Population-based genetic screening for the estimation of Type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci.

AIMS: To improve sensitivity and specificity of the diabetes risk assessment of the population-based genetic screening used in the Finnish Diabetes Prediction and Prevention (DIPP) trial. METHODS: One thousand consecutive newborns enrolled in the DIPP were compared with 316 samples from children with Type 1 diabetes mellitus. A modification of the previously described technique based on hybridization of relevant PCR products with five lanthanide-labelled probes detected by time-resolved fluorometry (TRF) was used. A new probe was designed and allowed discrimination between DQB1*0602 and 0603 alleles, in addition to DQB1*02, *0301 or *0302, each of which required specific probes. A new, added screening strategy was developed for individuals carrying low-risk genotypes through specific typing of DQA1 *05 and *0201 alleles in DQB1*02 positive, and DRB1 typing for DR4 subtypes in DQB1*0302 positive subjects, with a new specifically designed high-resolution TRF-based DR4 subtyping technique. RESULTS: This two-step screening approach enhanced the sensitivity of the detection of genetic risk for Type 1 diabetes mellitus in this cohort up to 85.4%. In the general population cohort, 24.4% were identified for prospective follow-up, 2.6% of these are expected to develop Type 1 diabetes mellitus before the age of 15 years. Exclusive typing for HLA-DQB1 locus as an alternative screening strategy had sensitivities of 26.3-77.2% with general population cohorts of 2.3-23.1% identified for follow-up. CONCLUSIONS: The described strategy for genetic prediction of Type 1 diabetes mellitus relies on the convenient genotyping procedure and could be applied in large scale screening projects such as DIPP.     

Genetic analysis of HLA class II alleles and susceptibility to Type 1 (insulin-dependent) diabetes mellitus in Japanese subjects

Summary Although HLA-DQB1 alleles encoding aspartic acid at position 57 (Asp-57) are protective against Type 1(insulin-dependent) diabetes mellitus in Caucasians, most Japanese Type 1 diabetic patients carry at least one Asp-57 DQB1 allele. We analysed the DRB1, DQA1 and DQB1 genes of 99 Japanese patients and 86 control subjects with polymerase chain reaction and sequence-specific oligonucleotide hybridization. We found that (1) the DQA1*0301 allele was significantly increased in Type 1 diabetic patients (RR 7.8,pc < 0.0001); (2) the DRB1*0405 (Dw15) allele, which is a subtype of DR4 haplotype, was significantly increased in DR4-positive patients (RR 12.0,pc < 0.001); and (3) although the DRw8-DQw8 haplotype was positively associated with Type 1 diabetes, the DRBl*0406-DQw8 haplotype was decreased in the diabetic patients. These data indicate that DRB 1 and DQA1 genes also confer susceptibility to Type 1 diabetes in Japanese.     

Class II HLA genotype in fulminant type 1 diabetes: A nationwide survey with reference to glutamic acid decarboxylase antibodies

Aims/Introduction: Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin‐deficient hyperglycemia within a few days. The aim of the present study was to clarify characteristic class II HLA genotypes in a large number of patients with fulminant type 1 diabetes to date. Materials and Methods: We analyzed the HLA‐DRB1 and DQB1 genotypes, and their haplotypes in 207 patients with fulminant type 1 diabetes and 325 control subjects in the Japanese population. Results: The frequencies of the DRB1*04:05‐DQB1*04:01 and DRB1*09:01‐DQB1*03:03 haplotypes were significantly higher, and those of the DRB1*01:01‐DQB1*05:01, DRB1*15:02‐DQB1*06:01 and DRB1*08:03‐DQB1*06:01 haplotypes were significantly lower in patients with fulminant type 1 diabetes than in the control subjects. Combination analysis showed that the frequencies of homozygotes with DRB1*04:05‐DQB1*04:01 [odds ratio (OR) 7.0] and DRB1*09:01‐DQB1*03:03 (OR 9.5) were significantly higher in patients with fulminant type 1 diabetes. Within a limited portion of patients with fulminant type 1 diabetes with antibodies to glutamic acid decarboxylase (GADab; n = 25), the frequency of DRB1*09:01‐DQB1*03:03, but not DRB1*04:05‐DQB1*04:01, was significantly higher than in control subjects (44.0% vs 13.7%; Pc < 0.05, OR 5.0). [Correction to last line of Results, added after online publication 29 July 2011: “OR 5.1” is changed to “OR 5.0”.] Conclusions: Our large‐scale study showed the characteristic class II HLA genotypes in fulminant type 1 diabetes, and implicated that genetic contribution to disease susceptibility is distinct between GADab‐positive and GADab‐negative fulminant type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00139.x, 2012)     

Higher body mass index in adults at diagnosis of the slowly progressive form of type 1 diabetes mellitus is associated with lower risk HLA genes

We hypothesised that higher body weight, a proposed risk factor for type 1 diabetes mellitus, would be associated with increased penetrance of lower risk genes. In adults at diagnosis of the slowly progressive form of type 1 diabetes mellitus we found that higher body mass index was associated with the absence of the highest risk HLA genes.     

Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome.

AIMS: Gestational diabetes mellitus (GDM) is associated with adverse maternal and fetal outcome. Screening for GDM is therefore recommended but the best screening method remains controversial. This prospective, randomized study compared a risk factor-based screening programme with a universally based one. METHODS: Subjects were randomized at booking to one of two groups: the risk factor group had a 3-h 100-g oral glucose tolerance test (OGTT) at 32 weeks if any risk factor for GDM was present; the universal group had a 50-g glucose challenge test performed and if their plasma glucose at 1 h was > or = 7.8 mmol/l, a formal 3-h 100-g OGTT was then performed. RESULTS: Universal screening detected a prevalence of GDM of 2.7%, significantly more than the 1.45% detected in the risk factor screened group (P<0.03). Universal screening facilitated earlier diagnosis than risk factor screening - mean gestation 30 +/- 2.6 weeks vs. 33 +/- 3.7 weeks (P<0.05). A higher rate of spontaneous vaginal delivery at term, and lower rates of macrosomia, Caesarean section, prematurity, pre-eclampsia and admission to neonatal intensive care unit were observed in the universally screened, early diagnosis group. CONCLUSIONS: Universal screening for GDM is superior to risk factor based screening-detecting more cases, facilitating early diagnosis and is associated with improved pregnancy outcome.     

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Aims/hypothesis Prevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset.Methods Antibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40.Results On first sampling, 11.1% of the siblings presented at least one antibody type (p<0.001 vs other relatives). During follow-up (median 52 months) 43 subjects developed type 1 diabetes (31 siblings, ten offspring of a diabetic father, two offspring of a diabetic mother). Using Kaplan–Meier survival analysis and Cox regression, IA-2A conferred the highest 5-year diabetes risk (>50%) irrespective of the number of antibodies present. In initially IA-2A-positive relatives (n=58) progression to hyperglycaemia depended more on HLA DQ status than on type of kinship (84% progression in the presence of DQ2/DQ8 vs 32% in its absence; p<0.003). In IA-2A-negative relatives (n=4,531) 5-year progression to diabetes increased with the number of other antibodies (ICA, GADA and/or IAA) (p<0.001) but overall did not exceed 10% even for two or more antibodies. Among relatives initially positive for one or more antibody type other than IA-2A (n=315), there was significantly more progression to diabetes (overall still <10%) in carriers of DQ2 (p<0.001 vs no DQ2), regardless of DQ8 status.Conclusions/interpretation These observations suggest that the HLA-DQ-inferred risk of diabetes can proceed through two distinct pathways distinguished by IA-2A status. Combined positivity for DQ2/DQ8 and IA-2A defines a more homogeneous high-risk population for prevention trials than those used so far.Presented in part at the 38th Annual Meeting of the European Association for the Study of Diabetes, September 1–5, 2002, Budapest, Hungary.K. Decochez and I. Truyen contributed equally to the present work.     

Screening for diabetes in Indigenous populations using glycated haemoglobin: sensitivity, specificity, post-test likelihood and risk of disease.

AIMS: Screening for diabetes using glycated haemoglobin (HbA1c) offers potential advantages over fasting glucose or oral glucose tolerance testing. Current recommendations advise against the use of HbA1c for screening but test properties may vary systematically across populations, according to the diabetes prevalence and risk. We aimed to: (i) characterize the properties of test cut-offs of HbA1c for diagnosis of diabetes relative to a diagnosis based on a fasting plasma glucose concentration of 7.0 mmol/l for high-risk Indigenous populations; and (ii) examine test properties across a range of diabetes prevalence from 5 to 30%. METHODS: Data were collected from Aboriginal and Torres Strait Islander communities in Australia and a Canadian First Nations community (diabetes prevalence 12-22%) in the course of diabetes diagnostic and risk factor screening programmes (n = 431). Screening test properties were analyzed for the range of HbA1c observed (3-12.9%). RESULTS: In separate and pooled analyses, a HbA1c cut point of 7.0% proved the optimal limit for classifying diabetes, with summary analysis results of sensitivity = 73 (56-86)%, specificity = 98 (96-99)%, overall agreement (Youden's index) = 0.71, and positive predictive value (for an overall prevalence of 18%) = 88%. For diabetes prevalence from 5 to 30% the post-test likelihood of having diabetes given HbA1c = 7.0% (positive predictive value) ranged from 62.7 to 93.2%; for HbA1c < 7.0%, the post-test likelihood of having diabetes ranged from 4.5 to 27.7%. CONCLUSIONS: The results converge with research on the likelihood of diabetes complications in supporting a HbA1c cut-off of 7.0% in screening for diabetes in epidemiological research. Glycated haemoglobin has potential utility in screening for diabetes in high-risk populations.     

Cost-effectiveness of screening for coronary artery disease in asymptomatic patients with type 2 diabetes and additional atherogenic risk factors

OBJECTIVE: Screening for coronary artery disease (CAD) in asymptomatic diabetic patients with two additional atherogenic risk factors has been recommended by the American College of Cardiology/American Diabetes Association, but its cost-effectiveness is yet to be determined. The present study aims to evaluate the cost-effectiveness of screening and determine acceptable strategies. DESIGN: Cost-effectiveness analysis using a Markov model was performed from a societal perspective to measure the clinical benefit and economic consequences of CAD screening in asymptomatic men with diabetes and two additional atherogenic risk factors. We evaluated cohorts of patients stratified by different age groups, and 10 possible combination pairs of atherogenic risks. Incremental cost-effectiveness of no screening, exercise electrocardiography, exercise echocardiography, or exercise single-photon emission-tomography (SPECT) was calculated. Input data were obtained from the published literature. Outcomes were expressed as U.S. dollars per quality-adjusted life-year (QALY). MEASUREMENTS AND MAIN RESULTS: Compared with no screening, incremental cost-effectiveness ratio of exercise electrocardiography was $41,600/QALY in 60-year-old asymptomatic diabetic men with hypertension and smoking, but was weakly dominated by exercise echocardiography. Exercise echocardiography was most cost-effective, with an incremental cost-effectiveness ratio of $40,800/QALY. Exercise SPECT was dominated by other strategies. Sensitivity analyses found that results varied depending on age, combination of additional atherogenic risk factors, and diagnostic test performance. CONCLUSIONS: Incremental cost-effectiveness ratio of CAD screening in asymptomatic patients with diabetes and two or more additional atherogenic risk factors is shown to be acceptable from a societal perspective. Exercise echocardiography was the most cost-effective strategy, followed by exercise electrocardiography.     

Haplotype-based search for SNPs associated with differential type 1 diabetes risk among chromosomes carrying a specific HLA DRB1–DQA1–DQB1 haplotype

Aim:  The aim of this study was to test chromosomes carrying the same DRB1–DQA1–DQB1 haplotype for single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) that might mark subgroups of the haplotype with different risks for type 1 diabetes (T1D).
Methods:  Chromosomes from T1D children, their parents and non-diabetic siblings in families of the Type 1 Diabetes Genetics Consortium (T1DGC) were analysed by two haplotype-based methods: (i) logistic regression analysis restricted to phased chromosomes carrying the same DRB1–DQA1–DQB1 haplotype but differentiated by the two alleles at MHC SNPs, which were individually tested for association with T1D and (ii) homozygous parent transmission disequilibrium test (TDT) for biased transmission of a SNP allele to diabetic children from parents who are heterozygous at the SNP but homozygous for the specific DRB1–DQA1–DQB1 haplotype being evaluated.
Results:  A number of SNPs gave nominally significant (p < 0.05) evidence of marking two subsets of the 301–501–201 haplotype that might differ with respect to their diabetogenic potency. However, none of the SNPs achieved experiment-wide significance and hence may be false-positive associations.
Conclusions:  We discuss limitations and possible deficiencies of our study suggesting further work that might yield more robust SNP associations marking two subgroups of a DRB1–DQA1–DQB1 haplotype with different T1D risks.     

A combination of HbA1c, fasting glucose and BMI is effective in screening for individuals at risk of future type 2 diabetes: OGTT is not needed

Objective. To identify a screening model that predicts high risk of future type 2 diabetes and is useful in clinical practice. Design and methods. Incident case‐referent study nested within a population‐based health survey. We compared screening models with three risk criteria and calculated sensitivity, specificity, positive (PPV) and negative (NPV) predictive values and attributable proportion. We used fasting plasma glucose (FPG) alone or with an oral glucose tolerance test (OGTT), glycosylated haemoglobin A (HbA1c) (normal range 3.6–5.3%), body mass index (BMI), triglycerides and family history of diabetes (FHD). Setting. Participants in a health survey at all primary care centres (n = 33 336) and subjects with diagnosed type 2 diabetes in primary and hospital care (n = 6088) in Umeå during 1989–2001. Subjects. Each of the 164 subjects who developed clinically diagnosed type 2 diabetes (median time to diagnosis of 5.4 years) and 304 sex‐ and age‐matched referents without diabetes diagnosis. Results. Screening models with at least one criterion present had sensitivities of 0.90–0.96, specificities of 0.43–0.57 and PPVs of 8–9%. Combinations of the criteria, FPG ≥ 6.1 mmol L^?1 (capillary plasma), HbA1c ≥ 4.7% and BMI ≥ 27 in men and BMI ≥ 30 in women, had sensitivities, specificities and PPVs of 0.66%, 0.93% and 32%, and 0.52%, 0.97% and 46% respectively. Using FHD as one of three risk criteria showed comparable results. Addition of triglycerides or OGTT did not improve the prediction. Conclusions. The combination of HbA1c, FPG and BMI are effective in screening for individuals at risk of future clinical diagnosis of type 2 diabetes. OGTT or FHD is not necessary.     

Ezetimibe added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for coronary heart disease with diabetes mellitus,metabolic syndrome or neither

Aim: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are both associated with increased risk for atherosclerotic coronary heart disease (CHD). Thus, it is useful to know the relative efficacy of lipid‐altering drugs in these patient populations. Methods: A double‐blind, parallel group trial of adult patients with hypercholesterolaemia at high‐CHD risk receiving atorvastatin 40 mg/day compared atorvastatin 40 mg plus ezetimibe 10 mg (ezetimibe) vs. doubling atorvastatin to 80 mg. This post hoc analysis reports lipid efficacy results in patients grouped by diagnosis of T2DM, MetS without T2DM or neither. Per cent change from baseline at week 6 was assessed for LDL‐C, total cholesterol, HDL‐C , non‐HDL‐C , Apo A‐I, Apo B and triglycerides. Safety was monitored through clinical and laboratory adverse events (AEs). Results: Compared with doubling atorvastatin, atorvastatin plus ezetimibe resulted in greater reductions in LDL‐C, triglycerides, Apo B, non‐HDL‐C, total cholesterol and lipid ratios in the T2DM, MetS and neither groups. Treatment effects were of similar magnitude across patient groups with both treatments, except triglycerides, which were slightly greater in the T2DM and MetS groups vs. neither group. Changes in HDL‐C , Apo A‐I and high sensitivity C‐reactive protein (hs‐CRP) were comparable for both treatments in all three groups. Safety and tolerability profiles were generally similar between treatments and across patient groups, as were the incidence of liver and muscle AEs. Conclusions: Compared with doubling atorvastatin to 80 mg, addition of ezetimibe to atorvastatin 40 mg produced greater improvements in multiple lipid parameters in high‐CHD risk patients with T2DM, MetS or neither, consistent with the significantly greater changes observed in the full study cohort (clinical trial # NCT00276484).     

Physical activity as a proxy to ameliorate inflammation in patients with type 2 diabetes and periodontal disease at high cardiovascular risk

While the beneficial impact of physical activity has been ascertained in a variety of pathological scenarios, including diabetes and low-grade systemic inflammation, its potential remains still putative for periodontal health. Periodontal disease has been associated with inflammatory systemic alterations, which share a common denominator with type 2 diabetes mellitus and cardiovascular disease. Physical exercise, along with nutritional counseling, is a cornerstone in the treatment and prevention of type 2 diabetes, also able to reduce the prevalence of periodontal disease and cardiovascular risk. In addition, considering the higher incidence of periodontitis in patients with type 2 diabetes compared to healthy controls, the fascinating research question would be whether physical activity could relieve the inflammatory pressure exerted by the combination of these two diseases. This multi-disciplinary viewpoint discusses available literature in order to argument the hypothesis of a “three–way relationship” linking diabetes, periodontitis, and physical activity.     

Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-gamma coactivator-1 gene might be a risk factor for diabetic retinopathy in Slovene population (Caucasians) with type 2 diabetes and the Pro12Ala polymorphism of the PPARgamma gene is not

BACKGROUND: The peroxisome proliferator-activated receptor-gamma (PPARgamma) gene has been recently associated with type 2 diabetes, obesity and traits depending on VEGF expression (e.g. retinopathy). The PPARgamma gene and its coactivator, the peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1) gene, have been implicated to be involved in glucose uptake and altered lipid oxidation. We therefore hypothesized that the Gly482Ser polymorphism of the PPARGC1 gene and Pro12Ala polymorphism of the PPARgamma gene might confer susceptibility to diabetic retinopathy in type 2 diabetes. The aim of this study was to investigate the association between the Pro12Ala polymorphism in the PPARgamma gene and Gly482Ser polymorphism in the PPARGC1 gene and the development of diabetic retinopathy in the Slovene population (Caucasians) with type 2 diabetes. METHODS: One hundred and sixty subjects with type 2 diabetes and diabetic retinopathy were compared with 101 diabetic subjects without diabetic retinopathy. Chi-square test was used to compare discrete variables, and continuous clinical data were compared by unpaired students t - test. RESULTS: A significantly higher frequency of the AA genotype of the Gly482Ser polymorphism of the PPARGC1 gene was found in the patients with diabetic retinopathy compared to the patients without diabetic retinopathy (14.4% vs 5.9%; p = 0.035), whereas the Pro12Ala polymorphism of the PPARgamma gene failed to yield an association with diabetic retinopathy. CONCLUSIONS: The present study demonstrates that the AA genotype of the Gly482Ser polymorphism in the PPARGC1 gene might be a risk factor for diabetic retinopathy in the Slovene population (Caucasians) with type 2 diabetes (odds ratio 2.7, 95% confidence interval 1.0-6.8), whereas the Pro12Ala polymorphism of the PPARgamma gene failed to confer susceptibility to diabetic retinopathy.