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Andreas Luchner,
Gundula Behrens,
Jan Stritzke,
Marcello Markus,
Klaus Stark,
Annette Peters,
Christa Meisinger,
Michael Leitzmann,
Hans-Werner Hense,
Heribert Schunkert, Iris M Heid
[show abstract]
[hide abstract]
ABSTRACT: AIMS: The natriuretic peptides BNP and NT-proBNP are potent cardiac markers, but knowledge of long-term changes is sparse. We thus quantified determinants of change in BNP and NT-proBNP in a study of south German residents (KORA). METHODS AND RESULTS: A total of 1005 men and women (age 25-74 years, mean 48 years) underwent physical examination and echocardiography at baseline and at follow-up after 10 years. The current analysis comprised 877 subjects with dual measurements of BNP and NT-proBNP. Both markers increased in both sexes (P < 0.001) during the 10-year follow-up, and higher levels in women persisted across time (P for sex difference <0.001). Among baseline covariates, predictors for 10-year change of NT-proBNP, BNP, or both were age, sex, diabetes status, and heart rate (multivariable regression analysis, each P < 0.05). However, changes of covariates over the 10-year follow-up were much stronger determinants. Specifically, incident myocardial infarction, new beta-blocker medication, and increased cardiac parameters (left atrial diameter, LV end-diastolic diameter, and LV mass index) were associated with increasing BNP, NT-proBNP, or both, whereas increased heart rate, haematocrit, and body mass index (BMI) were associated with decreasing BNP and NT-proBNP (all P < 0.05). CONCLUSION: Next to ageing and sex, a variety of changes in covariates reflecting the sequelae of cardiac remodelling as well as myocardial infarction and diabetes influence long-term changes of BNP and NT-proBNP. Of note, diabetes and increased BMI exert opposite effects. For interpretation of individual marker concentrations, a host of covariates needs to be considered, especially in subjects without prevalent or incident cardiac disease.
European Journal of Heart Failure 04/2013; · 4.90 Impact Factor
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Sonja I Berndt,
Stefan Gustafsson,
Reedik Mägi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
André Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
[show abstract]
[hide abstract]
ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
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Sonja I Berndt,
Stefan Gustafsson,
Reedik Magi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
Andre Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
[show abstract]
[hide abstract]
ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
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Benjamin F Voight,
Hyun Min Kang,
Jun Ding,
Cameron D Palmer,
Carlo Sidore,
Peter S Chines,
Noël P Burtt,
Christian Fuchsberger,
Yanming Li,
Jeanette Erdmann, [......],
Patricia B Munroe,
Christopher Newton-Cheh,
Arne Pfeufer,
Nilesh J Samani,
Heribert Schunkert,
Joel N Hirschhorn,
David Altshuler,
Mark I McCarthy,
Gonçalo R Abecasis,
Michael Boehnke
PLoS Genetics 04/2013; 9(4). · 8.69 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE).
DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro- and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e.g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness.
DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.
BMC Medical Genetics 01/2013; 14:25. · 2.33 Impact Factor
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Daniel I Chasman,
Christian Fuchsberger,
Cristian Pattaro,
Alexander Teumer,
Carsten A Böger,
Karlhans Endlich,
Matthias Olden,
Ming-Huei Chen,
Adrienne Tin,
Daniel Taliun, [......],
Inga Prokopenko,
Jacqueline Witteman,
Caroline Hayward,
Paul M Ridker,
Afshin Parsa,
Murielle Bochud, Iris M Heid,
W H Linda Kao,
Caroline S Fox,
Anna Köttgen
[show abstract]
[hide abstract]
ABSTRACT: In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Human Molecular Genetics 09/2012; · 7.64 Impact Factor
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Benjamin F Voight,
Hyun Min Kang,
Jun Ding,
Cameron D Palmer,
Carlo Sidore,
Peter S Chines,
Noël P Burtt,
Christian Fuchsberger,
Yanming Li,
Jeanette Erdmann, [......],
Patricia B Munroe,
Christopher Newton-Cheh,
Arne Pfeufer,
Nilesh J Samani,
Heribert Schunkert,
Joel N Hirschhorn,
David Altshuler,
Mark I McCarthy,
Gonçalo R Abecasis,
Michael Boehnke
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.
PLoS Genetics 08/2012; 8(8):e1002793. · 8.69 Impact Factor
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Vesna Boraska,
Ana Jeroncic,
Vincenza Colonna,
Lorraine Southam,
Dale R Nyholt,
Nigel William Rayner,
John R B Perry,
Daniela Toniolo,
Eva Albrecht,
Wei Ang, [......],
Sheila Ulivi,
Pim van der Harst,
Peter Vollenweider,
Henry Völzke,
Nicholas J Wareham,
H-Erich Wichmann,
James F Wilson,
Igor Rudan,
Yali Xue,
Eleftheria Zeggini
[show abstract]
[hide abstract]
ABSTRACT: The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
Human Molecular Genetics 07/2012; 21(21):4805-15. · 7.64 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) are useful to reveal an association between single nucleotide polymorphisms and different measures of obesity. A multitude of new loci has recently been reported, but the exact function of most of the according genes is not known. The aim of our study was to start elucidating the function of some of these genes.
We performed an expression analysis of fourteen genes, namely BDNF, ETV5, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MCR4, MTCH2, NEGR1, NRXN3, TMEM18, SEC16B and TFAP2B, via real-time RT-PCR in adipose tissue of the kidney capsule, the mesenterium and subcutaneum as well as the hypothalamus of obese Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats at an age of 22 weeks.
All of our target genes except for SEC16B showed the highest expression in the hypothalamus. This suggests a critical role of these obesity-related genes in the central regulation of energy balance. Interestingly, the expression pattern in the hypothalamus showed no differences between obese ZDF and lean ZL rats. However, LYPLAL1, TFAP2B, SEC16B and FAIM2 were significantly lower expressed in the kidney fat of ZDF than ZL rats. NEGR1 was even lower expressed in subcutaneous and mesenterial fat, while MTCH2 was higher expressed in the subcutaneous and mesenterial fat of ZDF rats.
The expression pattern of the investigated obesity genes implies for most of them a role in the central regulation of energy balance, but for some also a role in the adipose tissue itself. For the development of the ZDF phenotype peripheral rather than central mechanisms of the investigated genes seem to be relevant.
Cardiovascular Diabetology 05/2012; 11:48. · 3.35 Impact Factor
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Cristian Pattaro,
Anna Köttgen,
Alexander Teumer,
Maija Garnaas,
Carsten A Böger,
Christian Fuchsberger,
Matthias Olden,
Ming-Huei Chen,
Adrienne Tin,
Daniel Taliun, [......],
Jacqueline C M Witteman,
Caroline Hayward,
Paul Ridker,
Afshin Parsa,
Murielle Bochud, Iris M Heid,
Wolfram Goessling,
Daniel I Chasman,
W H Linda Kao,
Caroline S Fox
[show abstract]
[hide abstract]
ABSTRACT: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
PLoS Genetics 03/2012; 8(3):e1002584. · 8.69 Impact Factor
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Zari Dastani,
Marie-France Hivert,
Nicholas Timpson,
John R B Perry,
Xin Yuan,
Robert A Scott,
Peter Henneman, Iris M Heid,
Jorge R Kizer,
Leo-Pekka Lyytikäinen, [......],
Eric E Schadt,
David P Strachan,
Muredach P Reilly,
Nilesh J Samani,
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Sekar Kathiresan
[show abstract]
[hide abstract]
ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
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Lyudmyla Kedenko,
Claudia Lamina,
Tobias Kiesslich,
Karen Kapur,
Sven Bergmann,
Dawn Waterworth, Iris M Heid,
H-Erich Wichmann,
Igor Kedenko,
Florian Kronenberg,
Bernhard Paulweber
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin serum concentrations are an important biomarker in cardiovascular epidemiology with heritability etimates of 30-70%. However, known genetic variants in the adiponectin gene locus (ADIPOQ) account for only 2%-8% of its variance. As transcription factors are thought to play an under-acknowledged role in carrying functional variants, we hypothesized that genetic polymorphisms in genes coding for the main transcription factors for the ADIPOQ promoter influence adiponectin levels. Single nucleotide polymorphisms (SNPs) at these genes were selected based on the haplotype block structure and previously published evidence to be associated with adiponectin levels. We performed association analyses of the 24 selected SNPs at forkhead box O1 (FOXO1), sterol-regulatory-element-binding transcription factor 1 (SREBF1), sirtuin 1 (SIRT1), peroxisome-proliferator-activated receptor gamma (PPARG) and transcription factor activating enhancer binding protein 2 beta (TFAP2B) gene loci with adiponectin levels in three different European cohorts: SAPHIR (n = 1742), KORA F3 (n = 1636) and CoLaus (n = 5355). In each study population, the association of SNPs with adiponectin levels on log-scale was tested using linear regression adjusted for age, sex and body mass index, applying both an additive and a recessive genetic model. A pooled effect size was obtained by meta-analysis assuming a fixed effects model. We applied a significance threshold of 0.0033 accounting for the multiple testing situation. A significant association was only found for variants within SREBF1 applying an additive genetic model (smallest p-value for rs1889018 on log(adiponectin) = 0.002, β on original scale = -0.217 µg/ml), explaining ∼0.4% of variation of adiponectin levels. Recessive genetic models or haplotype analyses of the FOXO1, SREBF1, SIRT1, TFAPB2B genes or sex-stratified analyses did not reveal additional information on the regulation of adiponectin levels. The role of genetic variations at the SREBF1 gene in regulating adiponectin needs further investigation by functional studies.
PLoS ONE 01/2012; 7(12):e52497. · 4.09 Impact Factor
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ABSTRACT: Meta-analyses of genome-wide association studies require numerous study partners to conduct pre-defined analyses and thus simple but efficient analyses plans. Potential differences between strata (e.g. men and women) are usually ignored, but often the question arises whether stratified analyses help to unravel the genetics of a phenotype or if they unnecessarily increase the burden of analyses. To decide whether to stratify or not to stratify, we compare general analytical power computations for the overall analysis with those of stratified analyses considering quantitative trait analyses and two strata. We also relate the stratification problem to interaction modeling and exemplify theoretical considerations on obesity and renal function genetics. We demonstrate that the overall analyses have better power compared to stratified analyses as long as the signals are pronounced in both strata with consistent effect direction. Stratified analyses are advantageous in the case of signals with zero (or very small) effect in one stratum and for signals with opposite effect direction in the two strata. Applying the joint test for a main SNP effect and SNP-stratum interaction beats both overall and stratified analyses regarding power, but involves more complex models. In summary, we recommend to employ stratified analyses or the joint test to better understand the potential of strata-specific signals with opposite effect direction. Only after systematic genome-wide searches for opposite effect direction loci have been conducted, we will know if such signals exist and to what extent stratified analyses can depict loci that otherwise are missed.
Genetic Epidemiology 12/2011; 35(8):867-79. · 3.44 Impact Factor
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André Scherag,
Michaela Kleber,
Tanja Boes,
Andreea-Liliana Kolbe,
Anne Ruth,
Harald Grallert,
Thomas Illig, Iris M Heid,
André M Toschke,
Katrine Grau,
Thorkild I A Sørensen,
Johannes Hebebrand,
Anke Hinney,
Thomas Reinehr
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association analyses (GWAS) contributed to the detection of a number of single-nucleotide polymorphisms (SNPs) associated with obesity. However, little is known about the impact of the obesity-risk alleles on weight loss-related phenotypes after lifestyle interventions. A recent meta-analysis of GWAS reported five genomic loci near or in the genes FTO, MC4R, TMEM18, SDCCAG8, TNKS/MSRA that were associated with obesity in children and adolescents. Here, we analyzed the effect of the 10 SNPs representative of the five loci on measures of weight loss and cardiometabolic risk after a 1-year lifestyle intervention in 401 children and adolescents (mean age 10.74 years; 55.4% female; mean BMI 27.42 kg/m(2), mean BMI-standard deviation score (SDS) 2.37). For confirmation of one locus genotyping of three intronic SNPs in SDCCAG8 was performed in 626 obese adults who completed the 10-week hypoenergetic diet program. Intronic variants of SDCCAG8, which are associated with early onset obesity, are associated with reduced weight loss after a 1-year lifestyle intervention in overweight children and adolescents even after adjusting for age, sex, baseline measurement, or multiple testing (all P < 10(-6)). However, our results could not be confirmed in 626 obese adults undertaking a hypoenergetic diet intervention.
Obesity 11/2011; 20(2):466-70. · 4.28 Impact Factor
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Carsten A Böger,
Mathias Gorski,
Man Li,
Michael M Hoffmann,
Chunmei Huang,
Qiong Yang,
Alexander Teumer,
Vera Krane,
Conall M O'Seaghdha,
Zoltán Kutalik, [......],
Jacqueline Witteman,
Murielle Bochud,
David Siscovick,
Rainer Rettig,
Florian Kronenberg,
Christoph Wanner,
Ravi I Thadhani, Iris M Heid,
Caroline S Fox,
W H Kao
[show abstract]
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ABSTRACT: 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.
PLoS Genetics 09/2011; 7(9):e1002292. · 8.69 Impact Factor
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Fabiola Del Greco M,
Cristian Pattaro,
Andreas Luchner,
Irene Pichler,
Thomas Winkler,
Andrew A Hicks,
Christian Fuchsberger,
Andre Franke,
Scott A Melville,
Annette Peters,
H Erich Wichmann,
Stefan Schreiber, Iris M Heid,
Michael Krawczak,
Cosetta Minelli,
Christian J Wiedermann,
Peter P Pramstaller
[show abstract]
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ABSTRACT: High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the MTHFR-CLCN6-NPPA-NPPB gene cluster was replicated, after correction for multiple testing (replication one-sided P-value = 8.4 × 10(-10)). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the CLCN6 gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined P-values from 8.3 × 10(-03) to 9.3 × 10(-11)). The observed increase in the NT-proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the MTHFR-CLCN6-NPPA-NPPB cluster provides new insights into the biological mechanisms of cardiac dysfunction.
Human Molecular Genetics 02/2011; 20(8):1660-71. · 7.64 Impact Factor
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Carsten A Böger,
Ming-Huei Chen,
Adrienne Tin,
Matthias Olden,
Anna Köttgen,
Ian H de Boer,
Christian Fuchsberger,
Conall M O'Seaghdha,
Cristian Pattaro,
Alexander Teumer, [......],
Peter P Pramstaller,
L Adrienne Cupples,
Jacques S Beckmann,
Qiong Yang, Iris M Heid,
Rainer Rettig,
Albert W Dreisbach,
Murielle Bochud,
Caroline S Fox,
W H L Kao
[show abstract]
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ABSTRACT: Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
Journal of the American Society of Nephrology 02/2011; 22(3):555-70. · 9.66 Impact Factor
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ABSTRACT: Although light to moderate alcohol intake may reduce cardiovascular disease (CVD) mortality, the effect on total mortality requires further study, particularly among young and middle-aged women. We studied the association between alcohol consumption and mortality from all causes, from cancer, and from CVD in the Swedish Women's Lifestyle and Health Study, a cohort of 47,921 female residents of Sweden aged 30-49 years at baseline in 1991/1992 and followed up to 2006. We estimated the relative risk (RR) of mortality associated with alcohol intake using Cox regression adjusted for age, smoking, BMI, saturated fat intake, physical activity, and education. During 713,295 person-years of follow-up, 1,119 deaths occurred, including 158 deaths from CVD, 673 deaths from cancer, and 288 deaths from other causes. Compared with non-drinking, light to moderate drinking (0.1-19.9 g of alcohol per day) showed a statistically significant inverse association with total mortality (RR = 0.83, 95% CI = 0.71-0.98). Analyses of cause-specific mortality revealed an RR for CVD mortality of 0.69 (95% CI = 0.46-1.01) and an RR for cancer mortality of 0.92 (95% CI = 0.75-1.15). These results suggest that in younger women, a possibly beneficial effect of light to moderate drinking on future risk of mortality is limited to a prevention of CVD mortality but not cancer mortality.
European Journal of Epidemiology 02/2011; 26(2):81-90. · 4.71 Impact Factor
