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ABSTRACT: : The association between sex hormones and blood pressure (BP) in women has been investigated mostly in cross-sectional studies yielding inconsistent results.
: Data from 1428 women from the population-based Study of Health in Pomerania were used. Associations of total testosterone, androstenedione, sex hormone-binding globulin (SHBG), and free testosterone concentrations with BP and hypertension were analyzed in multivariable cross-sectional and longitudinal regression models in the full sample and stratified by menopausal status.
: A positive association between total testosterone and BP was revealed in the full sample [SBP: β per standard deviation (SD) increase: 3.22; pulse pressure (PP): β per SD increase: 2.30] and among postmenopausal women (DBP: β per SD increase: 3.33; SBP: β per SD increase: 7.11; PP: β per SD increase: 3.77). Longitudinal analyses also showed a positive association between baseline total testosterone and follow-up BP. Furthermore, low total testosterone concentrations were associated with a decreased risk of prevalent hypertension in all women [relative risk (RR) quartile 1 (Q1) vs. Q4, 0.79; 95% confidence interval, CI 0.67-0.94]. Low SHBG was associated with prevalent hypertension in postmenopausal women (RR 1.27; 95% CI 1.06-1.53) and with incident hypertension in the full sample (RR 1.73; 95% CI 1.10-2.75).
: The present population-based study is the first to show a consistent positive association between total testosterone and BP in both, cross-sectional and longitudinal analyses, suggesting high total testosterone as a risk marker of increased BP, as well as prevalent hypertension in women.
Journal of hypertension 06/2013; 31(6):1106-13. · 4.02 Impact Factor
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ABSTRACT: BACKGROUND: The prevalence of obese and overweight patients has increased dramatically worldwide. Both are common risk factors for chronic kidney disease (CKD) as indicated by a diminished estimated glomerular filtration rate (eGFR) or microalbuminuria. This study aimed to investigate whether anthropometric parameters [waist circumference (WC), waist-to-height ratio (WHtR) and body mass index (BMI)] are associated with renal function in a population-based study of Caucasian subjects. METHODS: Data from 3749 subjects (1825 women) aged 20 to 81 years from the Study of Health in Pomerania (SHIP) were analysed. Renal indices, including the urinary albumin-to-creatinine ratio (uACR), microalbuminuria, eGFR and CKD, were studied. Parameters of anthropometry (WC, WHtR and BMI) were categorised into sex-specific quintiles. RESULTS: Analysis of variance (ANOVA) models, adjusting for age, sex, type 2 diabetes mellitus and hypertension, revealed that a high and low WC or WHtR and low BMI were independently related to a higher uACR. Logistic regression models confirmed these results with respect to uACR and showed that subjects with a high or low WC or a high WHtR had increased odds of microalbuminuria. The ANOVA models revealed no relations of the investigated anthropometric parameters with eGFR. However, subjects with high values for these parameters had increased odds of CKD. CONCLUSIONS: Our results demonstrate U-shaped associations between markers of central fat distribution and uACR or microalbuminuria in the general population, suggesting that both obese and very thin subjects have a higher risk of renal impairment.
BMC Nephrology 04/2013; 14(1):87. · 2.18 Impact Factor
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ABSTRACT: BACKGROUND: Osteocalcin (OC) is a bone-specific protein produced primarily by osteoblasts during bone formation. Besides its role in bone formation, osteocalcin may play a role in the regulation of energy metabolism and male fertility. To interpret serum OC data, reference intervals adapted to a specific laboratory method are needed. METHODS: A healthy reference population was selected from the first follow-up of the Study of Health in Pomerania. Serum OC concentrations were measured with the IDS-iSYS N-Mid Osteocalcin assay on the IDS-iSYS Automated System (Immunodiagnostic Systems, Frankfurt am Main, Germany). The reference interval was defined as the central 95% range (2.5th-97.5th percentile). Age-specific reference intervals were calculated by quantile regression for 1107 men (25--79 years) and 545 premenopausal women (25--54 years). The reference interval for 498 postmenopausal women (50--79 years) was calculated irrespective of age. RESULTS: Median (1st-3rd quartile) serum OC concentrations were 15.4 ng/mL (12.0-19.4 ng/mL) in men, 14.4 ng/mL (11.3-18.5 ng/mL) in premenopausal women, and 18.6 ng/mL (13.6-25.6 ng/mL) in postmenopausal women. Serum OC concentrations were highest in men and premenopausal women aged 25--29 years, were stable during midlife, and rose again after 65 years of age in men and at transition to menopause in women. Serum OC concentrations were lower in women taking oral contraceptives or who were under hormone replacement therapy after menopause and in subjects with diabetes mellitus or with body mass index < 18 or > 30 kg/m2 than in subjects without these conditions. CONCLUSIONS: We established sex-specific adult reference intervals for the serum OC concentration measured by the IDS-iSYS N-Mid Osteocalcin assay.
BMC Endocrine Disorders 03/2013; 13(1):11. · 2.16 Impact Factor
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Matthias Olden,
Alexander Teumer,
Murielle Bochud,
Cristian Pattaro,
Anna Köttgen,
Stephen T Turner, Rainer Rettig,
Ming-Huei Chen,
Abbas Dehghan,
Francois Bastardot, [......],
Gary F Mitchell,
Joshua C Bis,
Christopher J O'Donnell,
Ching-Yu Cheng,
Xueling Sim,
David S Siscovick,
Josef Coresh,
W H Linda Kao,
Caroline S Fox,
Conall M O'Seaghdha
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ABSTRACT: BACKGROUND: Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits. STUDY DESIGN: We conducted 2 targeted analyses. First, we examined whether known single-nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5×10-4 (0.05/325 tests). SETTING & PARTICIPANTS: Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395), and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium. PREDICTOR: We used 19 kidney SNPs and 64 vascular SNPs. OUTCOMES & MEASUREMENTS: Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber, and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria. RESULTS: In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were nonsignificant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (P = 9.3 ×10-10) and diastolic (P = 1.6 ×10-14) blood pressure and coronary artery disease (P = 2.2 ×10-6), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were nonsignificant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (P = 1.06 ×10-07 and P = 7.05 ×10-08). LIMITATIONS: The combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations. CONCLUSIONS: Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.
American Journal of Kidney Diseases 03/2013; · 5.43 Impact Factor
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Till Ittermann,
Daniel Tiller,
Christa Meisinger,
Carsten Agger,
Matthias Nauck, Rainer Rettig,
Albert Hofman,
Oscar Franco,
Torben Joergensen,
Allan Linneberg,
Jacqueline Witteman,
Halina Greiser,
Karl Werdan,
Angela Döring,
Alexander Kluttig,
Bruno Stricker,
Henry Völzke
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ABSTRACT: Background: Recent data from a population-based study in children and adolescents suggests that serum thyroid-stimulating hormone levels (TSH) are associated with arterial blood pressure and hypertension. These results are in agreement with some, but not all population-based studies in adults. Discrepancies in results might be explained by drug intake, different iodine supplies and sizes of populations investigated. In addition, it is not clear, whether an association between TSH and hypertension exists longitudinally rather than only cross-sectionally. Thus, our aim was to investigate cross-sectional and longitudinal associations between thyroid function and arterial blood pressure in a large consortium of cohort studies in adults. Methods: Data from five population-based studies were pooled resulting in 17,023 individuals being available for cross-sectional and 10,048 individuals for longitudinal analyses. Associations of baseline TSH with baseline blood pressure or hypertension were analyzed by multivariable median or logistic regression models. Multivariable median or Poisson regression models were used to investigate associations of baseline TSH with 5-year-change in arterial blood pressure or incident hypertension. Results: There was a cross-sectional positive association of TSH with arterial blood pressure (p<0.001) and hypertension (odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.24 - 2.50; p=0.002). Likewise, hypothyroidism was associated systolic (β=1.1; 95% CI= 0.1 - 2.1; p=0.040) and diastolic blood pressure (β=1.4; 95% CI= 0.7 - 2.0; p<0.001). TSH, however, was not consistently associated with a 5-year-change in blood pressure or incident hypertension. Conclusions: High serum TSH levels were associated with current hypertension and blood pressure but not with 5-year-change in blood pressure and incident hypertension. This argues for an only short-term effect of thyroid hormone levels on arterial blood pressure or a spurious association that needs further evaluation in population-based studies.
Thyroid: official journal of the American Thyroid Association 02/2013; · 2.60 Impact Factor
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ABSTRACT: BACKGROUND: Insulin-like growth factor I (IGF-I), which is mostly carried in blood by IGF-binding protein 3 (IGFBP-3), was associated to the glomerular filtration rate and chronic kidney disease in a multiethnic study among US adults. The aim of the present study was to investigate whether serum IGF-I or IGFBP-3 are associated with estimated glomerular filtration rate (eGFR) in a population-based study of Caucasian adults. METHODS: Data from 4028 subjects (2048 women) aged 20 to 81 years from the Study of Health in Pomerania (SHIP) were analyzed. Total serum IGF-I and IGFBP-3 concentrations were determined by chemiluminescence immunoassays and categorized into sex- and age-specific quartiles. RESULTS: After adjusting for age, waist circumference and type 2 diabetes mellitus, analysis of variance (ANOVA) revealed inverse associations between serum IGF-I concentrations and eGFR in men as well as between serum IGFBP-3 concentrations and eGFR in men and women. Logistic regression analyses confirmed these findings and showed that high IGF-I or IGFBP-3 concentrations were associated with an increased risk of decreased eGFR (<60 mL/min/1.73m2) in men or women. These relations became stronger when lower eGFR cut-offs were used for the analyses. CONCLUSION: Our data revealed associations of increased serum IGF-I concentrations and decreased eGFR in men but not in women and an association of increased serum IGFBP-3 concentrations and decreased eGFR in both sexes.
BMC Nephrology 12/2012; 13(1):169. · 2.18 Impact Factor
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ABSTRACT: Background: Hypothyroidism may be a risk factor for obesity, because metabolic rates tend to be decreased in this disorder. Currently it is under debate whether smoking may modify the association between hypothyroidism and obesity. Against this background the aims of our study were to investigate whether there is an association between serum thyroid-stimulating hormone (TSH) and body mass index (BMI) in children and adolescents and whether smoking mediates this association. Methods: Data from 6,435 children (ages 3 to 10) and 5,918 adolescents (ages 11 to 17) from the "The German Health Interview and Examination Survey for Children and Adolescents" (KiGGS) were analyzed. Smoking status was categorized into two categories, smokers and non-smokers. A subject was classified as being exposed to environmental tobacco smoke (ETS) if someone in the parental home smoked more than 1 day a week. Serum TSH levels were measured with an ELISA method. Serum TSH levels were associated with BMI and obesity by multivariable linear regression stratified by smoking status and exposure to ETS. Results: In adolescents, there was an association between serum TSH levels and BMI and it was stronger in smokers (β=0.62; 95%-confidence interval (CI)=0.38-0.85) than in non-smokers (β=0.18; CI=0.09-0.28). Likewise, it was stronger in adolescents exposed to ETS and adolescents not exposed to ETS. In children, who were either exposed or not exposed to ETS, there was an association between serum TSH levels and BMI. In them, however, the strength of this association was similar in those exposed and not exposed to ETS. Conclusions: Active and passive smoking may mediate the association between thyroid function and BMI in adolescents. In smoking adolescents hypothyroidism may lead to an increase of the BMI, whereas this is not the case in non-smoking adolescents.
Thyroid: official journal of the American Thyroid Association 10/2012; · 2.60 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
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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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Nicole Aumann,
Sebastian E Baumeister,
André Werner,
Henri Wallaschofski,
Anke Hannemann,
Matthias Nauck, Rainer Rettig,
Stephan B Felix,
Marcus Dörr,
Henry Völzke,
Wolfgang Lieb,
Sylvia Stracke
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ABSTRACT: BACKGROUND: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular disease in the general population and in patients with chronic kidney disease. The objective of this study was to investigate the association of estimated glomerular filtration rate (eGFR) with left ventricular mass index (LVMI), LVH and left ventricular geometry. A question of clinical relevance is whether estimated glomerular filtration rate based on cystatin C (eGFR(cystatinC)) is a better marker for cardiovascular risk than estimated glomerular filtration rate based on creatinine (eGFR(creatinine)). METHODS: The study sample included 2830 individuals from the population-based Study of Health in Pomerania (SHIP). LVH was defined as echocardiographic LVMI >48g/m(2.7) in men and >44g/m(2.7) in women. Kidney function, as assessed by eGFR, was determined from established equations: the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and a cystatin-based multivariable equation. RESULTS: We found an inverse association between eGFR and LVMI. This association was stronger in models with eGFR(cystatinC) than in models with eGFR(creatinine). Subjects with moderately-to-severely decreased kidney function (defined as eGFR 15-<60mL/min per 1.73m(2)) had higher odds for abnormal geometric patterns of the left ventricle than subjects with normal eGFR when eGFR(cystatinC) was used. CONCLUSIONS: The findings suggest that eGFR(cystatinC) is superior to eGFR(creatinine) for assessing the risk of cardiovascular disease.
International journal of cardiology 08/2012; · 7.08 Impact Factor
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ABSTRACT: To evaluate the usefulness of the cyp1a1ren-2 transgenic rat model of inducible hypertension for studies of the development and regression of cardiac hypertrophy.
Cyp1a1ren-2 rats received a diet containing 0% or 0.167% indole-3-carbinonl (I3C) for 4 weeks to induce hypertension. Cardiac magnetic resonance imaging (MRI) at 7 T was performed every second week for 10 weeks to measure left ventricular mass and the ejection fraction. Concomitantly, in six cyp1a1ren-2 rats blood pressure was recorded telemetrically.
Plasma prorenin concentrations rose from 138 ± 38 to 15,490 ± 3990 ng/angiotensin I/mL/h (P < 0.001) in I3C-treated transgenic rats and returned to basal levels after cessation of I3C. Mean blood pressure increased to a plateau of 169 ± 11 mmHg by the second week of induction. After cessation of I3C (day 28), arterial pressure dropped to values slightly below those prior to induction within 4 days (basal: 106 ± 7 mmHg, day 32: 103 ± 21 mmHg; NS). At day 28, left ventricular mass was increased by 39% vs. 4% in controls (P < 0.001) without changes of the ejection fraction. Cardiac hypertrophy was completely reversed at day 70, as evaluated by MRI.
The cyp1a1ren-2 transgenic rat is a useful model to study reversal and healing in the absence of surgical interventions.
Journal of Magnetic Resonance Imaging 04/2012; 36(2):373-8. · 2.70 Impact Factor
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A Hannemann,
M Bidlingmaier,
N Friedrich,
J Manolopoulou,
A Spyroglou,
H Völzke,
F Beuschlein,
J Seissler, R Rettig,
S B Felix,
R Biffar,
A Döring,
C Meisinger,
A Peters,
H E Wichmann,
M Nauck,
H Wallaschofski,
M Reincke
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ABSTRACT: The prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30-79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects.
Data were obtained from the first follow-ups of the population-based study of health in Pomerania (SHIP; n=1392) and the cooperative health research in the region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies.Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC.
The frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A-C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects.
A maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients.
European Journal of Endocrinology 04/2012; 167(1):7-15. · 3.42 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
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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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ABSTRACT: Increased renal vascular resistance contributes to the pathogenesis of hypertension. The new Rho kinase (ROCK) inhibitor SAR407899 more potently lowers arterial pressure than the commercially available ROCK inhibitor Y27623. We tested whether ROCK inhibition more effectively reduced agonist-induced vasoconstriction in renal than in nonrenal resistance arteries and if SAR407899 more potently inhibits agonist-induced vasoconstriction than Y27632.
The effects of the ROCK inhibitors on endothelin-1 (ET-1) induced vasoconstriction were investigated in isolated renal and coronary arteries from lean, normotensive Dark Agouti and obese, type 2 diabetic Zucker diabetic fatty (ZDF) rats as well as in isolated human resistance arteries from the kidney and thymus. Vascular ROCK mRNA abundance was studied by real-time PCR (RT-PCR).
ET-1-induced constriction depended more on ROCK in rat and human renal resistance arteries than in rat coronary or human thymic arteries, respectively. SAR407899 was more effective than Y27632 in reducing ET-1-induced vasoconstriction in ZDF rat renal resistance arteries. Maximum ET-1-induced vasoconstriction in SAR407899-treated and Y27632-treated human renal resistance arteries was 23 ± 5 and 48 ± 6% of control values, respectively. Transcripts of both ROCK isoforms were detected in rat and human renal resistance arteries. In human thymic arteries, only the ROCK2 transcript was found.
ET-1-induced vasoconstriction is more ROCK-dependent in renal than in nonrenal resistance arteries. SAR407899 causes a greater inhibition of ET-1-induced vasoconstriction in renal resistance arteries from ZDF rats and patients than Y27632. The greater efficacy in renal vessels may contribute to the higher antihypertensive potency of SAR407899 compared with Y27632.
Journal of hypertension 02/2012; 30(5):980-9. · 4.02 Impact Factor
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Claudia Schurmann,
Katharina Heim,
Arne Schillert,
Stefan Blankenberg,
Maren Carstensen,
Marcus Dörr,
Karlhans Endlich,
Stephan B Felix,
Christian Gieger,
Harald Grallert, [......],
Konstantin Strauch,
Uwe Völker,
Henry Völzke,
Simone Wahl,
Henri Wallaschofski,
Philipp S Wild,
Tanja Zeller,
Alexander Teumer,
Holger Prokisch,
Andreas Ziegler
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ABSTRACT: Microarray profiling of gene expression is widely applied in molecular biology and functional genomics. Experimental and technical variations make meta-analysis of different studies challenging. In a total of 3358 samples, all from German population-based cohorts, we investigated the effect of data preprocessing and the variability due to sample processing in whole blood cell and blood monocyte gene expression data, measured on the Illumina HumanHT-12 v3 BeadChip array.Gene expression signal intensities were similar after applying the log(2) or the variance-stabilizing transformation. In all cohorts, the first principal component (PC) explained more than 95% of the total variation. Technical factors substantially influenced signal intensity values, especially the Illumina chip assignment (33-48% of the variance), the RNA amplification batch (12-24%), the RNA isolation batch (16%), and the sample storage time, in particular the time between blood donation and RNA isolation for the whole blood cell samples (2-3%), and the time between RNA isolation and amplification for the monocyte samples (2%). White blood cell composition parameters were the strongest biological factors influencing the expression signal intensities in the whole blood cell samples (3%), followed by sex (1-2%) in both sample types. Known single nucleotide polymorphisms (SNPs) were located in 38% of the analyzed probe sequences and 4% of them included common SNPs (minor allele frequency >5%). Out of the tested SNPs, 1.4% significantly modified the probe-specific expression signals (Bonferroni corrected p-value<0.05), but in almost half of these events the signal intensities were even increased despite the occurrence of the mismatch. Thus, the vast majority of SNPs within probes had no significant effect on hybridization efficiency.In summary, adjustment for a few selected technical factors greatly improved reliability of gene expression analyses. Such adjustments are particularly required for meta-analyses.
PLoS ONE 01/2012; 7(12):e50938. · 4.09 Impact Factor
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ABSTRACT: It is currently unclear whether subclinical thyroid dysfunction is associated with blood pressure. Furthermore, data on the potential relation of thyroid function with blood pressure in children and adolescents are sparse. We investigated the association between serum TSH levels and blood pressure in a population-based study conducted in children aged 3-10 yr and adolescents aged 11-17 yr.
Data from 6435 children and 5918 adolescents of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were analyzed. Two readings of systolic and diastolic blood pressure were taken in a sitting position after 5 min of rest. Hypertension was defined by an increased systolic or an increased diastolic blood pressure using age-, sex-, and height-specific reference values from the KiGGS study. Serum TSH levels were measured with the electrochemiluminescence method. High and low serum TSH levels were defined according to age-specific reference limits for the assay. Continuous and categorized serum TSH levels were associated with hypertension by multivariable logistic regression.
Serum TSH levels were significantly associated with hypertension in children (odds ratio=1.12; 95% confidence interval=1.00-1.25; P=0.045) and adolescents (odds ratio=1.19; 95% confidence interval=1.12-1.26; P<0.001). High serum TSH levels were positively associated with systolic and diastolic blood pressure, but not with hypertension in children and adolescents.
There is a positive relationship between serum TSH levels and hypertension in children and adolescents, suggesting that subclinical hypothyroidism is associated with an increased risk of hypertension.
The Journal of clinical endocrinology and metabolism 12/2011; 97(3):828-34. · 6.50 Impact Factor
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Anke Hannemann,
Nele Friedrich,
Kathleen Dittmann,
Christin Spielhagen,
Henri Wallaschofski,
Henry Völzke, Rainer Rettig,
Karlhans Endlich,
Uwe Lendeckel,
Sylvia Stracke,
Matthias Nauck
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ABSTRACT: Abstract Background: Early detection of patients with chronic kidney disease is of great importance. This study developed reference limits for serum creatinine and serum cystatin C concentrations and for the estimated glomerular filtration rate (eGFR) in healthy subjects from the general population aged 25-65 years. Methods: This study defined a reference population including 985 subjects from the first follow-up of the Study of Health in Pomerania. Serum creatinine was measured with a modified kinetic Jaffé method. Serum cystatin C was measured with a nephelometric assay. The eGFR was calculated from serum creatinine according to the Cockcroft-Gault (eGFRCG) and the Modification of Diet in Renal Disease (eGFRMDRD) equation, respectively, as well as from serum cystatin C according to the formula by Larsson (eGFRLarsson). Non-parametric quantile regression was used to estimate the reference limits. For serum creatinine and serum cystatin C the 95th percentile and for eGFRCG, eGFRMDRD and eGFRLarsson the 5th percentile were selected as reference limits. All data was weighted to reflect the age- and sex-structure of the German population in 2008. Results: The reference limits for serum creatinine (men: 1.11-1.23 mg/dL; women: 0.93-1.00 mg/dL) and serum cystatin C levels (men: 0.92-1.04 mg/L; women: 0.84-1.02 mg/L) increased with advancing age. The reference limits for eGFR decreased with increasing age (eGFRCG men: 106.0-64.7 mL/min, women 84.4-57.9 mL/min; eGFRMDRD men: 82.5-62.2 mL/min/1.73 m2, women 75.0-58.2 mL/min/1.73 m2; eGFRLarsson men: 85.5-72.9 mL/min, women 94.5-75.7 mL/min). Conclusions: This study presents age- and sex-specific reference limits for five measures of renal function based on quantile regression models.
Clinical Chemistry and Laboratory Medicine 11/2011; 50(5):919-26. · 2.15 Impact Factor
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Simon Gebhard,
Leif Steil,
Barbara Peters,
Manuela Gesell-Salazar,
Elke Hammer,
Beate Kuttler,
Kenneth J Clemetson,
Christian Scharf,
Jörg Peters,
Uwe Völker, Rainer Rettig,
Andreas Greinacher
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ABSTRACT: Hypertension is a risk factor for arterial thrombosis. We investigated the effects of angiotensin II (ANG II)-dependent hypertension on the platelet proteome.
Hypertension was induced in cyp1a1ren-2 transgenic rats by feeding indole-3-carbinol (n = 10) and in Fischer 344 rats by subcutaneously infusing ANG II (n = 7). After 14 days of hypertension (SBP 180 mmHg) and 10 days after normalization of blood pressure, changes in the platelet proteome were assessed by two-dimensional differential in-gel electrophoresis. In a subset of animals (n = 4), repeated blood withdrawals were performed. Of 1040 protein spots, 45 displayed hypertension-associated changes (>1.5-fold, P < 0.01) in both models (34 increased, 11 decreased). All were reversible within 10 days. Thirty-eight spots were identified by mass spectrometry and assigned to 20 distinct proteins. The majority of spots with increased intensity constituted protein fragments. Repeated blood withdrawals and stimulation of megakaryocytopoiesis by a thrombopoietin receptor agonist induced changes in the same protein spots but in the opposite direction to those induced by ANG II-dependent hypertension.
ANG II-dependent hypertension is associated with enhanced protein degradation in platelets. As these changes are reversible, the proteins identified might be used to develop a biomarker for monitoring recent blood pressure history.
Journal of hypertension 09/2011; 29(11):2126-37. · 4.02 Impact Factor
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Louise V Wain,
Germaine C Verwoert,
Paul F O'Reilly,
Gang Shi,
Toby Johnson,
Andrew D Johnson,
Murielle Bochud,
Kenneth M Rice,
Peter Henneman,
Albert V Smith, [......],
Vilmundur Gudnason,
Christopher Newton-Cheh,
Daniel Levy,
Patricia B Munroe,
Bruce M Psaty,
Mark J Caulfield,
Dabeeru C Rao,
Martin D Tobin,
Paul Elliott,
Cornelia M van Duijn
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ABSTRACT: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Nature Genetics 09/2011; 43(10):1005-11. · 35.53 Impact Factor
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Georg B Ehret,
Patricia B Munroe,
Kenneth M Rice,
Murielle Bochud,
Andrew D Johnson,
Daniel I Chasman,
Albert V Smith,
Martin D Tobin,
Germaine C Verwoert,
Shih-Jen Hwang, [......],
Marjo-Riitta Järvelin,
Bruce M Psaty,
Gonçalo R Abecasis,
Aravinda Chakravarti,
Paul Elliott,
Cornelia M van Duijn,
Christopher Newton-Cheh,
Daniel Levy,
Mark J Caulfield,
Toby Johnson
[show abstract]
[hide abstract]
ABSTRACT: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Nature 09/2011; 478(7367):103-9. · 36.28 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
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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
