The Association between Vitamin D and Vascular Stiffness in Adolescents with and without Type 1 Diabetes

Objective

Vitamin D deficiency is common and associated with increased cardiovascular disease (CVD) risk. Pulse wave velocity (PWV) is a marker of vascular stiffness associated with CVD. We hypothesized that Vitamin D (25 (OH) D) levels would be inversely associated with PWV in youth with and without type 1 diabetes (T1D).

Study Design

Comparisons were made between adolescents with T1D (n = 211; age = 17.5±2.3 years; diabetes duration = 10.9±3.2 years; A1c = 9.1±1.7%) and non-DM controls (n = 67; age = 16.9±1.9 years). PWV was measured in the carotid-femoral segment (Sphygmocor Vx, AtCor Medical, Lisle, IL).

Results

Vitamin D levels were similar in adolescents with T1D and controls (27.7±0.7 v. 26.0±1.3 ng/ml; p = 0.26). Vitamin D was significantly inversely associated with PWV after adjusting for age, sex, quarter of the year, and race-ethnicity in adolescents with T1D (beta  = −0.01±0.004, p = 0.02) but not in the non-DM adolescents (beta  = −0.008±0.008, p = 0.32). Vitamin D remained significantly associated with PWV after additionally adjusting for hs-CRP in adolescents with T1D (−0.01±0.004, p = 0.01). After adjusting for BMI z-score, lipids, or blood pressure, the relationship of Vitamin D with PWV was not significant.

Conclusions

Vitamin D levels were inversely associated with PWV in adolescents with T1D, but not independently of BMI, lipids, or blood pressure. Our data contrast with other reports and suggest further research is indicated to determine if Vitamin D supplementation would be beneficial to lower CVD risk in adolescents with T1D with vitamin D insufficiency or deficiency.     

Bone Marrow Stem Cell Treatment for Ischemic Heart Disease in Patients with No Option of Revascularization: A Systematic Review and Meta-Analysis

Objective

To evaluate bone marrow stem cell treatment (BMSC) in patients with ischemic heart disease (IHD) and no option of revascularization.

Background

Autologous BMSC therapy has emerged as a novel approach to treat patients with acute myocardial infarction or chronic ischemia and heart failure following percutaneous or surgical revascularization, respectively. However, the effect of the treatment has not been systematic evaluated in patients who are not eligible for revascularization.

Methods

MEDLINE (1950–2012), EMBASE (1980–2012), CENTRAL (The Cochrane Library 2012, Issue 8) and ongoing trial databases were searched for relevant randomized controlled trials. Trials where participants were diagnosed with IHD, with no option for revascularization and who received any dose of stem cells by any delivery route were selected for inclusion. Study and participant characteristics, details of the intervention and comparator, and outcomes measured were recorded by two reviewers independently. Primary outcome measures were defined as mortality and measures of angina; secondary outcomes were heart failure, quality of life measures, exercise/performance and left ventricular ejection fraction (LVEF).

Results

Nine trials were eligible for inclusion. BMSC treatment significantly reduced the risk of mortality (Relative Risk 0.33; 95% Confidence Interval 0.17 to 0.65; P = 0.001). Patients who received BMSC showed a significantly greater improvement in CCS angina class (Mean Difference −0.55; 95% Confidence Interval −1.00 to −0.10; P = 0.02) and significantly fewer angina episodes per week at the end of the trial (Mean Difference −5.21; 95% Confidence Interval −7.35 to −3.07; P<0.00001) than those who received no BMSC. In addition, the treatment significantly improved quality of life, exercise/performance and LVEF in these patients.

Conclusions

BMSC treatment has significant clinical benefit as stand-alone treatment in patients with IHD and no other treatment option. These results require confirmation in large well-powered trials with long-term follow-up to fully evaluate the clinical efficacy of this treatment.     

Genetic Associations with Diabetes: Meta-Analyses of 10 Candidate Polymorphisms

Aims

The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility.

Methods

Bibliographic databases were searched from 1970 to Dec 2012 for studies that reported on genetic association study of diabetes. After a comprehensive filtering procedure, 10 candidate gene variants with informative genotype information were collected for the current meta-anlayses. Using the REVMAN software, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the combined contribution of the selected genetic variants to diabetes.

Results

A total of 37 articles among 37,033 cases and 54,716 controls were involved in the present meta-analyses of 10 genetic variants. Three variants were found to be significantly associated with type 1 diabetes (T1D): NLRP1 rs12150220 (OR = 0.71, 95% CI = 0.55–0.92, P = 0.01), IL2RA rs11594656 (OR = 0.86, 95% CI = 0.82–0.91, P<0.00001), and CLEC16A rs725613 (OR = 0.71, 95% CI = 0.55–0.92, P = 0.01). APOA5 −1131T/C polymorphism was shown to be significantly associated with of type 2 diabetes (T2D, OR = 1.27, 95% CI = 1.03–1.57, P = 0.03). No association with diabetes was showed in the meta-analyses of other six genetic variants, including SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C.

Conclusion

Our results demonstrated that IL2RA rs11594656 and CLEC16A rs725613 are protective factors of T1D, while NLRP1 rs12150220 and APOA5 −1131T/C are risky factors of T1D and T2D, respectively.     

Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study

Background

Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.

Methods and Findings

The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10⁻⁴). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10⁻³) and waist circumference (p for interaction  = 7.49×10⁻⁹). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score.

Conclusions

The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention. Please see later in the article for the Editors'' Summary     

The Urinary Cytokine/Chemokine Signature of Renal Hyperfiltration in Adolescents with Type 1 Diabetes

Objective

Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFR_cystatin. Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors.

Methods

Urine and serum cytokines/chemokines (Luminex platform) and GFR_cystatin were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m²) and hyperfiltering (n = 31, T1D-H, GFR≥135 ml/min/1.73 m²) adolescents with T1D (ages 10–16), and in age and sex matched healthy control subjects (HC, n = 59).

Results

We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076).

Conclusions

Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study.     

Total Blood Mercury Levels and Depression among Adults in the United States: National Health and Nutrition Examination Survey 2005–2008

Background

Mercury is a neurotoxicant linked with psychiatric symptoms at high levels of exposure. However, it is unclear whether an association is present at the low exposure levels in the US adult population.

Materials and Methods

Cross-sectional associations of total blood mercury and depression were assessed in 6,911 adults age ≥20 in the National Health and Nutrition Examination Survey (NHANES), 2005–2008. The Patient Health Questionnaire-9 was used to assess depression (high likelihood of a depressive spectrum disorder diagnosis; score 5–27).

Results

Unadjusted survey weighted logistic regression suggested that higher total blood mercury was associated with lower odds of depression (Odds Ratio  = 0.49, 95% Confidence Interval: 0.36–0.65, comparing the highest and lowest mercury quintiles). This association largely disappeared after adjustment for sociodemographic variables (income-poverty ratio, education, marital status). However, in age-stratified analyses, this inverse relationship remained in older adults (age ≥40) even after adjustment for sociodemographic variables. Simulation analyses adjusting for expected confounding effects of fish intake suggested that the inverse relationship among older adults may be plausibly attributed to residual confounding (Odds Ratio  = 0.75, 95% Confidence Interval: 0.50–1.12, comparing the highest and lowest mercury quintiles).

Conclusions

Higher total blood mercury was not associated with increased odds of depression. The lower odds of depression in older adults with higher total blood mercury may be due to residual confounding.     

Adiponectin-11377CG Gene Polymorphism and Type 2 Diabetes Mellitus in the Chinese Population: A Meta-Analysis of 6425 Subjects

Background

Although adiponectin −11377CG gene polymorphism is implied to be associated with increased type 2 diabetes mellitus (T2DM) risk, results of individual studies are inconsistent.

Objective and Methods

A meta-analysis consisting of 12 individual studies, including a total of 6425 participants, was carried out in order to investigate the association of adiponectin −11377CG gene polymorphism with T2DM. The pooled odds ratio (OR) and its corresponding confidence interval (CI) at 95% were assessed through the random- or fixed- effect model.

Results

A significant relationship was observed between adiponectin −11377CG gene polymorphism and T2DM under allelic (OR: 1.150, 95% CI: 1.060 to 1.250, P = 0.001), recessive (OR: 1.450, 95% CI: 1.180–1.770, P = 0.0004), dominant (OR: 1.071, 95% CI: 1.013–1.131, P = 0.015), additive (OR: 1.280, 95% CI: 1.090–1.510, P = 0.002), and homozygous genetic models (OR: 1.620, 95% CI: 1.310–1.990, P<0.00001). No significant association was found between them under the heterozygous genetic model (OR: 1.640, 95% CI: 0.850–3.170, P = 0.140).

Conclusions

Adiponectin −11377CG gene polymorphism was significantly associated with T2DM risk susceptibility. G allele carriers are predisposed to T2DM risk.     

Effect of High- versus Low-Intensity Supervised Aerobic and Resistance Training on Modifiable Cardiovascular Risk Factors in Type 2 Diabetes; The Italian Diabetes and Exercise Study (IDES)

Background

While current recommendations on exercise type and volume have strong experimental bases, there is no clear evidence from large-sized studies indicating whether increasing training intensity provides additional benefits to subjects with type 2 diabetes.

Objective

To compare the effects of moderate-to-high intensity (HI) versus low-to-moderate intensity (LI) training of equal energy cost, i.e. exercise volume, on modifiable cardiovascular risk factors.

Design

Pre-specified sub-analysis of the Italian Diabetes and Exercise Study (IDES), a randomized multicenter prospective trial comparing a supervised exercise intervention with standard care for 12 months (2005–2006).

Setting

Twenty-two outpatient diabetes clinics across Italy.

Patients

Sedentary patients with type 2 diabetes assigned to twice-a-week supervised progressive aerobic and resistance training plus exercise counseling (n = 303).

Interventions

Subjects were randomized by center to LI (n = 142, 136 completed) or HI (n = 161, 152 completed) progressive aerobic and resistance training, i.e. at 55% or 70% of predicted maximal oxygen consumption and at 60% or 80% of predicted 1-Repetition Maximum, respectively, of equal volume.

Main Outcome Measure(s)

Hemoglobin (Hb) A_1c and other cardiovascular risk factors; 10-year coronary heart disease (CHD) risk scores.

Results

Volume of physical activity, both supervised and non-supervised, was similar in LI and HI participants. Compared with LI training, HI training produced only clinically marginal, though statistically significant, improvements in HbA_1c (mean difference −0.17% [95% confidence interval −0.44,0.10], P = 0.03), triglycerides (−0.12 mmol/l [−0.34,0.10], P = 0.02) and total cholesterol (−0.24 mmol/l [−0.46, −0.01], P = 0.04), but not in other risk factors and CHD risk scores. However, intensity was not an independent predictor of reduction of any of these parameters. Adverse event rate was similar in HI and LI subjects.

Conclusions

Data from the large IDES cohort indicate that, in low-fitness individuals such as sedentary subjects with type 2 diabetes, increasing exercise intensity is not harmful, but does not provide additional benefits on cardiovascular risk factors.

Trial Registration

www.ISRCTN.org ISRCTN-04252749.     

Common Genetic Variants of Surfactant Protein-D (SP-D) Are Associated with Type 2 Diabetes

Context

Surfactant protein-D (SP-D) is a primordial component of the innate immune system intrinsically linked to metabolic pathways. We aimed to study the association of single nucleotide polymorphisms (SNPs) affecting SP-D with insulin resistance and type 2 diabetes (T2D).

Research Design and Methods

We evaluated a common genetic variant located in the SP-D coding region (rs721917, Met³¹Thr) in a sample of T2D patients and non-diabetic controls (n = 2,711). In a subset of subjects (n = 1,062), this SNP was analyzed in association with circulating SP-D concentrations, insulin resistance, and T2D. This SNP and others were also screened in the publicly available Genome Wide Association (GWA) database of the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC).

Results

We found the significant association of rs721917 with circulating SP-D, parameters of insulin resistance and T2D. Indeed, G carriers showed decreased circulating SP-D (p = 0.004), decreased fasting glucose (p = 0.0002), glycated hemoglobin (p = 0.0005), and 33% (p = 0.002) lower prevalence of T2D, estimated under a dominant model, especially among women. Interestingly, these differences remained significant after controlling for origin, age, gender, and circulating SP-D. Moreover, this SNP and others within the SP-D genomic region (i.e. rs10887344) were significantly associated with quantitative measures of glucose homeostasis, insulin sensitivity, and T2D, according to GWAS datasets from MAGIC.

Conclusions

SP-D gene polymorphisms are associated with insulin resistance and T2D. These associations are independent of circulating SP-D concentrations.     

Eosinophil Inversely Associates with Type 2 Diabetes and Insulin Resistance in Chinese Adults

Context

Limited population-based study focused on relationship between eosinophil and type 2 diabetes (T2D).

Objectives

We aimed to evaluate the relationship between peripheral eosinophil percentage and glucose metabolism and insulin resistance in a large sample size of Chinese population aged 40 and older.

Design and Methods

A cross-sectional study was performed among 9,111 Chinese adults including 3,561 men and 5,550 women. The glucose metabolism status was confirmed by 75-g oral glucose tolerance test. Homeostasis model assessment of insulin resistance index and serum insulin levels were used to evaluate insulin resistance. Homeostasis model assessment-B was used to evaluate β cell function.

Results

The average age of participants was 58.5 years. The prevalence of T2D decreased across the tertiles of eosinophil percentage (21.3%, 18.2% and 16.9%, P<0.0001). Each one tertile increase of eosinophil percentage inversely associated with risk of T2D when referred not only to normal glucose tolerance (NGT) (odds ratio (OR) 0.81, 95% CI 0.76–0.87, P< 0.0001), but also to impaired glucose regulation (OR 0.89, 95% CI 0.83–0.97, P = 0.006), respectively, after adjustment for the confounding factors. Compared with the first tertile, the third tertile of eosinophil percentage associated with a 23% decrease of insulin resistance in NGT participants after full adjustments (P = 0.005). Each 1-standard deviation of increment of eosinophil percentage associated with a 37% decrease of insulin resistance (P = 0.005).

Conclusions

Higher peripheral eosinophil percentage was associated with decreased risk of T2D. The inverse relation to insulin resistance was detected in NGT participants.     

Financial Stress and Outcomes after Acute Myocardial Infarction

Background

Little is known about the association between financial stress and health care outcomes. Our objective was to examine the association between self-reported financial stress during initial hospitalization and long-term outcomes after acute myocardial infarction (AMI).

Materials and Methods

We used Prospective Registry Evaluating Myocardial Infarction: Event and Recovery (PREMIER) data, an observational, multicenter US study of AMI patients discharged between January 2003 and June 2004. Primary outcomes were disease-specific and generic health status outcomes at 1 year (symptoms, function, and quality of life (QoL)), assessed by the Seattle Angina Questionnaire [SAQ] and Short Form [SF]-12. Secondary outcomes included 1-year rehospitalization and 4-year mortality. Hierarchical regression models accounted for patient socio-demographic, clinical, and quality of care characteristics, and access and barriers to care.

Results

Among 2344 AMI patients, 1241 (52.9%) reported no financial stress, 735 (31.4%) reported low financial stress, and 368 (15.7%) reported high financial stress. When comparing individuals reporting low financial stress to no financial stress, there were no significant differences in post-AMI outcomes. In contrast, individuals reporting high financial stress were more likely to have worse physical health (SF-12 PCS mean difference −3.24, 95% Confidence Interval [CI]: −4.82, −1.66), mental health (SF-12 MCS mean difference: −2.44, 95% CI: −3.83, −1.05), disease-specific QoL (SAQ QoL mean difference: −6.99, 95% CI: −9.59, −4.40), and be experiencing angina (SAQ Angina Relative Risk = 1.66, 95%CI: 1.19, 2.32) at 1 year post-AMI. While 1-year readmission rates were increased (Hazard Ratio = 1.50; 95%CI: 1.20, 1.86), 4-year mortality was no different.

Conclusions

High financial stress is common and an important risk factor for worse long-term outcomes post-AMI, independent of access and barriers to care.     

Inverse Association between Glycated Albumin and Insulin Secretory Function May Explain Higher Levels of Glycated Albumin in Subjects with Longer Duration of Diabetes

Background

Glycated albumin (GA) has been increasingly used as a reliable index for short-term glycemic monitoring, and is inversely associated with β-cell function. Because the pathophysiologic nature of type 2 diabetes (T2D) is characterized by progressive decline in insulin secretion, the aim was to determine whether GA levels were affected by diabetes duration in subjects with T2D.

Methods

To minimize the effect of glucose variability on GA, subjects with stably maintained HbA_1c levels of <0.5% fluctuation across 6 months of measurements were included. Patients with newly diagnosed T2D (n = 1059) and with duration>1 year (n = 781) were recruited and categorized as New-T2D and Old-T2D, respectively. Biochemical, glycemic, and C-peptide parameters were measured.

Results

GA levels were significantly elevated in HbA_1c-matched Old-T2D subjects compared to New-T2D subjects. Duration of diabetes was positively correlated with GA, whereas a negative relationship was found with C-peptide increment (ΔC-peptide). Among insulin secretory indices, dynamic parameters such as ΔC-peptide were inversely related to GA (r = −0.42, p<0.001). Multiple linear regression analyses showed that duration of diabetes was associated with GA (standardized β coefficient [STDβ] = 0.05, p<0.001), but not with HbA_1c (STDβ = 0.04, p<0.095). This association disappeared after additional adjustment with ΔC-peptide (STDβ = 0.02, p = 0.372), suggesting that β-cell function might be a linking factor of close relationship between duration of diabetes and GA values.

Conclusions

The present study showed that GA levels were significantly increased in subjects with longer duration T2D and with decreased insulin secretory function. Additional caution should be taken when interpreting GA values to assess glycemic control status in these individuals.     

Effect of Tree Nuts on Glycemic Control in Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Dietary Trials

Background

Tree nut consumption has been associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent.

Objective

To provide better evidence for diabetes guidelines development, we conducted a systematic review and meta-analysis of randomized controlled trials to assess the effects of tree nuts on markers of glycemic control in individuals with diabetes.

Data Sources

MEDLINE, EMBASE, CINAHL, and Cochrane databases through 6 April 2014.

Study Selection

Randomized controlled trials ≥3 weeks conducted in individuals with diabetes that compare the effect of diets emphasizing tree nuts to isocaloric diets without tree nuts on HbA1c, fasting glucose, fasting insulin, and HOMA-IR.

Data Extraction and Synthesis

Two independent reviewer’s extracted relevant data and assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% CI’s. Heterogeneity was assessed (Cochran Q-statistic) and quantified (I²).

Results

Twelve trials (n = 450) were included. Diets emphasizing tree nuts at a median dose of 56 g/d significantly lowered HbA1c (MD = −0.07% [95% CI:−0.10, −0.03%]; P = 0.0003) and fasting glucose (MD = −0.15 mmol/L [95% CI: −0.27, −0.02 mmol/L]; P = 0.03) compared with control diets. No significant treatment effects were observed for fasting insulin and HOMA-IR, however the direction of effect favoured tree nuts.

Limitations

Majority of trials were of short duration and poor quality.

Conclusions

Pooled analyses show that tree nuts improve glycemic control in individuals with type 2 diabetes, supporting their inclusion in a healthy diet. Owing to the uncertainties in our analyses there is a need for longer, higher quality trials with a focus on using nuts to displace high-glycemic index carbohydrates.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01630980","term_id":"NCT01630980"}}NCT01630980     

Determination of 14 Circulating microRNAs in Swedes and Iraqis with and without Diabetes Mellitus Type 2

Background

Recent reports suggest that immigrants from Middle Eastern countries are a high-risk group for type 2 diabetes (T2D) compared with Swedes, and that the pathogenesis of T2D may be ethnicity-specific. Deregulation of microRNA (miRNA) expression has been demonstrated to be associated with T2D but ethnic differences in miRNA have not been investigated. The aim of this study was to explore the ethnic specific expression (Swedish and Iraqi) of a panel of 14 previously identified miRNAs in patients without T2D (including those with prediabetes) and T2D.

Methods

A total of 152 individuals were included in the study (84 Iraqis and 68 Swedes). Nineteen Iraqis and 14 Swedes were diagnosed with T2D. Expression of the 14 selected miRNAs (miR-15a, miR-20, miR-21, miR-24, miR-29b, miR-126, miR-144, miR-150, miR-197, miR-223, miR-191, miR-320a, miR-486-5p, and miR-28-3p) in plasma samples was measured by real-time PCR.

Results

In the whole study population, the expression of miR-24 and miR-29b was significantly different between T2D patients and controls after adjustment for age, sex, waist circumference, family history of T2D, and a sedentary lifestyle. Interestingly, when stratifying the study population according to country of birth, we found that higher expression of miR-144 was significantly associated with T2D in Swedes (OR = 2.43, p = 0.035), but not in Iraqis (OR = 0.54, p = 0.169). The interaction test was significant (p = 0.017).

Conclusion

This study suggests that the association between plasma miR-144 expression and T2D differs between Swedes and Iraqis.     

Role of IL-4 Gene Polymorphisms in HBV-Related Hepatocellular Carcinoma in a Chinese Population

Background

Interleukin-4 (IL-4) is best known as an important mediator and modulator of immune and inflammatory responses. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer, and genetic variations in the IL-4 gene may be associated with the risk of hepatitis B virus (HBV)-related HCC. However, few studies have been conducted on their association.

Objectives

To clarify the effects of IL-4 gene polymorphisms on the risk of HBV-related HCC, two common variants, −590C/T (rs2243250) and −33C/T (rs2070874), and their relationship with HBV-related disease risk were investigated in a Chinese population.

Methods

IL-4 −590C/T and −33C/T polymorphisms were examined in 154 patients with HBV-related HCC, 62 patients with HBV-induced liver cirrhosis (LC), 129 patients with chronic hepatitis B (CHB), and 94 healthy controls, using the polymerase chain reaction-restriction fragment length polymorphism method and DNA sequencing.

Results

Overall, no significant differences were observed regarding the IL-4 −590C/T and −33C/T polymorphism genotypes, alleles, or haplotypes between the patient groups and the healthy controls. However, the CC genotypes of IL-4 −590C/T and −33C/T polymorphisms were observed to be significantly associated with CHB in subgroup analysis in males [CC versus TT (OR: 4.193, 95% CI: 1.094–16.071, P = 0.037; and OR: 3.438, 95% CI: 1.032–11.458, P = 0.044) and CC versus TT+CT (OR: 4.09, 95% CI: 1.08–15.49, P = 0.038; and OR: 3.43, 95% CI: 1.04–11.28, P = 0.042)].

Conclusions

These findings suggest that genetic variants in IL-4 −590C/T and −33C/T polymorphisms may be a risk factor for CHB in Chinese males but not for HBV-related LC or HCC.     

Posttraumatic Stress Disorder and Not Depression Is Associated with Shorter Leukocyte Telomere Length: Findings from 3,000 Participants in the Population-Based KORA F4 Study

Background

A link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD.

Methods

Data are derived from the population-based KORA F4 study (2006–2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed.

Results

The multiple model revealed a significant association between partial PTSD and TL (beta = −0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = −0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations.

Conclusions

Participants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.     

Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology

Background

The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).

Methodology/Principal Findings

Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.

Conclusions/Significance

These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.     

Polymorphisms in the Calcium-Sensing Receptor Gene Are Associated with Clinical Outcome of Neuroblastoma

Background

Neuroblastic tumors include the neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Clinical behavior of these developmental malignancies varies from regression to aggressive growth with metastatic dissemination. Several clinical, histological, genetic, and biological features are associated with this diversity of clinical presentations. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor with a key role in calcium homeostasis. We have previously reported that it is expressed in benign, differentiated neuroblastic tumors, but silenced by genetic and epigenetic events in unfavorable neuroblastomas. We have now analyzed three functionally relevant polymorphisms clustered at the signal transduction region of the CaSR (rs1801725, rs1042636 and rs1801726) to assess if genetic variants producing a less active receptor are associated with more aggressive disease course.

Methods

Polymorphisms were analyzed in DNA samples from 65 patients using specific Taqman Genotyping Assays.

Results

Mildly inactivating variant rs1801725 was associated with clinical stage 4 (P = 0.002) and the histological subgroup of undifferentiated neuroblastomas (P = 0.046). Patients harboring this polymorphism had significantly lower overall (P = 0.022) and event-free survival (P = 0.01) rates than those who were homozygous for the most common allele among Caucasians. However, this single locus genotype was not independently associated with outcome in multivariate analyses. Conversely, the tri-locus haplotype TAC was independently associated with an increased risk of death in the entire cohort (Hazard Ratio = 2.45; 95% Confidence Interval [1.14–5.29]; P = 0.022) and also in patients diagnosed with neuroblastomas (Hazard Ratio = 2.74; 95% Confidence Interval [1.20–6.25]; P = 0.016).

Conclusions

The TAC haplotype includes the moderately inactivating variant rs1801725 and absence of the gain-of-function rs1042636 polymorphism. Thus, its association with metastatic disease and poor outcome would add to our previous data and further support that inactivation of the CaSR gene is a mechanism associated with neuroblastoma malignant behavior.     

Elevated Peripheral Frequencies of Th22 Cells: A Novel Potent Participant in Obesity and Type 2 Diabetes

Objective

Chronic low-grade inflammation has long been recognized as the central link between obesity and type 2 diabetes (T2D). The novel subset of T helper (Th) cells, Th22, plays an emerging role in chronic inflammation. We investigated the potential association between Th22 and the pathogenesis of obesity and T2D.

Methods

Ninety T2D inpatients (T2D group), 30 healthy participants with BMI ranged from 19 to 23.9 kg/m2 (CTL group) and 30 metabolically healthy obese controls with BMI ≥ 30 kg/m2 (MHO group) were employed in our study. Peripheral frequencies of Th22 and Th1 and Th17 cells were determined by flow cytometry based on their specific cytokine patterns. Cytokine levels in fresh plasma were quantified by ELISA.

Results

Compared to that in CTL group (1.18±0.06%, n = 28), peripheral frequency of Th22 cells was significantly increased in MHO group (1.88±0.10%, n = 30) and in T2D group (2.247±0.10%, n = 89). There was a consistent notable increase in plasma interleukin (IL)-22 of T2D patients [47.56 (30.55–76.89) pg/mL] as compared with that of MHO group [36.65 (29.52–55.70) pg/ml; *P<0.0001] and CTLs [36.33 (31.93–40.62) pg/mL; *P<0.0001]. Furthermore, other than Th1/Th17, previously frequently described participants in obesity and T2D, there was a strong correlation between Th22 frequency and the homeostasis model of assessment for insulin resistance index (r = 0.6771, *P<0.0001) and HOMA for β-cell function (r = −0.7264, *P<0.0001).

Conclusions

There were increased Th22 frequencies and IL-22 levels in obesity and T2D. Elevated Th22 and IL-22 also aided in the differentiation of MHO from T2D patients. The notable correlation implied that Th22 might play a more determinant role in both insulin resistance and β-cell impairment.