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Biomedical subjects

A Demaine

Publications and source records attributed to A Demaine.

At least 19 recordsLinked to original sources
PubMed2004

Polymorphisms of chemokine and chemokine receptor genes in Type 1 diabetes mellitus and its complications.

Cytokines and chemokines have been implicated in the pathogenesis of Type 1 diabetes mellitus (T1DM) and its microvascular complications. Recently, genetic variants of monocyte chemotactic protein-1 (MCP-1), CC-chemokine receptor 2 (CCR2), CC-chemokine receptor 5 (CCR5) genes have been identified. The aim was to investigate whether genetic variants of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 Delta32 are associated with T1DM and its microvascular complications. Two hundred and sixty patients with T1DM with and without diabetic microvascular complications, and 104 normal controls were recruited for this study. Genotypes of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 delta32 were performed by polymerase chain reaction followed by digestion with appropriate restriction endonucleases. Frequencies of the MCP-1 A(-2518) allele (74.6% vs. 63.5%, p < 0.003) and A/A genotype (54.5% vs. 34.6%, p < 0.001, Pc = 0.002) were significantly higher in patients with T1DM compared with normal controls. CCR5 G(59029) was slightly increased in the patients with microvascular complications compared with the uncomplicated (21.4% vs. 10%, p < 0.03, Pc = ns). The frequency of haplotype G/G/W was slightly increased in the patients with diabetic complications compared to the uncomplicated (39.6% vs. 28.8%, p < 0.02, Pc = ns). These results suggest that polymorphisms of the MCP-1, CCR2 and CCR5 genes may be associated with T1DM and its complications.

Adolescent↗
PubMed2003

Functional differences between the susceptibility Z-2/C-106 and protective Z+2/T-106 promoter region polymorphisms of the aldose reductase gene may account for the association with diabetic microvascular complications.

Studies have shown that polymorphisms located at positions -106 and approximately -2100 base pairs (5'ALR2) in the regulatory region of the aldose reductase gene are associated with susceptibility to microvascular complications in patients with diabetes. The aim was to investigate the functional roles of these susceptibility alleles using an in vitro gene reporter assay. Susceptibility, neutral and protective 5'ALR2/-106 alleles were transfected into HepG2 cells and exposed to excess D-glucose (D-glucose at final concentrations 14 or 28 mmol/l). Transcriptional activities were determined using a dual luciferase reporter gene assay. The "susceptibility alleles" Z-2 with C-106 had the highest transcriptional activity when compared with the "protective" combination of Z+2 with C-106 alleles (58.7+/-9.9 vs. 10.1+/-0.7; P<0.0001). Those constructs with either the Z or Z-2 in combination with the C-106 allele had significantly higher transcriptional activities when compared to those with the T-106 allele (Z/C-106, 37.4+/-5.4 vs. Z/T-106 7.7+/-1.6, P<0.003; Z-2/C-106, 58.7+/-9.9 vs. Z-2/T-106 10.9+/-0.6, P<0.0001). These results demonstrate that the Z-2/C-106 haplotype is associated with elevated transcriptional activity of the aldose reductase gene. This in turn may explain the role of these polymorphisms in the susceptibility to diabetic microvascular complications.

Aldehyde Reductase↗
PubMed2001

Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Alleles↗
PubMed2001

Analysis of the expression of critical activation/interaction markers on peripheral blood T cells in B-cell chronic lymphocytic leukaemia: evidence of immune dysregulation.

B-cell chronic lymphocytic leukaemia (B-CLL) is characterized by an accumulation of clonal malignant B cells. The intrinsic characteristics that permit this accumulation have been extensively studied and described. However, it is possible that proliferation and survival of this malignant clone is facilitated by a disruption in the interaction between B and T cells that normally regulate the immune system. In this study, using flow cytometry and cell culture techniques, marked abnormalities of the expression of certain key activation and interaction molecules on the peripheral blood T cells of patients with B-CLL were demonstrated. In particular, on comparison with normal controls, there was a marked reduction in the number of circulating T cells expressing CD25 (interleukin 2 receptor) (P = 0.007), CD28 (P = 0.01) and CD152 (CTLA-4) (P = 0.001). There was also a reduction in the number of circulating T cells expressing CD4 (P = 0.03), CD5 (P = 0.05) and CD11a (P = 0.01). There was no difference in the number expressing T-cell receptor alphabeta (P = 0.1), CD8 (P = 0.4), CD54 (P = 0.4) and CD154 (P = 0.5), and the only marker expressed on a greater number of circulating T cells in B-CLL patients was HLA-DR (P = 0.05). These results suggest that there is a profound T-cell dysregulation that may contribute to the survival of the malignant B cells in patients with B-CLL and to the related autoimmune phenomena of the disease.

Abatacept↗
PubMed2001

Pediatric autoimmune liver diseases: the molecular basis of humoral and cellular immunity.

Pediatric autoimmune liver disease is mainly represented by two similar liver disorders: autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), both characterized by hypergammalobulinemia, interface hepatitis and the presence of a wide range of circulating autoantibodies. Although similar features are seen in AIH and inflammatory bowel disease, histological biliary changes are more common in ASC. In addition to their role as diagnostic markers, autoantibodies, such as anti-extractable nuclear antigen (ENA) antibodies and liver kidney microsomal antibody type 1 (LKM1) may be involved directly in inducing aggressive liver diseases. Although the cellular immune response in pediatric autoimmune liver disease has been less intensively investigated than humoral immunity, the importance of antigen specific T cells has been explored. Both alphabeta and gammadelta T cells derived from either peripheral blood and liver biopsies have highly heterogeneous TCR gene usage and cytolytic activity has been demonstrated. There have been attempts to seek triggers of liver autoimmunity and several sequences shared in common between autoantigens and hepatotropic viruses, namely hepatitis B, C and cytomegalovirus have been identified. The presence of cross-reactivity between homologous sequences, especially between HCV and cytochromes, supports the possibility that molecular mimicry plays a role in the induction of autoantibodies and autoreactive cytotoxic T cells.

Amino Acid Sequence↗
PubMed2000

Tracing European founder lineages in the Near Eastern mtDNA pool.

Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2, 804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans.

DNA, Mitochondrial↗
PubMed2000

A CA repeat polymorphism of the IFN-gamma gene is associated with susceptibility to type 1 diabetes.

Recent studies have shown that loci outside the HLA region are involved in determining susceptibility to type 1 diabetes. Polymorphisms in the coding and noncoding regions of the genes encoding cytokines may be involved in modulating the immune response to self and nonself antigens. There is increasing evidence that an imbalance and disruption of the Thl and Th2 T cell subsets play a key role in the development of experimental and clinical type 1 diabetes. The aim of this study was to investigate the frequency of a CA dinucleotide repeat polymorphism in the interferon-gamma (IFN-gamma) gene (IFNG) and a C(-590)T polymorphism of the interleukin-4 (IL-4) gene in 236 Caucasoid patients with type 1 diabetes. There was a highly significant increase in the 3/3 IFNG genotype in the patients compared with normal healthy controls (34.3% vs. 13.5%, p<0.0001) as well as a significant increase in allele 3 of the IFNG locus in the patients compared with controls (51.9% vs. 31.7%, p<0.00001). In contrast, no significant differences were found in the frequency of the C(-590)T IL-4 polymorphism between patients and controls. These results suggest that polymorphisms of the IFNG gene may modify the function of this proinflammatory mediator and the response to pancreatic islet beta cells.

Adolescent↗
PubMed2000

Polymorphisms of the aldose reductase gene and susceptibility to retinopathy in type 1 diabetes mellitus.

PURPOSE: Aldose reductase (ALR2) is the first and rate-limiting enzyme of the polyol pathway and is involved in the pathogenesis of diabetic retinopathy. Polymorphisms of the ALR2 gene are associated with susceptibility to diabetic retinopathy in Chinese and Japanese patients with type 2 diabetes. There are no reports investigating these polymorphisms in white patients with type 1 diabetes from either Western Europe or North America. A CA dinucleotide repeat polymorphism (5'ALR2; located at -2100 bp) as well as a novel C(106)T polymorphism was investigated in 229 white patients with type 1 diabetes, with or without retinopathy. METHODS: The DNA was typed for these polymorphisms using conventional polymerase chain reaction techniques. RESULTS: There was a highly significant increase in the frequency of the Z-2 5'ALR2 allele and Z-2/X (where X is not Z+2) genotype in patients with diabetic retinopathy (n = 159) compared with those without who had diabetes of 20 years' duration (uncomplicated, n = 70; chi(2) = 17.0, P < 0.0001). There was a similar decrease in the Z+2/Y genotype (where Y is not Z-2; chi(2) = 30.1, P < 0.000,001) in the patients with retinopathy compared with the uncomplicated diabetes group. The C/Z-2 C(-106)T/5' ALR2 haplotype was found in 33.3% of the patients with retinopathy and 8.7% of the patients with uncomplicated diabetes. CONCLUSIONS: These results confirm previous studies in other populations and in type 2 diabetes showing that polymorphisms in the promoter region of the ALR2 gene are associated with susceptibility to diabetic retinopathy.

Adolescent↗
PubMed1999

A study of cytokine protein secretion, frequencies of cytokine expressing cells and IFN-G gene polymorphisms in normal individuals.

BACKGROUND: Cytokines are major regulators of immune responses, and there is evidence that they play a role in allograft rejection. Before embarking on a detailed study of pretransplant cytokine profiles in renal allograft recipients, we wished to investigate variations in cytokine protein secretion, numbers of cytokine expressing T cells, and cytokine gene polymorphisms in normal volunteers. METHODS: Twenty normal healthy volunteers were studied. Cytokine protein secretion [interleukin- (IL) 2, IL-4, IL-10, and interferon- (IFN) y] and numbers of cytokine expressing CD3+ T cells (IL-2, IL-4, IL-10, and IFN-gamma) were quantified by means of enzyme-linked immunosorbent assay and two-color flow cytometry respectively. IFN-gamma gene polymorphisms were determined by polymerase chain reaction and autoradio graphy. RESULTS: Large interindividual variations in both the quantity of IL-2, IL-4, IL-10, and IFN-gamma cytokine protein secreted and numbers of IL-2 and IFN-gamma expressing T cells were demonstrated. However, numbers of IL-4 and IL-10 expressing cells were found to be below detectable limits by flow cytometry. In the case of IFN-gamma, a bi-modal distribution was seen for the quantity of protein secreted. In addition, correlations were observed between IL-2 protein and frequency of IL-2 expressing T cells. However, no relationship was found between IFN-gamma protein levels, numbers of IFN-gamma expressing cells and IFN-gamma gene polymorphisms. CONCLUSIONS: We have demonstrated large differences in both numbers of T helper 1 cytokine expressing cells and the quantity of T helper 1 and T helper 2 cytokine protein secreted between normal individuals. Although the amount of IL-2 protein secreted appeared to be determined by the frequency of IL-2 expressing cells, this was not the case for IFN-gamma.

Adult↗
PubMed1999

A susceptibility region for myasthenia gravis extending into the HLA-class I sector telomeric to HLA-C.

We have analyzed a series of HLA region markers in 207 UK Caucasoids with early-onset myasthenia gravis (EOMG, onset before age 40), where there is a strong female bias. The well known associations with HLA-DR3 and -B8 have now proved to be significantly stronger in the 165 females than in the 42 males. In patients (of either sex) lacking -DR3, there was also a significant increase in HLA-DR2. Although the muscle weakness in EOMG is clearly mediated by autoantibodies, the associations are consistently stronger with HLA-B8 (in class I) than with HLADR3 (in class II), as confirmed here. We therefore typed 87-137 cases for polymorphisms at four loci in the intervening class III region, and also at three in the adjacent stretch of class I. At each locus, one allele tended to co-occur with HLA-B8 and showed strong and highly significant associations in the patients. There appeared to be a region of maximal susceptibility extending from HSP70 (in class III) past HLA-B and HLA-C at least 600 kb telomerically into the class I region, which is now being mapped in detail. Any candidate genes here that act shortly after puberty may allow more precise localization of susceptibility.

Adult↗
PubMed1999

Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.

The transcription factor insulin promoter factor-1 (IPF-1) plays a central role in both the development of the pancreas and the regulation of insulin gene expression in the mature pancreatic beta cell. A dominant-negative frameshift mutation in the IPF-l gene was identified in a single family and shown to cause pancreatic agenesis when homozygous and maturity-onset diabetes of the young (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense mutations (C18R, D76N, and R197H) were identified in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human beta-cell line Nes2y. These mutations are present in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25-53 years of age. We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation.

Adult↗
PubMed1996

Paleolithic and neolithic lineages in the European mitochondrial gene pool.

Phylogenetic and diversity analysis of the mtDNA control region sequence variation of 821 individuals from Europe and the Middle East distinguishes five major lineage groups with different internal diversities and divergence times. Consideration of the diversities and geographic distribution of these groups within Europe and the Middle East leads to the conclusion that ancestors of the great majority of modern, extant lineages entered Europe during the Upper Paleolithic. A further set of lineages arrived from the Middle East much later, and their age and geographic distribution within Europe correlates well with archaeological evidence for two culturally and geographically distinct Neolithic colonization events that are associated with the spread of agriculture. It follows from this interpretation that the major extant lineages throughout Europe predate the Neolithic expansion and that the spread of agriculture was a substantially indigenous development accompanied by only a relatively minor component of contemporary Middle Eastern agriculturalists. There is no evidence of any surviving Neanderthal lineages among modern Europeans.

Agriculture↗
PubMed1994

Analysis of the peripheral T-cell receptor V beta repertoire in newly diagnosed patients with type I diabetes.

Type I diabetes is an autoimmune disease characterised by a marked activation of peripheral T cells around the time of clinical diagnosis. Studies of T-cell antigen receptor V beta (TCRBV) gene usage in type I diabetes have been conflicting. Using a semi-quantitative polymerase chain reaction technique and flow cytometry we have investigated the TCRBV gene usage of 13 newly diagnosed patients with type I diabetes and 11 normal healthy controls. No preferential TCRBV gene usage was found between patients and controls even after matching for HLA-DR3 and/or -DR4. In addition, no significant differences in TCRBV gene usage were found between sequential samples taken over a period of up to 7 months following diagnosis. These results suggest that the TCR repertoire of these patients is heterogeneous and it is unlikely that a single 'pathogenic' T-cell clone is dominant at the clinical onset of the disease.

Adult↗
PubMed1992

Immunoglobulin heavy chain gene associations in myasthenia gravis: new evidence for disease heterogeneity.

Susceptibility to myasthenia gravis (MG) is known to involve genes residing in the major histocompatibility complex class I and II regions (HLA-B8 and DR3). Immunoglobulin heavy chain constant region (IgCH) allotypes have also shown some associations with MG. We have used restriction fragment length polymorphism analysis with probes to the IgCH switch (S) regions mu and alpha 1 and the downstream marker D14S1 to investigate 189 Caucasoid patients with well-defined MG. A highly significant increase in the frequency of the 2.6 kilobase (kb) S mu homozygous genotype and the 2.6 kb S mu allele was found in patients with disease onset after the age of 40 years (late onset) compared with normal controls (P less than 0.00075 and P less than 0.025 respectively). No association was found at the S alpha 1 or D14S1 loci. In patients with an associated thymoma there was a moderate increase in the frequency of the 2.6 kb S mu and 7.4 kb S alpha 1 genotypes. These results independently support the previous separation of the late-onset subgroup. Finally, the stronger association at S mu rather than at the downstream S alpha 1, Gm and D14S1 loci suggest that the genes predisposing to MG are located within the variable region of the Ig heavy chain loci.

Adult↗