Stephen C. Bain

A search for type 1 diabetes susceptibility genes in families from the United Kingdom

Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (λs = 2.5; Refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at λs = 3 and lod = –2, of which two showed evidence of linkage: chromosome 10p13–p11 (maximum lod score (MLS) = 4.7, P = 3 × 10 –6, λs = 1.56) and chromosome 16q22–16q24 (MLS = 3.4, P = 6.5 × 10–5, λ s = 1.6). These and other novel regions, including chromosome 14q12–q21 and chromosome 19p13–19q13, could potentially harbour disease loci but confirmation and fine mapping cannot be pursued effectively using conventional linkage analysis. Instead, more powerful linkage disequilibrium-based and haplotype mapping approaches must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage.

Mutations in the Hepatocyte Nuclear Factor–1α Gene Are a Common Cause of Maturity-Onset Diabetes of the Young in the U.K.

Mutations in the hepatocyte nuclear factor–1α (HNF-1α) gene have recently been shown to cause maturityonset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-1α gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (<40 years of age) NIDDM showed the mutation in two additional families. This common mutation was present on at least three different haplotypes, suggesting that its high frequency is due to recurrent mutation rather than a founder effect. We have demonstrated that mutations in the HNF-1α gene are a common cause of MODY in U.K. families and result in early onset NIDDM with a progressive clinical course. Mutation-based genetic counseling can now be considered for the majority of patients with MODY.

Altered Insulin Secretory Responses to Glucose in Diabetic and Nondiabetic Subjects With Mutations in the Diabetes Susceptibility Gene MODY3 on Chromosome 12

One form of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3, located on chromosome 12 in band q24. The present study was undertaken to define the interactions between glucose and insulin secretion rate (ISR) in subjects with mutations in MODY3. Of the 13 MODY3 subjects, six subjects with normal fasting glucose and glycosylated hemoglobin and seven overtly diabetic subjects were studied as were six nondiabetic control subjects. Each subject received graded intravenous glucose infusions on two occasions separated by a 42-h continuous intravenous glucose infusion designed to prime the β-cell to secrete more insulin in response to glucose. ISRs were derived by deconvolution of peripheral C-peptide levels. Basal glucose levels were higher and insulin levels were lower in MODY3 subjects with diabetes compared with nondiabetic subjects or with normal healthy control subjects. In response to the graded glucose infusion, ISRs were significantly lower in the diabetic subjects over a broad range of glucose concentrations. ISRs in the nondiabetic MODY3 subjects were not significantly different from those of the control subjects at plasma glucose levels <8 mmol/l. As glucose rose above this level, however, the increase in insulin secretion in these subjects was significantly reduced. Administration of glucose by intravenous infusion for 42 h resulted in a significant increase in the amount of insulin secreted over the 5–9 mmol/l glucose concentration range in the control subjects and nondiabetic MODY3 subjects (by 38 and 35%, respectively), but no significant change was observed in the diabetic MODY3 subjects. In conclusion, in nondiabetic MODY3 subjects insulin secretion demonstrates a diminished ability to respond when blood glucose exceeds 8 mmol/l. The priming effect of glucose on insulin secretion is preserved. Thus, β-cell dysfunction is present before the onset of overt hyperglycemia in this form of MODY. The defect in insulin secretion in the nondiabetic MODY3 subjects differs from that reported previously in nondiabetic MODY1 or mildly diabetic MODY2 subjects.

Fine Mapping of the Diabetes-Susceptibility Locus, IDDM4, on Chromosome 11q13

Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 (IDDM4). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (lambda(s)=1.09) with linkage (MLS>=0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [P=.02, corrected P=.72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P=3x10-4, corrected P=. 01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917*03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P=1.5x10-6, corrected P=4.3x10-4). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated.

Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the mitochondrial DNA 3243 tRNALeu A to G mutation1

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.

A Practical Approach to Identification of Susceptibility Genes for IDDM

Of all the common diseases that have a genetic component, IDDM is probably the most tractable to the experimentalist. Large numbers of nuclear multiplex families are available, which can be stored as permanent cell lines; diagnosis is relatively unambiguous; and a mouse strain, the NOD, spontaneously develops autoimmune IDDM similar to the human disorder. In addition, the resolution and accessibility of the human genome map has been revolutionized by the discovery and widespread application of the PCR, particularly the amplification of short, tandemly repeated segments of DNA called microsatellites, which display high levels of allelic polymorphism. With these reagents, the stage is set for dissection of the genetic factors that control the pathophysiology of IDDM.

Maternal Uniparental Disomy of Chromosome 1 with No Apparent Phenotypic Effects

URL for data in this article is as follows:Marshfield Center for Medical Genetics, http://www.marshmed.org/genetics (for marker mapping information)

Parental Origin of Diabetes-Associated HLA Types in Sibling Pairs With Type I Diabetes

Genetic susceptibility to type I diabetes is partly determined by genes located in the human leukocyte antigen (HLA) region on chromosome 6. It has been claimed that the transmission of HLA-encoded susceptibility is influenced by parental sex. Fathers are reported to transmit HLA-DR4 haplotypes more frequently to their diabetic offspring than mothers. More recently, it has been suggested that the presence of HLA-DR4 in a mother may influence susceptibility in her offspring, even when it is not inherited. We have analyzed 172 multiplex diabetic pedigrees from the U.K. and find no evidence to support an important effect of parental sex on the inheritance of HLA-encoded susceptibility. Examination of a further 110 pedigrees from the U.S. supports this finding. These results have important implications for strategies involving genetic screening for type I diabetes.

Rationale and design of diabetics exposed to telmisartan and enalapril (DETAIL) study

The DETAIL (diabetics exposed to telmisartan and enalapril) study will compare the long-term renal outcome of treatment with the angiotensin II receptor antagonist (ARA) telmisartan versus the angiotensin-converting enzyme (ACE) inhibitor enalapril in patients with mild-to-moderate hypertension and diabetic nephropathy. In short-term clinical studies, ACE inhibitors reduce microalbuminuria and, in the longer term, they are superior to conventional therapies in maintaining normal renal function. ARAs also appear to be renoprotective in diabetic animals. In this double-blind, parallel-group study, 252 patients with Type 2 diabetes and concurrent hypertension (mean seated systolic blood pressure < or = 180 mm Hg, on treatment seated diastolic blood pressure < or = 95 mm Hg) have been randomised to once-daily telmisartan 40 mg or enalapril 10 mg; doses are mandatorily titrated to 80 and 20 mg once daily, respectively, after 4 weeks. The primary endpoint will be the change from baseline in glomerular filtration rate (GFR) after 5 years of therapy, using the iohexol method and central laboratory analysis. The secondary endpoints to be evaluated will be: changes in GFR in relation to baseline after 1-4 years of therapy; percentage changes in albumin excretion rate after 1-5 years; and incidences of end-stage renal disease, cardiovascular events, all-cause mortality, and adverse events. The planned date for the completion of the study is 2005.

Cost-effective strategies in the prevention of diabetic nephropathy

A significant subgroup of patients with diabetes mellitus are predisposed to developing diabetic nephropathy and it is in this subgroup that other diabetesrelated complications, and in particular greatly increased cardiovascular disease risk, are concentrated. The high personal, social and financial costs of managing end-stage renal failure and the other complications associated with diabetic nephropathy make a powerful case for screening and effective intervention programmes to prevent the condition or retard its progression.As major breakthroughs in finding genetic susceptibility factors remain elusive, screening efforts continue to be based on microalbuminuria testing, despite increasing recognition of its limitations as a positive predictor of nephropathy.Interventions have been extensively studied, but results remain conflicting. Economic evaluations of such screening and intervention programmes are essential for health planners, yet models of the cost/benefit ratio of such interventions often rely on a rather slim evidence base. Where economic models are developed, they are frequently based on those papers that propound the greatest clinical benefits of a given intervention, leading to a possible over-estimation of the advantages of the chosen approach. Furthermore, the benefits of even such generally accepted interventions as ACE inhibitor treatment are less firmly established than generally appreciated. Lifestyle interventions are instinctively attractive, but are by no means a low-cost option (as is often assumed by both medical professionals and politicians).This review critically assesses the evidence for clinical efficacy and economic benefit of microalbuminuria screening and interventions such as intensive glycaemic control, antihypertensive treatment, ACE inhibition and angiotensin receptor blockade, dietary protein restriction and lipid-modifying therapy. The various costs associated with diabetic nephropathy are so great that even expensive interventions may have a favourable cost/benefit ratio, provided they are truly effective.