha (IκB-α) promoter polymorphisms in UK and Dutch sarcoidosis

Genes and Immunity, 2003

... For the identification of the polymorphism at position -826, we used the sequence-specific fo... more ... For the identification of the polymorphism at position -826, we used the sequence-specific forward primers 5'-TT ATG AAC ACA ATA GCT ACT CTG C and 5'-CTT ATG AAC ACA ATA GCT ACT CTG T and in haplotype combination with position -297 primers at a final ...

Research paper thumbnail of The source and role of RANTES in interstitial lung disease

European Respiratory Journal, 1997

The chemokine "regulated on activation, normal T-cell expressed and secreted" (RANTES) is a poten... more The chemokine "regulated on activation, normal T-cell expressed and secreted" (RANTES) is a potent eosinophil and lymphocyte attractant with particular preference for CD45RO+ T-cells and eosinophils. These cells accumulate in the lungs of patients with sarcoidosis and fibrosing alveolitis. The purpose of this study was to determine whether RANTES mediates the inflammatory cell influx in these diffuse lung diseases.

Research paper thumbnail of Mannose-binding lectin promoter and structural gene variants in sarcoidosis

European Journal of Clinical Investigation, 2000

Sarcoidosis is a chronic granulomatous disease of unknown aetiology. Studies have suggested that ... more Sarcoidosis is a chronic granulomatous disease of unknown aetiology. Studies have suggested that the causative agent may be an infectious micro-organism. The mannose binding lectin (MBL) is involved in innate immunity to a wide range of micro-organisms. Mutations in the promoter region and exon 1 of the MBL gene occur with high frequency and are associated with reduced serum levels of MBL and increased susceptibility to microbial diseases. This study investigated whether MBL variants predispose to sarcoidosis by increasing their susceptibility to micro-organisms. MBL gene promoter and exon 1 variants were detected by sequence specific primer polymerase chain reaction (SSP-PCR) in 167 UK Caucasian sarcoidosis patients and 164 control subjects. Severity of pulmonary disease outcome among patients was assessed by radiography after a minimum of 4 years from disease onset and classified as mild, moderate, and severe disease categories, accordingly. MBL variant frequencies were similar in patients and controls studied. Among sarcoidosis patients, the frequencies of variants were similar regardless of severity of disease outcome. The average patient ages at time of diagnosis were similar for all MBL genotypes. MBL gene variants do not appear to influence susceptibility to sarcoidosis, age of disease onset, or severity of disease.

Research paper thumbnail of The TGF-beta1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes

Diabetic Medicine, 2005

We hypothesize that transforming growth factor-beta (TGF-β), a multifunctional growth factor whic... more We hypothesize that transforming growth factor-beta (TGF-β), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of diabetic nephropathy. Our aim was to examine three polymorphisms within the TGF-β1 gene, in codons 10, 25 and 263, for association with nephropathy in Type 1 diabetes.

Research paper thumbnail of Chemokine gene polymorphisms in idiopathic anterior uveitis

Cytokine, 2006

The aim of this study was to determine whether there are any associations between single nucleoti... more The aim of this study was to determine whether there are any associations between single nucleotide polymorphisms of the chemokine genes IL-8, MCP-1, their corresponding receptors CXCR1 and CCR2 and disease outcome in patients with acute idiopathic anterior uveitis. 60 Caucasian patients with idiopathic acute recurrent anterior uveitis together with 120 healthy Caucasian control subjects were tested for the presence of 16 bi-allelic polymorphisms and HLA-B27 using polymerase chain reaction in association with sequence-specific primers with mismatches at the 3' end. The genetic data was then compared between patients and controls, and within the patient group itself for association with clinical disease outcome. As expected, the frequency of HLA-B27 was significantly higher in the patient group than the control group (63.33% versus 15.83%; Pearson's P<0.0001, Fisher's P<0.0001). In addition, the frequency of the T allele of MCP-1 63555 was found to be significantly higher in the control group when compared to the patient group (P=0.0160). This study describes an association between acute anterior uveitis and MCP-1 63555 polymorphisms where the T allele may be a protective marker against the disease.