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• W1976333070 abstract "Objectives. The heat shock proteins 60 and 70 (HSP60, HSP70) play an important role in cytoprotection. Under stress conditions they are released into the circulation and elicit an immune response. Anti-HSP60 and anti-HSP70 antibody levels have been associated with cardiovascular disease. Type 1 diabetes is associated with a greatly increased risk of micro- and macrovascular complications. Therefore, we investigated whether anti-HSP60 and anti-HSP70 antibody levels were associated with micro- and macrovascular complications in type 1 diabetic patients. Design. A cross-sectional nested case-control study from the EURODIAB Study of 531 type 1 diabetic patients was performed. Subjects. Cases (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were all those with no evidence of any complication. We measured anti-HSP60 and anti-HSP70 antibody levels and investigated their cross-sectional associations with diabetic complications. Results. Anti-HSP70 antibody levels were significantly greater in control than in case subjects, whereas anti-HSP60 antibody levels were similar in the two groups. In logistic regression analysis, anti-HSP70 levels in the upper quartiles were associated with a 47% reduced odds ratio of micro/macrovascular complications, independently of conventional risk factors, markers of inflammation and endothelial dysfunction [odds ratio(OR) = 0.53, 95% confidence intervals(CI): 0.28–1.02]. Conclusions. In this large cohort of type 1 diabetic subjects, we found an independent and inverse association between serum anti-HSP70 antibody levels and diabetic micro/macrovascular complications. This suggests that anti-HSP70 antibody levels may be a novel marker of protection from chronic diabetic complications. Heat shock proteins (HSP) are intracellular, highly conserved polypeptides, grouped into families accordingly to their molecular weight. HSP are important for the survival of prokaryotic and eukaryotic cells [1]. Under normal conditions, HSP function as intracellular molecular chaperones of newly synthesized polypeptide chains, preventing their aggregation during folding and favouring both subunit assembly and translocation across subcellular membranes to the appropriate cellular compartments. Under conditions of cellular stress, such as hyperthermia, hypoxia, reperfusion, haemodynamic and oxidative stress, most of the HSP are induced and play an important role in both refolding of partially denatured proteins and clearance of irreparably damaged proteins [1, 2]. Heat shock proteins are normally secluded in intracellular compartments; however, in stressed cells they can be exposed on the plasma membrane and/or released into the circulation, eliciting an immune response. Both HSP release and immune reactivity to HSP have been implicated in the pathogenesis of chronic inflammatory diseases, including atherosclerosis [3, 4]. However, data are often conflicting and experimental studies also suggest that HSP exposure/immune reactivity may be associated with downregulation rather than induction or propagation of inflammation [5]. Heterogeneity among HSP probably exists and, while HSP60 might have a role as autoantigen in atherosclerosis [6-8], the presence of HSP70 in human sera appears associated with protection against cardiovascular disease (CVD) [9, 10]. Human data are, however, quite limited and most of studies have been hampered by low number of examined people, recruitment of clinic-based rather than population-based cohorts of subjects, and reduced spectrum of risk factors assessed simultaneously, not including markers of inflammation and endothelial dysfunction, thus limiting the evaluation of potential independent relationships. Type 1 diabetes is associated with a greatly increased risk of micro- and macrovascular complications, which cannot be completely accounted for by conventional risk factors. We have recently reported that in type 1 diabetic patients higher serum levels of HSP27 are associated with a threefold increased risk of distal symmetrical polyneuropathy (DSP), independently of confounders, vascular risk factors, and albuminuria [11]. The study was carried out with a cross-sectional nested case–control study-design as part of the EURODIAB Prospective Complications Study. On the same study-base, we have now tested whether HSP60, HSP70, and their antibodies are independently associated with micro/macrovascular complications of type 1 diabetes. The EURODIAB IDDM Complications Study (1989–1991) was designed to explore risk factors for diabetic complications in 3250 randomly selected people with type 1 diabetes, aged 15–60 years, attending 31 diabetic centres in 16 European countries. Type 1 diabetes was clinically defined as a diagnosis made before the age of 36 years, with a continuous need for insulin therapy within 1 year of diagnosis. Ethics committee approval was obtained at each centre, and all subjects provided written informed consent. The EURODIAB Prospective Complications Study (PCS; 1997–1999) is a follow-up of the EURODIAB IDDM Complications Study [12, 13]. The response rate at follow-up examination was 57.8% (n = 1,880). A cross-sectional nested case–control study was designed at the follow-up examinations [14-17]. Full data on CVD, microvascular complications, and neuropathy were available on 1296 patients. Cases were selected to have the greatest complication burden as possible to provide sufficient numbers for subgroup analyses; thus, cases were all those with CVD or proliferative retinopathy or neuropathy or micro-macroalbuminuria at follow-up. Control subjects were selected to be completely free of complications. Cases and controls were unmatched, so that the impact of key variables, such as age, could still be assessed, and any adjustments were taken care of at the analysis stage. This design allowed us to compare individuals with single or multiple complications with individuals free of complications, according to the study question, as efficiently as possible. Applying these criteria, this yielded 363 cases and 168 controls with full data on complications and samples available for analysis. At the follow-up examination only 232 subjects of 1296 were free of any complications, and of these, stored samples were available for 168 subjects. The sample size provides a power of 95% (α=0.05) to detect a difference within the cohort in both log-anti-HSP60 and log-anti-HSP70 of at least one-third of a standard deviation. Samples from both cases and controls subjects were collected at the follow-up examination only and both groups had the same lag time as the original recruitment, therefore findings obtained are cross-sectional rather than prospective. The protocol for sample collection and handling was identical across sites. Only samples stored at −80 °C within 2 h from collection were included in the nested study to reduce variability because of protein degradation. Frozen serum aliquots were sent to the Coordinating Center in London, and stored at −80°. Patient evaluation for the presence of cardiovascular risk factors (hypertension, body mass index, waist to hip ratio, smoking, cholesterol, triglycerides, HbA1c) is described elsewhere [14-17]. Retinopathy was diagnosed and graded according to the EURODIAB protocol [18]. Albumin excretion rate (AER), assessed on two 24-h urine collections by immunoturbidimetric method, was categorized as normoalbuminuria (<20 μg min−1), microalbuminuria (20–200 μg min−1), and macroalbuminuria (>200 μg min−1). CVD was defined as physician diagnosed myocardial infarction, angina, coronary artery bypass graft, or stroke and/or ischemic changes on centrally Minnesota-coded electrocardiogram. DSP was diagnosed on the basis of: (i) presence of one or more neuropathic symptoms; (ii) absence of two or more ankle or knee reflexes; and (iii) abnormal vibration perception threshold, measured by centrally calibrated biothesiometers (Biomedical, Newbury, OH, USA) on the right big toe and on the right medial malleolus. Soluble vascular cell adhesion molecule (sVCAM-1), soluble E-selectin (s-E-selectin), IL6, and TNF-α were measured by commercially available ELISA (R&D Systems, Oxon, UK); plasma levels of C-reactive protein (CRP) and Amadori albumin by in-house ELISA [14, 15]. Plasma homocysteine was determined with an automated fluorescence polarization immunoassay on an Abbott IMx analyzer (Abbott Laboratories, Abbott Park, IL, USA) [19]. Anti-HSP60 and anti-HSP70 antibody levels were measured in serum samples (diluted 1:500 and 1:1000, respectively) using commercial ELISA (EKS-650, EKS-750 Stressgen Biotechnologies Corporation), which detect all immunoglobulin isotypes (IgA, IgG, IgM). Stressgen Biotechnologies Corporation ELISA were also used to measure the serum levels of HSP70 and HSP60 antigens (EKS-700, EKS-600). Assay sensitivity and range were 3.125 ng mL−1 (3.125–100 ng mL−1) for HSP60; 0.5 ng mL−1 (0.75–50 ng mL−1) for HSP70; 2.88 ng mL−1 (7.81–250 ng mL−1) for anti-HSP60 and 6.79 ng mL−1 (6.79–1000 ng mL−1) for anti-HSP70. The intra- and inter-assay coefficients of variation (CV) were below 10% for all assays. Serum immunoglobulins levels were determined by immunoturbidometry (Dade Behring® BN 100 Analyzer; Dade Behring, Eschborn, Germany) with anti-IgG, anti-IgM and anti-IgA reagents and calibrators (Dade Behring®). The CV for both intra- and inter-assay was <4%. Variables distributed normally are presented as mean and SD, whereas variables with skewed distribution were analysed after logarithmic transformation (triglycerides, AER, creatinine, CRP, IL-6, TNF-α, sVCAM, s-E-selectin, homocysteine, anti-HSP60, and anti-HSP70) and results presented as geometric means and interquartile range. Logistic regression analyses was employed to estimate the odds ratios (OR) of serum anti-HSP60 and anti-HSP70 levels for any complication (AER≥20 μg min−1, retinopathy, neuropathy, CVD), independently of confounders and known risk factors. Both backward and forward strategies examining all explanatory variables were employed to select models [20]. The likelihood ratio test was used to compare nested models examining the role of age, sex, diabetes duration, BMI, WHR, HbA1c, blood pressure, lipids, AER, CRP, IL-6, TNF-α, homocysteine, Amadori albumin, s-E-selectin, sVCAM, smoking status. Variables were retained in the final model if they added significantly to the likelihood of models or to the estimated coefficients of predictors. In the light of the hypothesis of a different role of anti-HSP60 and anti-HSP70 in the pathogenesis of different complications, logistic regression models were also fitted separately for each complication. To assess pattern of OR across increasing serum anti-HSP60 and anti-HSP70 levels, they were categorized by the quartile distribution in controls. We tested for linear trends across quartiles by entering a single ordinal term into the models. As OR in the upper quartiles of anti-HSP70 were similar, they were aggregated as the reference category in the final analysis and compared with the lower quartile. The study population (n = 531) had a mean age of 39.6 years, a diabetes duration of 21.5 years and an equal proportion of men and women. Those with vascular complications had a more adverse risk factor profile than control individuals (Table 1). Of the 363 cases, nephropathy was present in 206 (22.6% micro- and 34.3% macroalbuminuria), retinopathy in 292 (background 39.1% and proliferative 41.3%), DSP in 205 (56.5%), and autonomic neuropathy in 118 (27.6%). Most people, however, had more than one complication; indeed, 187 (51.5%) individuals had both AER≥20 μg min−1 and retinopathy; 128 (35.3%) had both AER≥20 μg min−1 and DSP; 123 (33.9%) had AER≥20 μg min−1, DSP and retinopathy. CVD was present in 146 subjects (40.2%), all of them having also at least one microvascular complication, apart from 12 individuals who had CVD only. Anti-HSP60 and anti-HSP70 were measurable in all the 531 samples, with right skewed distribution of values (Table 1). In contrast, HSP60 and HSP70 antigens were detectable in <5% of the study population, thus analysis was not performed for these variables. Levels of anti-HSP60 antibodies were similar in cases and control subjects, whereas levels of anti-HSP70 antibody levels were significantly higher in control than in case subjects (Table 1), even after age-adjustment (171.5 vs. 153.6 μg mL−1, P = 0.05). We then performed logistic regression analyses to assess whether anti-HSP60 and anti-HSP70 antibody levels were associated with any complication, independently of main risk factors. Models performed in all subjects and separately for each complication showed that higher levels of anti-HSP70 conferred lower OR, even after adjusting for age, diabetes duration, HbA1c, hypertension, smoking, TNF-α, homocysteine and AER. BMI, lipids, CRP, IL-6, sVCAM, s-E-selectin, homocysteine and study centre did not add significantly to the model or to the estimated coefficients of predictors. No significant trends across quartiles were evident, but ORs suggested a cut-off value of anti-HSP70 corresponding with the first quartile. In the fully adjusted model (model 3), anti-HSP70 values in the upper quartiles (≥119.6 μg mL−1) conferred a 47% reduced OR [95% confidence interval (CI): 0.28–1.02, P = 0.058] as compared with values in the lower quartile (<119.6 μg mL−1) (Table 2). When analysis was performed examining each complication separately, the magnitude of OR were similar and reached statistical significance for retinopathy and CVD. In contrast, no increased OR were observed for loganti-HSP60, either examining all complications or micro- and macrovascular complication separately (Table 3). Furthermore, there was no significant trend across quartiles for any complication (all complications P = 0.67; DSP P = 0.92; retinopathy P = 0.51; micro-macroalbuminuria P = 0.61; CVD P = 0.83) even after adjustment for age, diabetes duration, hypertension, HbA1c, smoking, log-TNFα, log-homocysteine, logAER (all complications P = 0.90; DSP P = 0.40; retinopathy P = 0.98, micro-macroalbuminuria P = 0.37, CVD P = 0.77). Our case–control study shows that in type 1 diabetic subjects serum anti-HSP70 antibody levels in the upper quartiles are associated with an almost 50% lower likelihood of micro- and macrovascular complications with respect to lower values, independently of conventional risk factors, markers of both inflammation and endothelial dysfunction. This is an entirely novel finding and indicates that anti-HSP70 may be a novel protective marker for diabetes complications. Experimental work has provided evidence that HSP70 is a very sensitive indicator of cellular stress [7]. However, the underlying cellular mechanism/s of the inverse association between anti-HSP70 antibody levels and diabetic micro/macrovascular complications, remains elusive. Higher anti-HSP70 antibody concentrations are likely to reflect a relatively greater exposure, either in the past or in the present, to extracellular HSP70 antigen in the circulation and/or on the plasma membrane. In this regard, it is noteworthy that extracellular HSP70 has been shown to protect stressed aortic cells in culture through interactions with the cell surface [21], suggesting the hypothesis that expression of HSP70 or immune reactivity to HSP70 may be associated with downregulation of inflammatory processes [5]. Clinical studies in nondiabetic subjects have shown that circulating HSP70 levels act as a protective marker for CVD in both cross-sectional and prospective studies [9, 10]. Consistently with our findings, a recent report in nondiabetic subjects has shown lower anti-HSP70 antibody levels in patients with stable and unstable angina compared with healthy controls [22]. Most of the available data in humans, however, could have been biased by the recruitment of rather limited numbers of subjects from clinic-based studies. Moreover, they did not examine the potential role of confounding and modification factors, thus evidence on an association between anti-HSP70 and atherosclerosis was not conclusive. Our epidemiological study is the first to measure anti-HSP70 antibody concentrations in diabetic subjects and is also one of the largest epidemiological studies on circulating anti-HSP70 antibody levels. In univariate analysis, we found that mean levels were higher in control than in case subjects, although the magnitude of this difference was quite limited. Analyses examining continuous variables, however, are less informative than analyses comparing distributions of cases and control subjects across quartiles of the variable. This approach allows to assess whether a linear or nonlinear trend is evident and to suggest a cut off value. In our analyses, indeed, we provide evidence of a protective cut-off level of anti-HSP70 at the lowest quartile, with no evidence of a trend across its increasing values. The upper limit of CI of OR for all complication was slightly over 1.00 and hence not statistically significant; however, our aim was to generate rather than to test hypotheses. The magnitude of the association with anti-HSP70 was similar when we examined each complication separately, but reached statistical significance for both CVD and retinopathy. Overlapping among micro- and macrovascular complications, however, does not allow drawing any conclusions on the differential association of anti-HSP70 antibody levels with single complications of diabetes. Although in multivariate analysis the role of confounders was properly taken into account, the presence of an inverse association between anti-HSP70 and complications does not imply causality, because other unknown factors might be associated with both. Little is known on variables correlated with anti-HSP70 and the case-control study design of our study did not allow us to further explore this issue. Another potential explanation for our results is reverse causation that would occur if anti-HSP70 levels are decreased by the disease process itself leading to diabetic micro/macrovascular complications. Prospective studies are required to establish whether antibodies against HSP70 have a causal role in diabetic complications or simply act as a biomarker. In contrast to our results on anti-HSP70, we found that anti-HSP60 antibody levels conferred no significant variation in the risk of diabetic vascular complications. Two previous epidemiological studies in nondiabetic subjects have shown an independent association between anti-HSP60 antibody levels and coronary artery disease [23, 24]. HSP60, a mitochondrial protein, is transported to the cytosol and the cell surface of endothelial stressed cells, which could be lysed by anti-HSP60 antibodies, thus being directly involved in the pathogenesis of atherosclerosis [6, 7, 25]. In our cohort, the lack of difference in anti-HSP60 antibody levels between cases and control subjects raises the possibility that diabetes per se induces an increase in anti-HSP60 levels, which is not further enhanced by the development of complications. Consistently with this hypothesis the serum level of antibodies against human HSP60/mycobacterial HSP65 is greater in type 1 diabetic children than in healthy controls [26]. Furthermore, antibodies to HSP60 were shown to be higher in patients with the autoimmune disease rheumatoid arthritis in comparison to controls, but not associated with CVD [27]. On the other hand, differences with respect to previous findings may also be methodological in nature. We used calibrated standards of anti-human HSP60 and HSP70 antibodies in our immunoassays, whereas in previous studies standard curves were often not included and results expressed as optical density or antibody titre. In addition, our assay measures all immunoglobulin isotypes and we cannot exclude that differences in the individual subtypes could be missed. In our study, comparison of circulating HSP70 and HSP60 antigen levels between cases and controls could not be performed, because both serum HSP60 and HSP70 levels were undetectable in most of the subjects. This is unlikely because of methodological reasons as samples were adequately stored and reasonable stability of HSP60 in stored serum has been reported over a 5-year period [28]. Using the same assay, previous studies have shown that the percentages of subjects with detectable HSP levels varies from as low as 10%, similar to the present study, to 100%, depending on the population studied [10, 29-31]. In comparison, higher serum levels of HSP60 and 70 have been reported in studies using in-house assays and may relate to different matrix effects on the reference serum used for standardization [32, 33]. On the other hand low levels of HSP70 in our study may also be specific for diabetes. Indeed, recent studies have shown reduced HSP70 expression in diabetic tissue [34] and link this to loss in cardiovascular protection of diabetic subjects. Thus, circulating HSP70 levels below the threshold of detection may reflect lower intracellular expression. On the other hand, high concentration of HSP70 in complexes with IgG have been shown in plasma from type 1 diabetic patients [35] and immunocomplex formation may also provide explanation for the absence of free antigen in the majority of our diabetic patients, both cases and controls. There are certain limitations to our study. First, this is a cross-sectional study and this restricts our ability to either assess temporal relationships between anti-HSP70 levels and diabetic complications. However, no data in large groups of diabetes patients exist; therefore this study may serve as a reasonable starting point to explore the role of these antibodies in type 1 diabetes. Secondly, although serum samples were adequately stored, the possibility of protein degradation cannot be excluded; however, random misclassification would have biased downward our estimates, without affecting significant associations. Unlike previous studies, a key strength here is the ability to account for confounding by other risk factors and complications, and the large sample size provides sufficient power for these analyses. In addition, our patients were from a representative sample of people with type 1 diabetes across Europe, and our results, therefore, are likely to be generalizable. In conclusion, this is the first study measuring serum anti-HSP60 and anti-HSP70 antibody levels in a large group of type 1 diabetic patients and our results provide evidence that serum anti-HSP70 are independently and inversely associated with vascular complications in type 1 diabetic patients. Further studies are required to determine causal relationships and elucidate underlying mechanisms of this association. The authors declare that there is no duality of interest associated with this manuscript. This work was supported by the ‘Compagnia di San Paolo’, the Piedmont Region, and the University of Turin." @default.
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• W1976333070 title "ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/ macrovascular complications in type 1 diabetes: the EURODIAB Study" @default.
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