The association between bacterial infections and the risk of coronary heart disease in type 1 diabetes

Background Diabetes increases the risk of infections as well as coronary heart disease (CHD). Whether infections increase the risk of CHD and how this applies to individuals with diabetes is unclear. Objectives To investigate the association between bacterial infections and the risk of CHD in type 1 diabetes. Methods Individuals with type 1 diabetes (n = 3781) were recruited from the Finnish Diabetic Nephropathy Study (FinnDiane), a prospective follow-up study. CHD was defined as incident events: fatal or non-fatal myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, identified through national hospital discharge register data. Infections were identified through national register data on all antibiotic purchases from outpatient care. Register data were available from 1.1.1995-31.12.2015. Bacterial lipopolysaccharide (LPS) activity was measured from serum samples at baseline. Data on traditional risk factors for CHD were collected during baseline and consecutive visits. Results Individuals with an incident CHD event (n = 370) had a higher mean number of antibiotic purchases per follow-up year compared to those without incident CHD (1.34 [95% CI: 1.16-1.52], versus 0.79 [0.76-0.82],P <0.001), as well as higher levels of LPS activity (0.64 [0.60-0.67], versus 0.58 EU mL(-1)[0.57-0.59],P <0.001). In multivariable-adjusted Cox proportional hazards models, the mean number of antibiotic purchases per follow-up year was an independent risk factor for incident CHD (HR 1.21, 95% CI: 1.14-1.29,P <0.0001). High LPS activity was a risk factor for incident CHD (HR 1.93 [1.34-2.78],P <0.001) after adjusting for static confounders. Conclusion Bacterial infections are associated with an increased risk of incident CHD in individuals with type 1 diabetes.Peer reviewe

Waist‑height ratio and waist are the best estimators of visceral fat in type 1 diabetes

Visceral fat is associated with cardiovascular and kidney disease. However, the relationship between body composition and anthropometric measures in type 1 diabetes is unknown. Using z-statistics, we ranked the ability of body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), waist-height ratio (WHtR) and a body shape index (ABSI) to capture measures of body composition from 603 Dual-energy-X-Ray-Absorptiometry scans of adults with type 1 diabetes. Albuminuria was defined as urinary albumin excretion rate of at least 30 mg/24 h. Women with albuminuria had higher visceral fat mass % (VFM%) (0.9 vs. 0.5%, p = 0.0017) and lower appendicular lean mass % (AppLM%) (25.4 vs 26.4%, p = 0.03) than those without. Men with albuminuria had higher VFM% (1.5 vs. 1.0%, p = 0.0013) and lower AppLM% (30.0 vs 32.3, p < 0.0001) than those without. In men, WHtR estimated VFM% best (z-statistics = 21.1), followed by WC (z = 19.6), BMI (z = 15.1), WHR (z = 14.6) and ABSI (z = 10.1). In women, the ranking was WC (z = 28.9), WHtR (z = 27.3), BMI (z = 20.5), WHR (z = 12.7) and ABSI (z = 10.5). Overall, the ranking was independent of albuminuria. Adults with type 1 diabetes and albuminuria have greater VFM% and lower AppLM% than those without. WHtR and WC best estimate the VFM% in this population, independently of albuminuria and sex.Peer reviewe

Associations of dietary macronutrient and fibre intake with glycaemia in individuals with Type 1 diabetes

Aims To study the association between dietary intake and glycaemia in Type 1 diabetes. Methods Data on energy and nutrient intakes, and the mean and coefficient of variation of self-monitored blood glucose measurements were obtained from records completed by 1000 adults with Type 1 diabetes. Associations between these measures of glycaemia and dietary intake were investigated using generalized linear regression, with and without macronutrient substitution. Results In the first set of analyses, fibre intake was associated with lower mean self-monitored blood glucose values (beta = -0.428, 95% CI -0.624 to -0.231; PPeer reviewe

Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes

Background: Type 1 diabetes (T1D) is an autoimmune disease affecting individuals in the early years of life. Although previous studies have identified genetic loci influencing T1D diagnosis age, these studies did not investigate the genome with high resolution.Objective and methods: We performed a genome-wide meta-analysis for age at diagnosis with cohorts from Finland (Finnish Diabetic Nephropathy Study), the United Kingdom (UK Genetic Resource Investigating Diabetes) and Sardinia. Through SNP associations, transcriptome-wide association analysis linked T1D diagnosis age and gene expression.Results: We identified two chromosomal regions associated with T1D diagnosis age: multiple independent variants in the HLA region on chromosome 6 and a locus on chromosome 17q12. We performed gene-level association tests with transcriptome prediction models from two whole blood datasets, lymphocyte cell line, spleen, pancreas and small intestine tissues. Of the non-HLA genes, lower PNMT expression in whole blood, and higher IKZF3 and ZPBP2, and lower ORMDL3 and GSDMB transcription levels in multiple tissues were associated with lower T1D diagnosis age (FDR = 0.05). These genes lie on chr17q12 which is associated with T1D, other autoimmune diseases, and childhood asthma. Additionally, higher expression of PHF20L1, a gene not previously implicated in T1D, was associated with lower diagnosis age in lymphocytes, pancreas, and spleen. Altogether, the non-HLA associations were enriched in open chromatin in various blood cells, blood vessel tissues and foetal thymus tissue.Conclusion: Multiple genes on chr17q12 and PHF20L1 on chr8 were associated with T1D diagnosis age and only further studies may elucidate the role of these genes for immunity and T1D onset.</p

Working people with type 1 diabetes in the Finnish population

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Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus

Aims Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D. Methods and results We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) =1.32, P = 1.50 x 10(-8)], and rs6055069 on DEFB127 promoter (OR= 4.17, P= 2.35 x 10(-9)), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P <1 x 10(-6)), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P=4.21 x 10(-7)). Conclusion While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on beta-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation. [GRAPHICS] .Peer reviewe

Decline in Titers of Anti-Idiotypic Antibodies Specific to Autoantibodies to GAD65 (GAD65Ab) Precedes Development of GAD65Ab and Type 1 Diabetes.

The humoral Idiotypic Network consisting of antibodies and their anti-idiotypic antibodies (anti-Id) can be temporarily upset by antigen exposure. In the healthy immune response the original equilibrium is eventually restored through counter-regulatory mechanisms. In certain autoimmune diseases however, autoantibody levels exceed those of their respective anti-Id, indicating a permanent disturbance in the respective humoral Idiotypic Network. We investigated anti-Id directed to a major Type 1 diabetes (T1D)-associated autoantibody (GAD65Ab) in two independent cohorts during progression to disease. Samples taken from participants of the Natural History Study showed significantly lower anti-Id levels in individuals that later progressed to T1D compared to non-progressors (anti-Id antibody index of 0.06 vs. 0.08, respectively, p = 0.02). We also observed a significant inverse correlation between anti-Id levels and age at sampling, but only in progressors (p = 0.014). Finally, anti-Id levels in progressors showed a significant decline during progression as compared to longitudinal anti-Id levels in non-progressors (median rate of change: -0.0004 vs. +0.0004, respectively, p = 0.003), suggesting a loss of anti-Id during progression. Our analysis of the Diabetes Prediction in Skåne cohort showed that early in life (age 2) individuals at risk have anti-Id levels indistinguishable from those in healthy controls, indicating that low anti-Id levels are not an innate characteristic of the immune response in individuals at risk. Notably, anti-Id levels declined significantly in individuals that later developed GAD65Ab suggesting that the decline in anti-Id levels precedes the emergence of GAD65Ab (median rate of change: -0.005) compared to matched controls (median rate of change: +0.001) (p = 0.0016). We conclude that while anti-Id are present early in life, their levels decrease prior to the appearance of GAD65Ab and to the development of T1D

CRP polymorphisms and chronic kidney disease in the third national health and nutrition examination survey

<p>Abstract</p> <p>Background</p> <p><it>CRP </it>gene polymorphisms are associated with serum C-reactive protein concentrations and may play a role in chronic kidney disease (CKD) progression. We recently reported an association between the gene variant rs2808630 and CKD progression in African Americans with hypertensive kidney disease. This association has not been studied in other ethnic groups.</p> <p>Methods</p> <p>We used data from 5955 participants from Phase 2 of The Third National Health and Nutrition Examination Survey (1991-1994) to study the association between <it>CRP </it>polymorphisms and CKD prevalence in a population-based sample. The primary outcome was CKD defined as estimated glomerular filtration rate (eGFR) <60 ml/min or the presence of albuminuria. Secondary outcomes were the presence of albuminuria (any degree) and continuous eGFR. Six single nucleotide polymorphisms (SNPs) from the <it>CRP </it>gene, rs2808630, rs1205, rs3093066, rs1417938, rs3093058, and rs1800947, were evaluated.</p> <p>Results</p> <p><it>CRP </it>rs2808630 AG compared to the referent AA genotype was associated with CKD in non-Hispanic blacks (n = 1649, 293 of whom had CKD) with an adjusted odds ratio (OR) of 3.09 (95% CI 1.65-5.8; p = 0.001). For the secondary outcomes, rs2808630 AG compared to the referent AA genotype was associated with albuminuria with an adjusted OR of 3.07 (95% CI 1.59-5.94; p = 0.002), however not with eGFR. There was no association between the SNPs and CKD, albuminuria or eGFR in non-Hispanic whites or Mexicans Americans.</p> <p>Conclusions</p> <p>In this cross-sectional study, the 3' flanking <it>CRP </it>gene variant rs2808630 was associated with CKD, mainly through its association with albuminuria in the non-Hispanic blacks. Despite not finding an association with eGFR, our results support our previous study demonstrating an association between <it>CRP </it>gene variant rs2808630 and CKD progression in a longitudinal cohort of African American with hypertensive kidney disease.</p