Archiv Publikationen

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
Nature Communications 1. Februar 2016 | PMID 26833098

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Nature Communications, 21. Januar 2016 | PMID 26831199

PCSK9 Plasma Concentrations Are Independent of GFR and Do Not Predict Cardiovascular Events in Patients with Decreased GFR

Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored. Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths. PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results. In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.
PLoS One Januar 2016 | PMID 26799206

Human Pigmentation, Cutaneous Vitamin D Synthesis and Evolution: Variants of Genes (SNPs) Involved in Skin Pigmentation Are Associated with 25(OH)D Serum Concentration

Vitamin D deficiency is common and associated with higher risk for and unfavourable outcome of many diseases. Limited data exist on genetic determinants of serum 25(OH)D concentration. In a cohort of the LURIC study (n=2974, median 25(OH)D concentration 15.5 ng/ml), we tested the hypothesis that variants (SNPs, n=244) of several genes (n=15) involved in different aspects of skin pigmentation, including melanosomal biogenesis (ATP7A, DTNBP1, BLOC1S5, PLDN, PMEL), melanosomal transport within melanocytes (RAB27A, MYO5A, MLPH); or various melanocyte signaling pathways (MC1R, MITF, PAX3, SOX10, DKK1, RACK1, CNR1) are predictive of serum 25(OH)D levels. Eleven SNPs located in 6 genes were associated (p<0.05) with low or high serum 25(OH)D levels, 3 out of these 11 SNPs reached the aimed significance level after correction for multiple comparisons (FDR). In the linear regression model adjusted for sex, body mass index (BMI), year of birth and month of blood sample rs7565264 (MLPH), rs10932949 (PAX3), and rs9328451 (BLOC1S5) showed a significant association with 25(OH)D. The combined impact on variation of 25(OH)D serum levels (coefficient of determination (R(2))) for the 11 SNPs was 1.6% and for the 3 SNPs after FDR 0.3%. In Cox Regression we identified rs2292881 (MLPH) as having a significant association (advantage) with overall survival. Kaplan-Meier analysis did not show any significant impact of individual SNPs on overall survival. In conclusion, these results shed new light on the role of sunlight, skin pigmentation and vitamin D for human evolution. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
Anticancer Research März 2016 | PMID 26977047
Kleber ME, Delgado G, Grammer TB, Silbernagel G, Huang J, Krämer BK, Ritz E, März W.

Uric Acid and Cardiovascular Events: A Mendelian Randomization Study.

Journal of the American Society of Nephrology | JASN, Epub 18.03.2015
Kleber ME, Seppälä I, Pilz S, Hoffmann MM, Tomaschitz A, Oksala N, Raitoharju E, Lyytikäinen LP, Mäkelä KM, Laaksonen R, Kähönen M, Raitakari OT, Huang J, Kienreich K, Fahrleitner-Pammer A, Drechsler C, Krane V, Boehm BO, Koenig W, Wanner C, Lehtimäki T, März W, Meinitzer A.

Genome-wide association study identifies 3 genomic loci significantly associated with serum levels of homoarginine: the AtheroRemo Consortium.

Circulation. Cardiovascular genetics, Epub 18.09.2013
Grammer TB, Hoffmann MM, Renner W, Kleber ME, Winkelmann BR, Bohm BO, März W.

Apolipoprotein E genotypes, circulating C-reactive protein and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health Study.

Atherosclerosis, Epub 21.01.2011
Lüblinghoff, Nicola

Einfluss von genetischen Varianten im Promotor des Hämoxygenase-1-Gens auf das koronare Risiko

Daten aus der LURIC-Studie

Dissertation Freiburg 2005 [Erstgutachter: Priv.-Doz. Dr. Karl Winkler]
Lebert-Kleiner, Ingrid

Analyse von Hyperhomocysteinämien und deren genetischer Ursache

Etablierung einer Methode für die HPLC und Suche nach weiteren Mutationen auf dem MTHFR-Gen

Dissertation Frankfurt a. M. 2003 [Erstgutachter: Prof. Dr. Werner Groß]
Müller, Christian

Die thrombozytären Rezeptorpolymorphismen GPIIIa T1565C (HPA-1)und GPIa C807T und das Risiko eines vorzeitigen Myokardinfarkts

Ein Modell zur Differenzierung von Risikofaktoren der Thrombogenität und Risikofaktoren der Arteriosklerose

Dissertation Düsseldorf 2003 [Erstgutachter: Prof. Dr. Rüdiger E. Scharf]