Although in the past century mortality in West Germany decreased similarly as in other Western nations, these changes were less pronounced in East Germany.^1,2 After German reunification in 1990, there was a lack of scientifically valid data from East Germany to explain the regional differences in life expectancy and, consequently, a need for population-based research in northeast Germany.

Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD. English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies. The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place. CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies. The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis. These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.

Here 106 genomic loci associated with age at menarche, a marker of puberty timing in females, are identified; these loci show enrichment for genes involved in nuclear hormone receptor function, body mass index, and rare disorders of puberty, and for genes located in imprinted regions, with parent-of-origin specific effects at several loci. The age at which females first experience menstruation, called menarche, is a heritable trait associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and general mortality. This large-scale genome-wide association study identifies 123 signals at 106 genomic loci associated with age at menarche. New findings include parent-of-origin-specific allelic associations (both maternally and paternally driven) at three imprinted loci and the implication of retinoic acid and GABAB receptor II signalling and lysine-specific histone demethylation. These data bring new insights into the genetic architecture of puberty timing and suggest a model involving thousands of genetic variants. Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10⁻⁸), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

Although the association of low serum testosterone levels with mortality has gained strength in recent research, there are few population-based studies on this issue. This study examined whether low serum testosterone levels are a risk factor for all-cause or cause-specific mortality in a population-based sample of men aged 20–79. We used data from 1954 men recruited for the prospective population-based Study of Health in Pomerania, with measured serum testosterone levels at baseline and 195 deaths during an average 7.2-year follow-up. A total serum testosterone level of less than 8.7 nmol/L (250 ng/dL) was classified as low. The relationships of low serum testosterone levels with all-cause and cause-specific mortality were analysed by Cox proportional hazards regression models. Men with low serum testosterone levels had a significantly higher mortality from all causes than men with higher serum testosterone levels (HR 2.24; 95% CI 1.41–3.57). After adjusting for waist circumference, smoking habits, high-risk alcohol use, physical activity, renal insufficiency, and levels of dehydroepiandrosterone sulfate, low serum testosterone levels continued to be associated with increased mortality (HR 2.32; 95% CI 1.38–3.89). In cause-specific analyses, low serum testosterone levels predicted increased risk of death from cardiovascular disease (CVD) (HR 2.56; 95% CI 1.15–6.52) and cancer (HR 3.46; 95% CI 1.68–6.68), but not from respiratory diseases or other causes. Low serum testosterone levels were associated with an increased risk of all-cause mortality independent of numerous risk factors. As serum testosterone levels are inversely related to mortality due to CVD and cancer, it may be used as a predictive marker.