Natriuretic Peptides and Risk of Type 2 Diabetes: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium.

OBJECTIVE: Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD. RESEARCH DESIGN AND METHODS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models. RESULTS: Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236). CONCLUSIONS: NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms.

Regional differences of macrovascular disease in Northeast and South Germany: the population-based SHIP-TREND and KORA-F4 studies.

BACKGROUND: Previous studies found regional differences in the prevalence and incidence of type 2 diabetes between Northeast and South of Germany. The aim of this study was to investigate if regional variations are also present for macrovascular disease in people with type 2 diabetes and in the general population. A further aim was to investigate if traditional risk factors of macrovascular complications can explain these regional variations. METHODS: Data of persons aged 30-79 from two regional population-based studies, SHIP-TREND (Northeast Germany, 2008-2012, n = 2539) and KORA-F4 (South Germany, 2006-2008, n = 2932), were analysed. Macrovascular disease was defined by self-reported previous myocardial infarction, stroke or coronary angiography. Multivariable logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for prevalence of macrovascular disease in persons with type 2 diabetes and in the general population. RESULTS: The prevalence of macrovascular disease in persons with type 2 diabetes and in the general population was considerably higher in the Northeast (SHIP-TREND: 32.8 and 12.0%) than in the South of Germany (KORA-F4: 24.9 and 8.8%), respectively. The odds of macrovascular disease in persons with type 2 diabetes was 1.66 (95% CI: 1.11-2.49) in the Northeast in comparison to the South after adjustment for sex, age, body mass index, hypertension, hyperlipidemia and smoking. In the general population, SHIP-TREND participants also had a significantly increased odds of macrovascular disease compared to KORA-F4 participants (OR = 1.63, 95% CI: 1.33-2.00). After excluding coronary angiography (myocardial infarction or stroke only), the ORs for region decreased in all models, but the difference between SHIP-TREND and KORA-F4 participants was still significant in the age- and sex-adjusted model for the general population (OR = 1.34, 95% CI: 1.01-1.78). CONCLUSIONS: This study provides an indication for regional differences in macrovascular disease, which is not explained by traditional risk factors. Further examinations of other risk factors, such as regional deprivation or geographical variations in medical care services are needed.

Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α.

Importance: Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision. Objective: To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings. Design, Setting, and Participants: This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events. Exposures: Circulating TNF-α concentration. Main Outcomes and Measures: DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. Results: The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (ß [SE] = -0.01 [0.003]; P = 7.36 × 10-8), cg08122652 (ß [SE] = -0.008 [0.002]; P = 2.24 × 10-7), and cg22930808(ß [SE] = -0.01 [0.002]; P = 6.92 × 10-8); NLRC5 at cg16411857 (ß [SE] = -0.01 [0.002]; P = 2.14 × 10-13) and cg07839457 (ß [SE] = -0.02 [0.003]; P = 6.31 × 10-10); or ABO, at cg13683939 (ß [SE] = 0.04 [0.008]; P = 1.42 × 10-7) and cg24267699 (ß [SE] = -0.009 [0.002]; P = 1.67 × 10-7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α-linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10-5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10-5). Conclusions and Relevance: We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.

Increased intake of carbohydrates from sources with a higher glycemic index and lower consumption of whole grains during puberty are prospectively associated with higher IL-6 concentrations in younger adulthood among healthy individuals.

Chronic low-grade inflammation represents a likely intermediary in the relation between carbohydrate nutrition and both type 2 diabetes and cardiovascular disease. This study assessed the prospective association between carbohydrate quantity and quality [dietary glycemic index (GI), glycemic load (GL), and added sugar, fiber, and whole-grain intake] during puberty, a potentially critical period for later disease, and low-grade inflammation in younger adulthood. The analysis was based on 205 participants (113 girls and 92 boys) from the DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) study with at least 2 3-d weighed dietary records during puberty (girls: 9-14 y, boys: 10-15 y) and blood samples in younger adulthood (18-36 y). Multivariable linear regression models were used to analyze the associations between carbohydrate nutrition and circulating concentrations of pro- and anti-inflammatory immune mediators [high-sensitivity C-reactive protein (hs-CRP), interleukin (IL) 6, IL-18, and adiponectin]. A higher intake of carbohydrates during puberty (P-trend = 0.005), particularly from higher-GI food sources (P-trend = 0.01), was prospectively related to higher concentrations of IL-6 in younger adulthood, independently of baseline BMI and early life, socioeconomic, and other nutritional factors. Furthermore, a higher dietary GL (P-trend = 0.002) and a lower intake of whole grains (P-trend = 0.01) were independently associated with higher IL-6 concentrations in adults. Dietary GI and added sugar and fiber intakes were not independently associated with IL-6 (P-trend ≥ 0.09). Carbohydrate nutrition during puberty was not independently related to hs-CRP, IL-18, and adiponectin concentrations (all P-trend > 0.1). During puberty, a higher intake of carbohydrates from higher-GI food sources and lower whole-grain consumption prospectively predict greater IL-6 concentrations in young adulthood. These data support the hypothesis that diet during puberty influences later inflammation and metabolic dysfunction.

Is inflammation a causal chain between low socioeconomic status and type 2 diabetes? Results from the KORA Survey 2000.

Low socioeconomic status (SES) is associated with type 2 diabetes. Inflammatory markers like C-reactive protein (CRP) are predictive of diabetes. It is unclear, whether inflammation may be a mechanism linking low SES to type 2 diabetes. In the population-based KORA Survey 2000, 766 men and 710 women aged 55 to 74 years were randomly selected in the Augsburg region (Southern Germany). An index for SES was defined using education, occupation, and income. In women but not in men, increased CRP concentrations were found with lower SES (p<0.01). This significant trend was no longer observed after adjusting for BMI and waist circumference (p=0.23). Low SES was significantly associated with the age-adjusted odds of having type 2 diabetes both in men (OR; 95%CI: 1.35; 1.14-1.60) and in women (2.01; 1.37-2.96). The risk of having diabetes associated with low SES was only slightly changed after adjusting for CRP, which was itself significantly related to diabetes. In multivariate analyses, adjusting for age, obesity, physical activity, smoking, alcohol intake, and CRP, low SES yielded only a borderline statistical significance in women (p=0.07), whereas no significant association with diabetes remained in men (p=0.14). After CRP was dropped from the full model, there was no change in the OR obtained for low SES (men: 1.30; 0.92-1.83; women: 1.54; 0.97-2.45). Low SES was not related to prediabetes (IFG, IGT), whereas CRP was significantly associated with diabetes precursors. In conclusion, inflammation appears not to play a major role linking low SES and type 2 diabetes in the elderly population.