No abstract

Genome wide association studies (GWAS) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, SNPs at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1 and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFRdecline of 3ml/min/1.73m2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11 and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 hours after gentamicin treatment compared to controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

Obesity and metabolic syndrome are associated with low serum testosterone levels. Hepatic steatosis contributes to the metabolic syndrome and might be regarded as its hepatic manifestation. In this study, we sought to investigate the relationship between hepatic steatosis, serum testosterone and dehydroepiandrosterone sulphate (DHEAS) levels in men. This is a cross-sectional population-based study. We used data of 1912 men recruited for the population-based Study of Health in Pomerania, which was conducted in a region with high prevalence of metabolic syndrome and related diseases. Hepatic steatosis was defined according to sonographic criteria. The relationship of hepatic steatosis with serum testosterone and DHEAS levels was analysed by multivariable logistic regression. Men with low serum testosterone levels had a higher risk of hepatic steatosis than men with high serum testosterone levels. Adjustment for age and further confounders attenuated this association, but did not affect statistical significance (odds ratio 2.36; 95% confidence interval 1.66-3.37; p < 0.05). In the full model, the highest risk of hepatic steatosis was found in subjects with the highest serum DHEAS levels (odds ratio 1.59; 95% confidence interval 1.04-2.43; p < 0.05). Exclusion of men with high alcohol consumption did not affect these results substantially. Hepatic steatosis is associated with low serum testosterone and high serum DHEAS levels. These associations are independent of alcohol consumption.

Type 1 diabetes mellitus is characterized by a progressive autoimmune destruction of insulin-producing b cells. Macrophages and T lymphocytes release cytokines, which induce the synthesis of oxygen and nitrogen radicals in the pancreatic islets. The resulting cellular and mitochondrial damage promotes b cell death. b cells are very sensitive to the autoimmune free radical-dependent attack due to their low content of antioxidant enzymes such as glutathione peroxidase and catalase. A focal point of b cell protection should be the control of the mitochondrial redox status, which will result in the preservation of metabolic stimulus-secretion coupling. For this reason, there is a considerable interest in the mitochondrial peroxiredoxin III (PRX III), a thioredoxindependent peroxide reductase, which was shown to be able to protect against both oxidative and nitrosative stress.Using the Tet-On-system, we generated stably transfected rat insulinoma cells over-or under-expressing PRX III in a doxycyclin-dependent manner to analyze the effect of increased or decreased amounts of cellular PRX III, following treatment with several stressors. We provide evidence that PRX III protects pancreatic b cells from cell stress induced by accumulation of hydrogen peroxide, or the induction of inducible nitric oxide synthase or caspase-9 and -3 by pro-inflammatory cytokines or streptozotocin. Basal insulin secretion was markedly decreased in cells expressing lower levels of PRX III. We suggest PRX III may be a suitable target for promoting deceleration or even prevention of stress-associated apoptosis in pancreatic b cells and the manifestation of insulin-dependent diabetes mellitus.

Objective: To study the association between socioeconomic status (SES) and annual relative change in anthropometric markers in the general German adult population. Methods: Longitudinal data of 56,556 participants aged 18-83 years from seven population-based German cohort studies (CARLA, SHIP, KORA, DEGS, EPIC-Heidelberg, EPIC-Potsdam, PopGen) were analyzed by meta-analysis using a random-effects model. The indicators of SES were education and household income. Results: On average, all participants gained weight and increased their waist circumference over the study's follow-up period. Men and women in the low education group had a 0.1 percentage points greater annual increase in weight (95% CI men: 0.06-0.20; and women: 0.06-0.12) and waist circumference (95% CI men: 0.01-0.45; and women: 0.05-0.22) than participants in the high education group. Women with low income had a 0.1 percentage points higher annual increase in weight (95% CI 0.00-0.15) and waist circumference (95% CI 0.00-0.14) than women with high income. No association was found for men between income and obesity markers. Conclusions: Participants with lower SES (education and for women also income) gained more weight and waist circumference than those with higher SES. These results underline the necessity to evaluate the risk of weight gain based on SES to develop more effective preventive measures.

No association between IGF-I levels and LVH was found. Potential hypertrophic effects of free serum IGF-I levels might be mediated by lower IGFBP-3 levels.

In this population-based sample, SCH had no impact on progression of LVMI and development of LVH during 5-year follow-up in subjects aged 45 years or older.

<b><i>Background/Aims: </i></b>Due to the increasing prevalence of risk factors for chronic kidney disease (CKD), kidney dysfunction becomes a major public health problem. We investigated the CKD prevalence and determined to what extent the variation of risk factors explains the different CKD prevalence in Germany. Methods: We analyzed data from 6,054 participants, aged 31 to 82 years, from the Study of Health in Pomerania (SHIP-1) in Northeast Germany and the Cooperative Health Research in the Region of Augsburg (KORA F4) Study in Southern Germany. Regional differences in selected percentiles corresponding to the cutpoints for estimated glomerular filtration rate (eGFR, <60 ml/min per 1.73 m²) and albumin-to-creatinine ratio (ACR, ≥30 mg/g) were tested using quantile regression models that adjusted for CKD risk factors. <b><i>Results: </i></b>The prevalence of decreased eGFR_{creatinine-cystatinC} (5.9 vs. 3.1 %, p <0.001) and albuminuria (20.2 vs. 8.8 %, p<0.001) were higher in SHIP-1 than in KORA F4. The differential distribution of risk factors explained 18-21% of the regional differences of decreased eGFR_{creatinine-cystatinC} and high ACR. Conclusions: The CKD prevalence is higher in Northeast than in Southern Germany. Differences in the prevalence of risk factors partly explain the higher disease burden of CKD in Northeast than in Southern Germany.