Insulin gene polymorphisms in type I diabetes, Addison's disease and the polyglandular autoimmune syndrome type II

Background: Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from ß-cell autoimmunity. Methods: We investigated the role of the -2221Msp(C/T) and -23HphI(A/T) polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317), Addison´s disease (AD, n = 107) or Hashimoto´s thyroiditis (HT, n = 61)], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62) as well as in healthy controls (HC, n = 275). Results: T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T) and "AA" -23HphI(A/T) polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively). The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion: We demonstrate that the allele "C" of the -2221Msp(C/T) and "A" -23HphI(A/T) insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II

Reduced decline of lung diffusing capacity in COPD patients with diabetes and metformin treatment

We studied whether in patients with COPD the use of metformin for diabetes treatment was linked to a pattern of lung function decline consistent with the hypothesis of anti-aging efects of metformin. Patients of GOLD grades 1–4 of the COSYCONET cohort with follow-up data of up to 4.5 y were included. The annual decline in lung function (FEV1, FVC) and CO difusing capacity (KCO, TLCO) in %predicted at baseline was evaluated for associations with age, sex, BMI, pack-years, smoking status, baseline lung function, exacerbation risk, respiratory symptoms, cardiac disease, as well as metformin-containing therapy compared to patients without diabetes and metformin. Among 2741 patients, 1541 (mean age 64.4 y, 601 female) fulflled the inclusion criteria. In the group with metformin treatment vs. non-diabetes the mean annual decline in KCO and TLCO was signifcantly lower (0.2 vs 2.3, 0.8 vs. 2.8%predicted, respectively; p < 0.05 each), but not the decline of FEV1 and FVC. These results were confrmed using multiple regression and propensity score analyses. Our fndings demonstrate an association between the annual decline of lung difusing capacity and the intake of metformin in patients with COPD consistent with the hypothesis of anti-aging efects of metformin as refected in a surrogate marker of emphysema

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

Serum uromodulin and decline of kidney function in older participants of the population-based KORA F4/FF4 study

Background: Uromodulin, a tissue-specific tubular glycoprotein, has recently emerged as a promising biomarker for kidney function and tubular integrity. However, the association of serum uromodulin (sUmod) with renal function decline is still unknown in an older general population. Methods: We analysed the association of sUmod with the estimated glomerular filtration rate (eGFR) and albuminuria in 1075 participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study, ages 62-81 years, at baseline and prospectively after a mean follow-up time of 6.5 years (n = 605) using logistic and linear regression models as well as receiver operating characteristics (ROC) analyses. Results: Cross-sectionally, sUmod was positively associated with eGFR (β = 0.31 ± 0.02 per higher standard deviation sUmod; P &lt; 0.001) and inversely associated with the urinary albumin:creatinine ratio (β = -0.19 ± 0.04; P &lt; 0.001) after adjustment for sex, age, body mass index, arterial hypertension, prediabetes and diabetes. After multivariable adjustment including baseline eGFR, sUmod was not associated with incident chronic kidney disease (CKD), defined as a decrease in eGFR &lt;60 mL/min/1.73 m2 after 6.5 years of follow-up {odds ratio [OR] 1.02 [95% confidence interval (CI) 0.77-1.36] per higher SD sUmod} but was inversely associated with advanced CKD, defined as incident eGFR &lt;45 mL/min/1.73 m2 [OR 0.64 (95% CI 0.42-0.98)]. The ROC showed no added predictive value of sUmod for kidney function decline in the fully adjusted model. Conclusions: Higher sUmod was inversely associated with progression to advanced kidney disease but does not provide additional predictive value for the development of CKD in elderly participants of the population-based KORA study

Supplementary data from: Serum uromodulin is associated with but does not predict type 2 diabetes in elderly KORA F4/FF4 study participants

Background: Serum uromodulin (sUmod) is a novel biomarker for kidney function and was suggested to be associated with type 2 diabetes (T2D) in patients admitted for coronary angiography (1). In the associated article, we show an association of sUmod with T2D in men, but not in women in the population-based KORA F4 study. Here, we analyzed the association of sUmod with parameters of glucose regulation. Methods: In 1119 participants of the KORA F4 study aged 62 - 81 years, sUmod was measured. The association of sUmod with HbA1c values, fasting glucose, fasting insulin, fasting proinsulin and HOMA-IR was assessed using logistic and linear regression models stratified for sex. Correction for confounders was performed in multinomial models as indicated in the tables. Participants with missing covariables were excluded from the respective analyses. The final numbers of participants included in each analysis in the respective fully adjusted model are indicated in the tables or table captions, respectively. Results: SUmod was inversely associated with HbA1c values in the diabetic range (≥ 48 mmol/mol (6.5%)) in the total cohort and in men after adjustment for age, BMI and eGFR. In women, the inverse relation of sUmod and HbA1c values ≥ 48 mmol/mol (6.5%) was no longer significant after adjustment for age and BMI (table 1). The relation of sUmod with moderately elevated HbA1c levels in the prediabetic range (39 – 46 mmol/mol (5.7 - 6.4 %)) was not significant in women and no longer significant in the total study cohort and in men after adjustment for age and BMI. SUmod was associated with a lower fasting glucose and a lower insulin resistance as determined by HOMA-IR. In women, the association with HOMA-IR was attenuated to non-significance after adjustment for age and BMI. After adjustment for age, BMI and eGFR, fasting insulin was weakly, but significantly inversely associated with sUmod in men, but not in women, whereas a relation of proinsulin with sUmod could not be established after correction for age, sex, BMI and eGFR (table 2). Table 3 displays the characteristics of the study participants included in the follow-up analysis of the KORA F4 study (KORA FF4 study with a mean follow-up time of 6.5 ± 0.3 years)

Serum uromodulin is associated with but does not predict type 2 diabetes in elderly KORA F4/FF4 study participants

Aims: Serum uromodulin has recently emerged as promising biomarker for kidney function and was suggested to be associated with type 2 diabetes (T2D) in patients with coronary heart disease. Here, we analyzed the association of serum uromodulin with T2D in the population-based KORA F4/FF4 study.Methods: In 1119 participants of the KORA F4 study aged 62 to 81 years, serum uromodulin was measured, and the association of serum uromodulin with T2D was assessed using logistic and linear regression models stratified for sex. After a mean follow-up time of 6.5 years, 635 participants where re-evaluated. Glucose tolerance status was determined by oral glucose tolerance test at baseline and at the follow-up examination except in cases of known T2D.Results: Serum uromodulin was inversely associated with T2D in the crude analysis and after adjustment for age and body mass index in men (P &lt; 0.001) and in women (P &lt; 0.05). After further adjustment for estimated glomerular filtration rate, serum uromodulin was significantly inversely associated with T2D in men (P &lt; 0.001) but not in women. Serum uromodulin was not associated with prediabetes after multivariate adjustment and did not predict T2D in men or in women after the follow-up time of 6.5 +/- 0.3 years.Conclusions: In participants of the KORA F4 study, serum uromodulin is independently associated with T2D in men but is not a predictor of future development of T2D

Serum uromodulin is inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1 in the population-based KORA F4 study

Objectives Uromodulin has been associated with arterial hypertension in genome-wide association studies, but data from clinical and preclinical studies are inconsistent. We here analyzed the association of serum uromodulin (sUmod) with arterial hypertension and vasoactive hormones in a population-based study. Methods In 1108 participants of the KORA F4 study aged 62-81 years, sUmod was measured and the association of sUmod with arterial hypertension was assessed using logistic regression models. The associations of sUmod with renin and aldosterone and with the vasoconstrictive prohormone C-terminal pro-endothelin-1 (CT-proET-1) were analyzed in 1079 participants and in 618 participants, respectively, using linear regression models. Results After multivariable adjustment including sex, age, eGFR, BMI, fasting glucose, current smoking, previous stroke and myocardial infarction, sUmod was inversely associated with arterial hypertension (OR 0.78; 95% CI 0.68-0.91; p = 0.001). SUmod was not significantly associated with renin and aldosterone after adjustment for sex, age and eGFR. However, sUmod was inversely associated with CT-proET-1 (beta -0.19 +/- 0.04; p &lt; 0.001) after adjustment for sex, age, eGFR, BMI, arterial hypertension, fasting glucose, current smoking, previous stroke and myocardial infarction. The association with CT-proET-1 was stronger in participants with hypertension (beta -0.22 +/- 0.04) than in normotensive participants (beta -0.13 +/- 0.06; p for interaction hypertension = 0.003 in the model adjusted for hypertension). Conclusions SUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of sUmod on blood pressure regulation

Serum uromodulin and risk for cardiovascular morbidity and mortality in the community-based KORA F4 study

Background and aims: Serum uromodulin, a novel biomarker of kidney function and tubular integrity, has been linked to cardiovascular events and total mortality in patients at high cardiovascular risk. Here, we analyze the association of serum uromodulin with cardiovascular morbidity and cardiovascular as well as total mortality in the population-based KORA F4 study stratified by sex.Methods: Baseline serum uromodulin was measured in 1079 participants of the KORA F4 study (age 62-81 years). Using multivariable adjusted Cox proportional hazards models, the associations of serum uromodulin with total mortality and cardiovascular mortality were analyzed after a median follow-up period of 8.6 years, and with non-fatal and fatal stroke and myocardial infarction/coronary death after a median follow-up time of 8.4 years.Results: Serum uromodulin was significantly inversely associated with total mortality (HR 0.65; 95% CI 0.53-0.79 per standard deviation of logarithmized serum uromodulin; p &lt; 0.001) and cardiovascular mortality (HR 0.70; 95% CI 0.52-0.93) in men, but not in women (HR for all-cause mortality in women 0.98; 95% CI 0.77-1.25, HR for cardiovascular mortality 0.78; 95% CI 0.56-1.11) after adjustment for age, BMI, diabetes and eGFR. In addition, serum uromodulin was significantly inversely associated with incident stroke in men (HR 0.68; 95% CI 0.50-0.92), but not in women (HR 0.96; 95% CI 0.68-1.38) after multivariable adjustment. The association of serum uromodulin with incident myocardial infarction was attenuated and lost significance after multivariable adjustment in both sexes.Conclusions: Serum uromodulin is an independent biomarker for total and cardiovascular mortality in men from the general community aged 62 years or older