S. C. Bain

Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus

The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1–kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By ‘cross–match’ haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent–of–origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.

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.

Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM.

SummaryPremature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n=242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n=187); a geographically defined cohort of newly diagnosed diabetic patients (n=341); and IDDM patients with long duration of disease (>15 years) and no evidence of overt nephropathy (n=166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p=0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p=0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young

Summary Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised by an early age of onset (< 25 years) and an autosomal dominant mode of inheritance. MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4α) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1α) [MODY3]. A nonsense mutation in the HNF-4α gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at θ = 0) for mutations in the coding region of the HNF-4α gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4α gene. [Diabetologia (1997) 40: 859–862]

Nitric oxide synthase gene polymorphisms and diabetic nephropathy

Aims/hypothesisSusceptibility 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.MethodsLarge 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.ResultsNOS3 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/interpretationIn 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.

Association Testing of Previously Reported Variants in a Large Case–Control Meta-Analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

The TGF‐β1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes

Aims  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.

Genetic variation of the heparan sulfate proteoglycan gene (perlecan gene). Association with urinary albumin excretion in IDDM patients.

Both in patients with IDDM (1) and in healthy control subjects (2,3), increased urinary albumin excretion rate (AER) is associated with high relative morbidity and mortality. In IDDM patients, genetic susceptibility factors are most likely contributing to an increased AER (4,5) resulting in a cumulative incidence of nephropathy (AER >300 mg/24 h) of -30% (6). So far, candidate genes, proposed as susceptibility markers linked to abnormal albuminuria, have been identified because of the knowledge of pathophysiological events related to diabetic nephropathy. Heparan sulfate proteoglycan (HSPG, i.e., Perlecan) constitutes an integrated part of the glomerular basement membrane. It consists of a central core protein to which anionie sulfated polysaccharide chains (heparan sulfate [HS]) are linked (7), thus contributing to the negative charge of the glomerular filtration barrier and thereby indirectly to the composition of the glomerular filtration product (8,9). In IDDM patients, it has been demonstrated that increased AER is reduced by the administration of heparin (10) most likely because of a stimulating effect on the HS synthesis (11).

Accuracy and Longevity of an Implantable Continuous Glucose Sensor in the PRECISE Study: A 180-Day, Prospective, Multicenter, Pivotal Trial

OBJECTIVE It is known that continuous glucose monitoring (CGM) systems can lower mean glucose compared with episodic self-monitoring of blood glucose. Implantable CGM systems may provide additional benefits. RESEARCH DESIGN AND METHODS We studied the Eversense (Senseonics Inc.) implantable CGM sensor in 71 participants aged 18 years and older with type 1 and type 2 diabetes in a 180-day multinational, multicenter pivotal trial. Participants used the CGM system at home and in the clinic. CGM accuracy was assessed during eight in-clinic visits with the mean absolute relative difference (MARD) for venous reference glucose values >4.2 mmol/L as the primary end point. Secondary end points included Clarke Error Grid Analysis and alarm performance. The primary safety outcome was device-related serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02154126. RESULTS The MARD value against reference glucose values >4.2 mmol/L was 11.1% (95% CI 10.5, 11.7). Clarke Error Grid Analysis showed 99.2% of samples in the clinically acceptable error zones A and B. Eighty-one percent of hypoglycemic events were detected by the CGM system within 30 min. No device-related serious adverse events occurred during the study. CONCLUSIONS Our results indicate the safety and accuracy of this new type of implantable CGM system and support it as an alternative for transcutaneous CGM.

Association between the rs4880 superoxide dismutase 2 (C>T) gene variant and coronary heart disease in diabetes mellitus.

Mitochondrial superoxide dismutase 2 (SOD2) is an endogenous anti-oxidant enzyme. The rs4880 gene variant results in a C>T substitution, influencing SOD enzymatic activity. This variant has been associated with micro- and macro-vascular complications in diabetes mellitus. Our aim was to examine the association between this variant and coronary heart disease (CHD) risk in a cross-sectional sample of subjects with diabetes. 776 Caucasian subjects with diabetes were genotyped. CHD risk, oxidised-LDL and plasma total anti-oxidant status (TAOS) were analysed in relation to genotype. In females, the TT genotype was associated with CHD (CC/CT/TT: No CHD vs. CHD: 22.4/56.0/21.6% vs. 12.0/50.0/38.0%, p=0.03; for CC/CT vs. TT, p=0.01). The odds ratio for CHD associated with the TT genotype compared to CC/CT was 2.22 [95%CI: 1.17-4.24], p=0.01. The TT genotype was also associated with significantly lower plasma TAOS. In males, no association was observed between genotype and CHD risk, but CHD was significantly associated with age, lower HDL, higher triglycerides, higher BMI and cigarette smoking. The TT genotype of this variant is associated with increased CHD risk and lower plasma anti-oxidant defences in females with diabetes. This modest genotype-effect is not apparent in males where traditional risk factors may play a greater role.