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Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79 x 10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

To get beyond the "low-hanging fruits'' so far identified by genome-wide association (GWA) studies, new methods must be developed in order to discover the numerous remaining genes that estimates of heritability indicate should be contributing to complex human phenotypes, such as obesity. Here we describe a novel integrative method for complex disease gene identification utilizing both genome-wide transcript profiling of adipose tissue samples and consequent analysis of genome-wide association data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of monozygotic twin pairs discordant for BMI (n = 13 pairs, age 24-28 years, 15.4 kg mean weight difference) and contrast the transcript profiles with those from a larger sample of non-related adult individuals (N=77). Using this approach, we were able to identify 27 genes with possibly causal roles in determining the degree of human adiposity. Testing for association of SNP variants in these 27 genes in the population samples of the large ENGAGE consortium (N=21,000) revealed a significant deviation of P-values from the expected (P=4x10(-4)). A total of 13 genes contained SNPs nominally associated with BMI. The top finding was blood coagulation factor F13A1 identified as a novel obesity gene also replicated in a second GWA set of similar to 2,000 individuals. This study presents a new approach to utilizing gene expression studies for informing choice of candidate genes for complex human phenotypes, such as obesity.

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested f

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms ( SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P <= 5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P <= 0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5610 26, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

In the Approbationsordnung für Ärzte (German regulation for the Curriculum in Medicine) of 27th June, 2002 the disciplines Epidemiology, Medical Biometry and Medical Informatics are combined in one obligatory cross-sectional subject of the second part of the medical exam. In addition, it is possible to study topics from these disciplines in more detail on a voluntary basis. The aim of teaching this cross-sectional subject is to qualify the students to assess their own actions critically, to apply recommendations with care, and to learn to use tools like systematic documentation and modern information technology.For the mentioned disciplines a catalogue has been developed which is subdivided in three parts. In the first part methods are described which are needed to support medical decisions. The second part refers to support of medical supply and quality management, whereas the third part deals with the basic elements of Public Health and Health Economics, with respect to causation of diseases and prevention., Mit der Approbationsordnung für Ärzte vom 27. Juni 2002 werden die Disziplinen Epidemiologie, Medizinische Biometrie und Medizinische Informatik zum prüfungspflichtigen Querschnittsfach für den 2. Abschnitt der ärztlichen Prüfung zusammengefasst. Darüber hinaus besteht die Möglichkeit Lehrinhalte aus diesem Fächerkanon intensiver als Wahlfach zu studieren. Das Ziel der Lehre im Querschnittsbereich ist es, die Studierenden zur kritischen Beurteilung des eigenen Handelns, zur kritischen Anwendung fremder Empfehlungen, zur systematischen Dokumentation und zum Umgang mit modernen Werkzeugen der Informationstechnologie im Rahmen der Berufsausübung zu befähigen. Für die genannten Disziplinen wurde ein Gegenstandskatalog entwickelt, der sich in drei Teilbereiche gliedert. In einem ersten Bereich werden die für die Unterstützung ärztlicher Entscheidungen notwendigen Methoden dargestellt. Der zweite Bereich bezieht sich auf die Unterstützung der ärztlichen Versorgungsaufgaben und des ärztlichen Qualitätsmanagements, während in einem dritten Teil die Grundelemente bevölkerungsbezogener und gesundheitsökonomischer Aspekte des ärztlichen Handelns in Hinblick auf Krankheitsursachen und Prävention dargestellt werden.

The aim of this study was to investigate to which extent 6th grade school children are exposed to tobacco smoke by others. As biomarker for the exposure to tobacco smoke nicotine and cotinine were measured in the urine. Our study population consisted of 771 schoolchildren aged 11-14 years who according to a questionnaire did not smoke. In addition we analysed the data of 459 school children who were not exposed to tobacco smoke at home. The nicotine and cotinine concentrations in the spontaneous urine sample were determined by HPLC methods.On average in about 20% of all non-smoking children, who were not exposed to tobacco smoke at home, biomarker (nicotine or cotinine) were detected in the urine. The percentage of the detected biomarker values (nicotine and/or cotinine) in the urine of the school children varied between 0% and 50% between schools. In addition we determined the proportion of smoking classmates per school. No positive association was found between the detected biomarker values of the non-smoking school children not exposed to tobacco smoke at home and the proportion of smokers per school.The concentration of biomarker depending on the time of day the urine samples were collected showed higher nicotine and cotinine values when the urine sample was collected between 10 and 12 o'clock in the morning compared to urine samples collected between 7 and 10 a.m. In spite of the limitations our study provides some evidence that children are exposed involuntarily to tobacco smoke by others at school. That is why our results support the requirement of a general legal ban on smoking for teachers, the school staff and students., Ziel der Studie war es zu untersuchen, inwieweit Jugendliche der 6. Klassen in Schulen dem Tabakrauch anderer ausgesetzt sind. Als Biomarker für die Exposition gegenüber Tabakrauch wurden Nikotin und Cotinin im Urin der Schüler gemessen. Von den 771 Jugendlichen im Alter von 11-14 Jahren, die angaben nicht zu rauchen, wurden speziell Daten von 459 Jugendlichen analysiert, die zu Hause keinem Tabakrauch ausgesetzt waren. Die Nikotin- und Cotininkonzentrationen im Spontanurin wurden mit Hilfe der HPLC-Methode bestimmt.Im Durchschnitt waren bei etwa 20% aller Nichtraucher-Jugendlichen, die Tabakrauch im häuslichen Bereich nicht ausgesetzt waren, Biomarker (Nikotin oder Cotinin) im Urin nachweisbar. Der prozentuale Anteil von nachgewiesenen Biomarkern im Urin variierte bei den Schülern je nach Schule zwischen 0% und 50%. Es wurde zusätzlich der Raucher-Anteil der Mitschüler pro Schule bestimmt. Dabei konnte kein positiver Zusammenhang zwischen den prozentual nachweisbaren Biomarker-Werten der Nichtraucher-Jugendlichen ohne häusliche Tabakrauchexposition und der Raucher-Anteile pro Schule gefunden werden.Die Biomarkerkonzentrationen in Abhängigkeit von der Tageszeit, zu der der Urin gesammelt wurde, zeigten erhöhte Werte von Nikotin und Cotinin, wenn die Urinprobe zwischen 10:00 und 12:00 Uhr genommen wurde im Vergleich zu den Probenahmen zwischen 7:00 und 10:00 Uhr. Trotz Vorbehalten und Einschränkungen bietet unsere Studie Hinweise dafür, dass die Jugendlichen in den Schulen unfreiwillig dem Tabakrauch anderer ausgesetzt sind. Deshalb unterstützen unsere Ergebnisse die Forderung nach einem generellen Rauchverbot in den Schulen für Lehrer, Schulpersonal und Schüler.