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Biomedical subjects

Derek Middleton

Publications and source records attributed to Derek Middleton.

At least 19 recordsLinked to original sources
PubMed2005

HLA genes in Madeira Island (Portugal) inferred from sequence-based typing: footprints from different origins.

Human leukocyte antigen (HLA)-A, HLA-B, and HLA-DRB1 polymorphisms were examined in Madeira Island populations. The data was obtained at high-resolution level, using sequence-based typing (SBT). The most frequent alleles at each loci were: A*020101 (24.6%), B*5101 (9.7%), B*440201 (9.2%), and DRB1*070101 (15.7%). The predominant three-loci haplotypes in Madeira were A*020101-B*510101-DRB1*130101 (2.7%) and A*010101-B*0801-DRB1*030101 (2.4%), previously found in north and central Portugal. The present study corroborates historical sources and other genetic studies that say Madeira were populated not only by Europeans, mostly Portuguese, but also sub-Saharan Africans due to slave trade. Comparison with other populations shows that Madeira experienced a stronger African influence due to slave trade than Portugal mainland and even the Azores archipelago. Despite this African genetic input, haplotype and allele frequencies were predominantly from European origin, mostly common to mainland Portugal.

Gene Frequency↗
PubMed2005

Analysis of KIR ligand incompatibility in human renal transplantation.

Natural killer cells express killer immunoglobulin-like receptors (KIR) that bind to MHC class I antigens. Lack of self-MHC on the target cell can cause NK-cell mediated killing. Here, we analyzed the effect of KIR ligand incompatiblity on renal allograft survival in humans. Kidney recipient/donor pairs were separated according to their HLA-Cw alleles and HLA-Bw4 specificity which are considered epitopes for KIR. A total of 2,757 renal transplants were examined. Graft survival rates were computed according to the Kaplan-Meier method. No effect of KIR ligand matching on graft survival was observed in cadaver kidney transplants. Our results indicate that KIR ligand matching cannot be recommended as a strategy for improving renal allograft survival.

Graft Survival↗
PubMed2005

HLA polymorphisms in Cabo Verde and Guiné-Bissau inferred from sequence-based typing.

Human leukocyte antigen (HLA)-A, -B, and -DRB1 polymorphisms were examined in the Cabo Verde and Guiné-Bissau populations. The data were obtained at high-resolution level, using sequence-based typing. The most frequent alleles in each locus was: A*020101 (16.7% in Guiné-Bissau and 13.5% in Cabo Verde), B*350101 (14.4% in Guiné-Bissau and 13.2% in Cabo Verde), DRB1*1304 (19.6% in Guiné-Bissau), and DRB1*1101 (10.1% in Cabo Verde). The predominant three loci haplotype in Guiné-Bissau was A*2301-B*1503-DRB1*1101 (4.6%) and in Cabo Verde was A*3002-B*350101-DRB1*1001 (2.8%), exclusive to northwestern islands (5.6%) and absent in Guiné-Bissau. The present study corroborates historic sources and other genetic studies that say Cabo Verde were populated not only by Africans but also by Europeans. Haplotypes and dendrogram analysis shows a Caucasian genetic influence in today's gene pool of Cabo Verdeans. Haplotypes and allele frequencies present a differential distribution between southeastern and northwestern Cabo Verde islands, which could be the result of different genetic influences, founder effect, or bottlenecks. Dendrograms and principal coordinates analysis show that Guineans are more similar to North Africans than other HLA-studied sub-Saharans, probably from ancient and recent genetic contacts with other peoples, namely East Africans.

Alleles↗
PubMed2005

KIR genes.

This review updates the on-going investigations into KIR genes and their alleles with the main emphasis on what has taken place in this laboratory over the last 3 years.

Alleles↗
PubMed2005

The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated.

Killer-cell Ig-like receptors (KIR) are structurally and functionally diverse, and enable human NK cells to survey the expression of individual HLA class I molecules, often altered in infections and tumors. Multiple events of non-reciprocal recombination have contributed to the rapid diversification of KIR. We show that approximately 4.5% of the individuals of a Caucasoid population bear a recombinant allele of KIR3DP1, officially designed KIR3DP1*004, that associates tightly with gene duplications of KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1. The KIR3DP1 gene is normally silent, but the recombinant allele carries a novel promoter sequence and, as a consequence, is transcribed in all tested individuals. Messenger RNA of KIR3DP1*004 is made up of six exons; of these, exons 1-5 are similar to, and spliced like, those encoding the leader peptide and Ig-domains of KIR3D. By contrast, exon 6 is homologous to no other human KIR sequence, but only to possible homologs in chimpanzees and rhesus macaques, and encodes a short hydrophilic tail. The putative KIR3DP1*004 product, like those of the related genes LAIR-2 and LILRA3/ILT6/LIR4, is predicted to be secreted to the extracellular medium rather than anchored to the cell membrane.

Alleles↗
PubMed2005

Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis.

Killer cell immunoglobulin-like receptor genotyping was performed on a cohort of American Caucasian patients with psoriasis to investigate any possible relationship between these chromosome 19 genes and autoimmune-linked disease. This patient cohort also contained a subgroup of patients who had been additionally diagnosed as positive for psoriatic arthritis (PsA). Because of the known association of human leucocyte antigen (HLA)-Cw*06 with psoriasis, the study concentrated on the five KIR genes that have HLA-C as their recognized ligand (i.e., KIR2DL1, -2DL2, -2DL3, -2DS1, and -2DS2). An increase in the frequency of the activating KIR2DS1 gene was detected in the PsA patients, compared with psoriasis patients negative for PsA and an unaffected American Caucasian control group.

Arthritis, Psoriatic↗
PubMed2004

Investigation of KIR diversity in immunosenescence and longevity within the Irish population.

Natural killer (NK) cells play a pivotal role in the innate immune response. During the ageing process, variations occur in NK cell number and function. The cytolytic activity of NK cells is controlled by an array of activating and inhibitory cell surface receptors, including the killer cell immunoglobulin-like receptors (KIRs). In the present study, genetic diversity of the KIR loci was analysed with respect to successful ageing in the Irish population. A PCR-SSOP KIR gene identification system was employed to determine the frequency of the named KIR genes/pseudogenes and KIR genotypes within a healthy aged cohort and young control group. Although, two KIR genes (2DS3, 2DL5) displayed an initial increased frequency in the aged group, the significance of this association was lost when repeated in a second cohort. In view of the lack of studies to date, investigating the role of the KIR gene system in healthy ageing, further analysis of KIR diversity is required to fully elucidate it's role in respect to age-related disease and longevity.

Adult↗
PubMed2004

High resolution HLA-DRB1 identification of a Caucasian population.

Polymerase chain reaction-sequence-specific oligonucleotide probes typing methods have been applied to 1000 individuals from the Northern Ireland population to give human leukocyte antigen DRB1 (HLA-DRB1) allele assignment. HLA-DRB1 allele frequencies and four-locus haplotypes (A/B/C/DR) for this Caucasian population, based on HLA class I and class II allele assignment, are now presented. No significant deviations from Hardy-Weinberg proportions were observed. The HLA-C locus exhibited marginal evidence of selection (p<0.03, uncorrected one-sided test) in the direction of balancing selection; the HLA-A, -B, and -DRB1 allele frequency distributions were compatible with expectations under a neutral model (which does not mean that selection is not operating). Evidence for selection was seen on haplotypes HLA-A*010101-B*0801-DRB1*030101 and HLA-A*290201-B*440301-DRB1*070101 based on their patterns of linkage disequilibrium.

Alleles↗
PubMed2004

Investigation of killer cell immunoglobulinlike receptor gene diversity: I. KIR2DL4.

Polymerase chain reaction-sequence-specific oligonucleotide probes typing procedures identifying alleles of the killer immunoglobulin-like gene (KIR2DL4) have been established. The methods, designed around the specific amplification of the D0 and D2 domains of this gene, produce discrimination of KIR2DL4 alleles. The methods have been applied to a healthy Northern Irish control group, establishing frequencies for this Caucasian population. Additionally, the KIR2DL4 allele status of cell line DNA and CEPH families, from the 13th International Histocompatibility Workshop and local families, have also been investigated.

Alleles↗
PubMed2004

Functional promoter region polymorphism of the proinflammatory chemokine IL-8 gene associates with Parkinson's disease in the Irish.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders and is characterized by the progressive loss of dopamine neurons in the substantia nigra. There is increasing evidence to suggest the inflammatory response of the brain contributes to the pathogenesis of PD. This study investigated the frequency of polymorphism located in the critical promoter region of the proinflammatory cytokine genes: interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) within a cohort of patients with PD in comparison to a group of healthy elderly individuals. No association was observed for single nucleotide polymorphism in the promoter regions of the IL-2, IL-6, and TNF-alpha genes. The single nucleotide polymorphism in the chemokine IL-8 gene was observed to associate with PD and appeared to be independent of age at onset. This association further supports the theory that the proinflammatory response in the brains of patients with PD plays a role in the pathogenesis of the disease and warrants further investigation into the role of chemokines in the brain, and a more detailed analysis of the genetics involved in the immune response of the brain.

Aged↗
PubMed2004

Investigation of killer cell immunoglobulin-like receptor gene diversity: II. KIR2DS4.

A polymerase chain reaction sequence-specific oligonucleotide probe typing method identifying and distinguishing alleles of the KIR2DS4 gene has been established. The system is based on the specific amplification of a region of this gene, followed by hybridization with 11 sequence-specific oligonucleotide probes. The method has been applied to a healthy group of Northern Irish caucasian individuals, establishing frequencies of alleles of this locus within the local population. Furthermore, cell line DNA and families from the 13th International Histocompatibility Workshop, in addition to local families, have also been allele typed at the KIR2DS4 locus. Haplotype segregation, with respect to KIR2DS4 alleles, has been examined by using the local family data. Within all sample groups investigated, four KIR2DS4 alleles were identified, two of which are novel to this investigation.

Alleles↗
PubMed2004

Investigation of killer cell immunoglobulin-like receptor gene diversity: IV. KIR3DL1/S1.

The polymorphic nature of the KIR3DL1/S1 gene complex has been investigated through the development of a polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) allele typing system. The KIR3DL1/S1 system was applied to a healthy group of Northern Irish individuals to establish allele frequencies within this Caucasian population. Additionally, cell line DNA and CEPH families, both from the 13th International Histocompatibility Workshop, and local families have been investigated. The generated data emphasize the complexity and highly polymorphic nature of this KIR gene complex; 11 allelic variations were identified, 2 of which are novel to this study. Use of the PCR-SSOP system has confirmed the presence of multiple copies of KIR3DL1/S1 alleles in a number of individuals.

Alleles↗
PubMed2003

Study of age-association with cytokine gene polymorphisms in an aged Irish population.

The release of cytokines is of crucial importance in the regulation of the type and magnitude of the immune response in the elderly. A number of studies have shown different levels of cytokine production in the elderly. In the present study, a range of polymorphisms were chosen within the genes of cytokines (IL-2, IL-6, IL-8, IL-10, IL-12 and IFN-gamma) that have been observed at different levels within the elderly and analysed for age-association. No association was observed for the polymorphic cytokine markers and the healthy aged Irish population (or with respect to gender) examined in this study. These findings would suggest that polymorphism of cytokine genes may not play as crucial a role in healthy ageing as previously believed.

Adult↗
PubMed2003

Interleukin-6-gene C/G 174 polymorphism in nonagenarian and octogenarian subjects in the BELFAST study. Reciprocal effects on IL-6, soluble IL-6 receptor and for IL-10 in serum and monocyte supernatants.

In this study, we have assessed any change in the frequency of the GG homozygotes of the 174 IL-6 polymorphism with increasing age, arguing that if IL-6 tracks with functional disability and age-related diseases, then there may be attrition or reduction in the frequency of homozgyous subjects, who produce higher levels of IL-6 in serum, in older survivors in a population. We have tested this hypothesis in a large group of free-living, mentally competent, nonagenarian and octogenarian subjects from the Belfast Elderly Longitudinal Ageing Study-BELFAST study and found that the frequency of GG homozygotes with IL-6-174C/G polymorphism decreases with age by about 10%, compared with young controls. In addition we find that CC homozygotes have higher serum levels of IL-6 levels compared with GG (P=0.055), with reciprocal and significant changes in the anti-inflammatory IL-10 (P=0.05). Both IL-6 and IL-10 were spontaneously produced from separated mononuclear cell monolayers in elderly subjects, with significantly higher levels of secreted IL-10 supernatant levels (P=0.05) at 20 h, for G allele subjects carrying the IL-6-174C/G polymorphism. In conclusion, in the BELFAST study, there appears to be a reduction in the frequency of GG homozygotes in the octo/nonagenarian age group and a higher serum IL-6 level associated with CC homozygotes with reciprocal changes for the anti-inflammatory cytokine IL-10.

Aged↗
PubMed2003

HLA haplotypes and TNF polymorphism do not associate with longevity in the Irish.

Polymorphism of the human leukocyte antigen has been implicated in a number of autoimmune disorders including ageing. In the course of the present study, no association of the human leukocyte antigen (HLA)-A1, B8, DR3 haplotype with a male Irish aged population, as previously reported, was observed. Two polymorphic nucleotides in the TNF cluster (G-308A TNF-alpha and G+252A TNF-beta), associated with increased TNF-alpha production, were shown to be in tight linkage disequilibrium with the class I and II HLA loci, generating HLA haplotypes with extended linkage disequilibrium. However, no age-related allele or genotype frequencies were observed for either polymorphic nucleotide.

Adult↗
PubMed2003

A multi-laboratory characterization of the KIR genotypes of 10th International Histocompatibility Workshop cell lines.

Killer immunoglobulinlike receptors (KIRs) are expressed on natural killer and T cells. Both inhibitory and noninhibitory forms have been described, leading to inhibition or continuation of cellular killing activity. The natural ligands identified so far of KIRs are class I human leukocyte antigens (HLA). In particular, the interaction of some KIRs with HLA-Cw has been well characterized. Recent work has implicated KIRs in affecting the outcome of hematopoietic stem-cell transplant (HSCT). This may well lead to a requirement for prospective KIR typing of donor and recipient. We have utilized different typing systems (two using polymerase chain reaction-sequence-specific primers, and one using polymerase chain reaction-sequence-specific oligonucleotide probes) in three separate laboratories to characterize the KIR gene complement of 25 cell lines from the 10th International Histocompatibility Workshop. There were consistent results in 22, and minor differences in 3. When compared with previous results for some of these cell lines, no further differences were found. The differences are due to typing of KIRs KIR2DL1 and KIR2DS5, and may be explained by technical differences or the inability to type new variants. Further improvements in typing may be required if population and clinical studies are to produce accurate results.

Cell Line↗