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S C Bain

Publications and source records attributed to S C Bain.

At least 19 recordsLinked to original sources
PubMed2006

Simultaneous pulmonary and cerebral oedema, and multiple CNS infarctions as complications of diabetic ketoacidosis: a case report.

We present a case of a 29-year-old woman with known Type 1 diabetes who presented with diabetic ketoacidosis (DKA). Despite appropriate treatment and initial improvement, 12 h after initiation of treatment she deteriorated rapidly and developed pulmonary oedema, cerebral oedema and multiple infarctions of the brain and cervical spinal cord. This resulted in spastic quadraparesis and she has remained wheelchair-bound. These complications of DKA are rare and unpredictable. In this case report we discuss the proposed aetiologies of these complications with reference to our case report and highlight the importance of vigilance for early signs of these complications during the treatment of all patients with DKA.

Adult↗
PubMed2005

The TGF-beta 1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes.

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed2004

Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository.

AIMS: Autoimmune disorders co-exist in the same individuals and in families, implying a shared aetiology. The aim of this study was to compare the prevalence of the common autoimmune diseases in the parents of siblings from the Type 1 diabetes Warren repository with the general population. METHODS: Between 1989 and 1996, 505 British families with at least two siblings affected by Type 1 diabetes were recruited. Clinical information was collected regarding the presence of autoimmune disease in the parents and the prevalence of disease in the parents was compared with that expected in the general population. RESULTS: The prevalence of autoimmune disease in the parents was significantly higher in the repository compared with that expected in the general population [P-value = 1.98 x 10(-5) (female), P-value = 1.1 x 10(-8) (male)]. Type 1 diabetes was recorded in 63/1010 (6.2%) parents with a marked paternal preponderance (9.5 vs. 3%P = 0.002). Other autoimmune diseases affected 27% of parents with diabetes and 13.2% of parents without diabetes (P < 0.01). CONCLUSION: These data confirm the importance of family history as a significant risk factor for the development of Type 1 diabetes and support the hypothesis that the common autoimmune diseases share at least some aetiological mechanisms.

Adult↗
PubMed2003

Nitric oxide synthase gene polymorphisms and diabetic nephropathy.

AIMS/HYPOTHESIS: Susceptibility to diabetic nephropathy in subjects with Type 1 diabetes is mainly genetically determined. Excess cardiovascular risk associated with diabetes is overwhelmingly concentrated in patients with nephropathy. Endothelial dysfunction is a feature of cardiovascular disease, hypertension, dyslipidaemia and smoking, all of which are associated with diabetic nephropathy. Nitric oxide regulates endothelial function and so genes encoding nitric oxide synthases could confer susceptibility to nephropathy. Recently positive associations have been reported. We examined polymorphisms within NOS3 and NOS2A, the genes encoding endothelial- and inducible nitric oxide synthase, for association with nephropathy. METHODS: Large case-control studies of patients with Type 1 diabetes and overt nephropathy who had hypertension and diabetic retinopathy. The control group comprised Type 1 diabetic subjects who have been on insulin for 50 or more years and have an extremely low risk of nephropathy. Genotyping was by PCR and agarose- or automated polyacrylamide gel electrophoresis using fluorescence-labelled primers. RESULTS: NOS3 intron 4 genotype frequencies (n=860: 464 cases, 396 control subjects) were 2.6%, 23.3%, 74.1% and 2.3%, 22.7%, 75.0% for aa, ab and bb genotypes; p=0.935. NOS2A promoter genotype frequencies (n=715: 358 cases, 357 control subjects) were 0.3%, 16.8%, 83.0% and 0.3% 17.6% and 82.1% for +/+, +/- and -/- genotypes (p=0.952). CONCLUSION/INTERPRETATION: In our cohort of Caucasian subjects with Type 1 diabetes there is no association between either of the polymorphisms studied and diabetic nephropathy. The previous suggestion from smaller studies that the intron 4 polymorphism in NOS3 could play a role in susceptibility to the disease is not confirmed.

Alleles↗
PubMed2003

Characteristics of Type 1 diabetes of over 50 years duration (the Golden Years Cohort).

BACKGROUND: Type 1 diabetes mellitus is associated with high levels of premature morbidity and mortality. Prolonged survival is possible, however, and some patients appear to be protected from the long-term complications of this condition. METHODS: Diabetes UK awards medals to patients who have had Type 1 diabetes for 50 years or more. By examining medal-holders, we have established the clinical and biochemical features of a group of 400 subjects (54% male) with Type 1 diabetes of long duration. RESULTS: Mean age of the subjects was 68.9 years and mean age-at-onset of diabetes 13.7 years. Features of long duration diabetes in this cohort include normal body mass (mean BMI 25.0 kg m-2), low insulin dose (mean 0.52 units kg-2) and greatly elevated HDL-cholesterol (mean 1.84 mmol/l). Mean HbA1c was 7.6% (normal range 3.8-5.0%) and no patient had a normal HbA1c at the time of venesection. As a group, they have long-lived parents and consume moderate amounts of alcohol. Medical contact has often been sporadic. A significant proportion (29%) were taking anti-hypertensive medication. Screening for micro- and macroalbuminuria was positive in 35.7%. CONCLUSIONS: Patients with long-duration (> 50 years) Type 1 diabetes are relatively protected from clinical diabetic nephropathy and large vessel disease; our data are consistent with protection possibly being genetically determined in part via elevated HDL-cholesterol levels. An abnormal urinary albumin/creatinine ratio is common in these patients, despite their low risk of significant renal deterioration; this may have implications for microalbuminuria screening programmes.

Aged↗
PubMed2001

A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.

In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.

Adolescent↗
PubMed2001

Genetics of diabetic nephropathy.

Diabetic nephropathy can develop in up to one-third of patients with type 1 diabetes and approximately 25% of patients with type 2 diabetes. This complication is important as it not only leads to renal failure but is associated with a high risk of coronary artery disease and other vascular complications. Although hyperglycaemia is necessary for the development of diabetic nephropathy, it is not sufficient, genetic factors also being important. This is evidenced by studies showing that only a subgroup of patients are at risk of nephropathy and that nephropathy clusters in families. The genes involved in susceptibility to diabetic nephropathy have yet to be identified. Most studies to date have been case-control in design, and there have been conflicting results. Genes suggested as having a role include those encoding angiotensin-1 converting enzyme, apolipoprotein E, heparan sulphate and aldose reductase. In order to clarify the role of these and other candidate genes in nephropathy, association studies in families are necessary. Because of the large number required, this will require international collaboration. A genetic marker for nephropathy would enable the earlier detection of this complication, thus facilitating screening and targeted intervention. An understanding of the role of susceptibility genes will ultimately allow the development of novel therapeutic strategies.

Aldehyde Reductase↗
PubMed2001

Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases.

Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and self-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; lambdas = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 x 10(-4)). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 x 10(-8), respectively, empirical P = 0.01 and 2 x 10(-4), respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 x 10(-6)). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species.

Animals↗
PubMed2001

The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1.

The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1.

Alleles↗
PubMed2000

Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21.

The positional cloning of multifactorial disease genes is a major challenge in human genetics. We have therefore empirically tested the utility of the available polymorphic microsatellite map to locate the already identified type 1 diabetes locus IDDM1 (sibling risk/population prevalence ratio lambda(s)= 2.7) within a 14 Mb region of chromosome 6p21 linked to disease. In a two-stage approach to fine mapping, linkage was evaluated in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers. The whole 14 Mb showed strong linkage. Then, each marker was analysed for evidence of allelic association, revealing evidence of disease association at one marker located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 markers flanking this marker revealed a highly specific region of 570 kb associated with disease ( P = 7.5 x 10(-35)), which included the HLA class II genes, known to be the primary determinants of IDDM1. The peak of association was as close as 85 kb centromeric of the disease-predisposing class II gene HLA-DQB1. We investigated the importance of the underlying inter-marker linkage disequilibrium, marker informativity and recombination for fine mapping and demonstrate that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. We demonstrate that fine mapping of a multifactorial disease gene is possible with high accuracy even in a region with extraordinary linkage disequilibrium across distances of several Mb. The results will be applicable to association studies of disease loci with lambda(s)values <2.7 except that much larger data sets will be required.

Adolescent↗
PubMed2000

Conditional ETDT analysis of the human leukocyte antigen region in type 1 diabetes.

Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.

Adolescent↗
PubMed1999

Human leucocyte antigen and insulin gene regions and nephropathy in type I diabetes.

AIMS/HYPOTHESIS: Diabetic nephropathy seems to have a strong genetic component. Genes involved in the genetic susceptibility to Type I (insulin-dependent) diabetes have been suggested to have a role in the development of diabetic nephropathy. This study aimed to examine the role of human leucocyte antigen and insulin genes in susceptibility to nephropathy in patients with Type I diabetes. METHODS: We carried out a genetic association study examining insulin gene polymorphisms using three large cohorts of patients with Type I diabetes: nephropathy (n = 258), long duration non-nephropathy (n = 153) and a recently diagnosed (sporadic) diabetic cohort (n = 264). Human leucocyte antigen typing results were obtained in a smaller number due to assay failures (n = 182, 126 and 200 respectively). RESULTS: No significant difference was seen in the distribution of human leucocyte antigen A, B, C, DR, DQA1 and DQB1 haplotypes and alleles between the three diabetic cohorts. No significant difference was seen in insulin '+' and '-' genotypes and alleles between the three diabetic cohorts. CONCLUSIONS/INTERPRETATION: Human leucocyte antigen and insulin gene loci are unlikely to have a major role in the susceptibility to nephropathy in Caucasian patients with Type I diabetes in the United Kingdom.

Adult↗
PubMed1999

Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the mitochondrial DNA 3243 tRNA(Leu) A to G mutation.

OBJECTIVE: To study the association of retinal disease and the syndrome of maternally inherited diabetes and deafness caused by an A to G mutation in the tRNA leucine gene at base pair 3243 (A3243G) of the mitochondrial genome. DESIGN: Observational study of a genetically defined subject group. PARTICIPANTS: Thirteen subjects with the mitochondrial DNA A3243G mutation from seven different pedigrees with maternally inherited diabetes and deafness. INTERVENTION: Assessment of visual symptoms and visual acuity, dilated indirect ophthalmoscopy, retinal photography, and retinal electrophysiology. MAIN OUTCOME MEASURES: Loss of vision, funduscopic evidence of pigmentary retinal disease or diabetic retinopathy, and electrophysiologic evidence of defective functioning of the retinal pigment epithelium/photoreceptor complex. RESULTS: Funduscopic examination revealed abnormalities of retinal pigmentation in ten subjects (77%). Defects included speckled and patchy hyperpigmentation at the posterior pole of the fundus, particularly in the macular area, and varying degrees of loss of retinal pigmentation. Three subjects (23%) had visual symptoms, which included night blindness, visual loss, and photophobia. Electrophysiologic studies revealed impaired electro-oculogram responses in four of nine subjects with defects of retinal pigmentation (44%), two of whom also had much reduced scotopic and, to a lesser extent, flicker electroretinogram b wave potentials. Two subjects had diabetic retinopathy, including one with retinal depigmentation and impaired electro-oculogram activity. Both subjects with diabetic retinopathy had unilateral reduced electroretinogram responses, especially oscillatory potentials. CONCLUSIONS: Abnormalities of retinal pigmentation are common in subjects with maternally inherited diabetes and deafness caused by the mitochondrial DNA A3243G mutation. Visual symptoms, in particular loss of visual acuity, appear to be infrequent. The combination of deficits in the electro-oculogram and scotopic and flicker electroretinograms suggests that the retinal dystrophy includes defective functioning of retinal pigment epithelial cells and of both rod and cone photoreceptors. The pigmentary retinopathy does not prevent diabetic retinopathy; a single subject had funduscopic and electrophysiologic evidence of both diseases. Current evidence suggests that the mitochondrial DNA A3243G mutation accounts for 0.5% to 2.8% of diabetes. Most ophthalmic and diabetic clinics are therefore likely to contain such patients, who may benefit from identification of the genetic defect causing their disease and from genetic counseling.

Adenine↗
PubMed1999

Genetic determinants of diabetic nephropathy.

Diabetic nephropathy is the most serious complication of diabetes mellitus. Progression of the condition leads to end-stage renal failure, and other complications of diabetes are also common in this group of patients. The onset of overt albuminuria in a patient with diabetes heralds an increased risk of death, particularly from cardiovascular disease. There is considerable evidence to show that nephropathy is influenced by genetic factors. Epidemiological studies show that only a minority of patients with diabetes develop nephropathy irrespective of glycaemic control, suggesting that a subgroup of patients are at higher risk of nephropathy. Marked ethnic variation is observed, with nephropathy being more common in certain ethnic groups. Familial clustering of nephropathy is also observed. Parental history of hypertension, diabetes or cardiovascular disease appears to predispose to nephropathy in patients with diabetes. A number of methods are available to dissect polygenic disease: animal models, genetic association studies (case-control studies), affected sib-pair studies, discordant sib-pair studies and transmission distortion analysis. Most published work has been based on association studies. Association studies have shown conflicting results often due to small numbers of cases and controls, and poor phenotypic characterization. The angiotensin-converting enzyme gene insertion (I)/deletion (D) polymorphism has been studied in detail, but does not appear to be a strong risk marker for nephropathy. It does, however, appear to have a role in response to angiotensin-converting enzyme inhibition, with II homozygotes being the most responsive and DD homozygotes the least. A number of other genetic loci have also shown positive associations with nephropathy, including apolipoprotein E, heparan sulphate and aldose reductase. More recently, affected sib-pair analysis and discordant sib-pair analysis have suggested possible genetic loci on chromosomes 3, 7, 9, 12 and 20. These have yet to be reproduced in larger numbers of families, and the specific gene regions on these chromosomes remain elusive. The evidence presented in this review strongly supports the role of genetic factors in nephropathy. Detection of strong genetic risk markers for nephropathy will allow further insights into the pathogenesis of nephropathy, and possibly the development of novel therapeutic agents for its treatment. It will also allow preventive therapy to be directed at those patients with the greatest risk for development of diabetic nephropathy.

Animals↗
PubMed1998

Factors associated with clinic non-attendance in adults with type 1 diabetes mellitus.

In order to examine the causes of non-attendance in a diabetic clinic, a 1-year retrospective casenote review of 259 diabetic patients with no evidence of major complications was undertaken. Frequency of clinic attendance, clinic non-attendance, and glycaemic control (HbA1c) were recorded. In a sub-sample of 82 patients, more detailed demographic data was obtained via questionnaire. During the previous year 39% of patients had failed to attend the clinic on at least one occasion and 10% were recurrent non-attenders. Non-attenders had a significantly higher mean HbA1c compared with those who did attend (8.1 +/- 2.2 vs 7.6 +/- 1.6%; p = 0.03). They were also significantly younger (mean age 27 + 7 vs 29 +/- 9 yrs; p = 0.02) and had a significantly shorter duration of diabetes (12 +/- 8 vs 15 +/- 10 yrs; p = 0.02). Attendance did not differ according to gender or age of onset of diabetes. Sub-sample analysis showed that smokers, those with children at home, and single parents were all more likely to default from their appointments. Non-attendance is a significant problem at our diabetic clinic, however, by addressing the reasons why patients fail to attend clinic we hope to develop strategies to encourage regular attendance. This may be translated into improved glycaemic control and ultimately reduce the risk of late diabetic complications.

Adolescent↗