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1.  Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study 
Gottlieb, Daniel J. | Hek, Karin | Chen, Ting-hsu | Watson, Nathaniel F. | Eiriksdottir, Gudny | Byrne, Enda M. | Cornelis, Marilyn | Warby, Simon C. | Bandinelli, Stefania | Cherkas, Lynn | Evans, Daniel S. | Grabe, Hans J. | Lahti, Jari | Li, Man | Lehtimäki, Terho | Lumley, Thomas | Marciante, Kristin D. | Pérusse, Louis | Psaty, Bruce M. | Robbins, John | Tranah, Gregory J. | Vink, Jacqueline M. | Wilk, Jemma B. | Stafford, Jeanette M. | Bellis, Claire | Biffar, Reiner | Bouchard, Claude | Cade, Brian | Curhan, Gary C. | Eriksson, Johan G. | Ewert, Ralf | Ferrucci, Luigi | Fülöp, Tibor | Gehrman, Philip R. | Goodloe, Robert | Harris, Tamara B. | Heath, Andrew C. | Hernandez, Dena | Hofman, Albert | Hottenga, Jouke-Jan | Hunter, David J. | Jensen, Majken K. | Johnson, Andrew D. | Kähönen, Mika | Kao, Linda | Kraft, Peter | Larkin, Emma K. | Lauderdale, Diane S. | Luik, Annemarie I. | Medici, Marco | Montgomery, Grant W. | Palotie, Aarno | Patel, Sanjay R. | Pistis, Giorgio | Porcu, Eleonora | Quaye, Lydia | Raitakari, Olli | Redline, Susan | Rimm, Eric B. | Rotter, Jerome I. | Smith, Albert V. | Spector, Tim D. | Teumer, Alexander | Uitterlinden, André G. | Vohl, Marie-Claude | Widen, Elisabeth | Willemsen, Gonneke | Young, Terry | Zhang, Xiaoling | Liu, Yongmei | Blangero, John | Boomsma, Dorret I. | Gudnason, Vilmundur | Hu, Frank | Mangino, Massimo | Martin, Nicholas G. | O’Connor, George T. | Stone, Katie L. | Tanaka, Toshiko | Viikari, Jorma | Gharib, Sina A. | Punjabi, Naresh M. | Räikkönen, Katri | Völzke, Henry | Mignot, Emmanuel | Tiemeier, Henning
Molecular psychiatry  2014;20(10):1232-1239.
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35–80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 ×10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
doi:10.1038/mp.2014.133
PMCID: PMC4430294  PMID: 25469926
Sleep; Genome-wide association study
2.  THE METABOLIC SYNDROME ACROSS EUROPE – DIFFERENT CLUSTERS OF RISK FACTORS 
Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se’- were associated with accelerated arterial ageing and with CV events. To investigate whether the distribution of the “risky” clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and 1 from US participants in the MARE (Metabolic syndrome and Arteries REsearch) Consortium. In accordance with the ATP III criteria, MetS was defined as an alteration ≥3 of the following 5 components: elevated glucose (G): fasting glucose ≥110 mg/dl; low HDL cholesterol (H): <40 mg/dl for M or < 50 mg/dl for W; high triglycerides (T) ≥150 mg/dl; elevated BP (B): ≥130/≥85 mmHg; abdominal obesity (W): waist circumference > 102 cm for M or >88 cm for W.
MetS had a 24.3% prevalence (8468 subjects) (23.9% in men vs 24.6% in women, p<0.001) with an age-associated increase in its prevalence in all the cohorts.
The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p< 0.0001) and in men and women (gender effect p<0.0001). In details, the cluster T-B-W was observed in 12% of the subjects with MetS, but was far more common in the cohorts from UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and USA (2.5%). The cluster G-B-W accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal - with 31.4%, 18.4%, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania - with 7.6%, 9.4%, and 9.6% respectively).
The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries.
doi:10.1177/2047487314525529
PMCID: PMC4544872  PMID: 24647805
blood pressure; epidemiology; Europe; glucose; metabolic syndrome; triglycerides; HDL cholesterol; waist circumference
3.  Genome-Wide Association Study for Endothelial Growth Factors 
Background
Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2) and hepatocyte growth factor (HGF) play important roles in angiogenesis, vascular remodeling, local tumor growth and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown.
Methods and Results
We performed a genome-wide association study for circulating Ang-2, sTie-2, and HGF in 3571 Framingham Heart Study (FHS) participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania (SHIP). In multivariable-adjusted models, sTie-2 and HGF concentrations were associated with single nucleotide polymorphisms (SNPs) in the genes encoding the respective biomarkers (top p=2.40×10−65 [rs2273720] and 3.64×10−19 [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (p=5.05×10−8 in FHS and 8.39×10−5 in SHIP). Furthermore, SNPs in the AB0 gene were associated with sTie-2 (top SNP rs8176693 with p=1.84×10−33 in FHS; p=2.53×10−30 in SHIP) and Ang-2 (rs8176746 with p=2.07×10−8 in FHS; p=0.001 in SHIP) levels on a genome-wide significant level. The top genetic loci explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the inter-individual variation in biomarker levels.
Conclusions
Genetic variation contributes to the inter-individual variation in growth factor levels and explains a modest proportion of circulating HGF, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.
doi:10.1161/CIRCGENETICS.114.000597
PMCID: PMC4406801  PMID: 25552591
Genome Wide Association Study; genetics; endothelial growth factors; HGF; Ang-2; Tie-2
4.  Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium 
PLoS ONE  2016;11(3):e0144997.
Background
Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
Methods
We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
Results
In Stage I 15 loci passed the threshold of 5×10−6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10−3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10−9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10−3).
Conclusions
QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
doi:10.1371/journal.pone.0144997
PMCID: PMC4780701  PMID: 26950853
5.  Serum Thyrotropin Concentrations Are Not Associated with the Ankle-Brachial Index: Results from Three Population-Based Studies 
European Thyroid Journal  2015;4(Suppl 1):101-107.
Background
There is only limited data on the potential association between thyroid dysfunction and peripheral arterial disease (PAD).
Objective
The aim of our study was to investigate the potential association of thyroid function, as defined by serum concentrations of the clinically used primary thyroid function marker thyrotropin [i.e. thyroid-stimulating hormone (TSH)] and 3,5-diiodothyronine (3,5-T2), with the ankle-brachial index (ABI) as a marker of PAD.
Methods
We used data from 5,818 individuals from three cross-sectional population-based studies conducted in Northeast (SHIP-2 and SHIP-TREND) and Central Germany (CARLA). Measurement of serum TSH concentrations was conducted in one central laboratory for all three studies. In a randomly selected subpopulation of 750 individuals of SHIP-TREND, serum 3,5-T2 concentrations were measured with a recently developed immunoassay. ABI was measured either by a hand-held Doppler ultrasound using the Huntleigh Dopplex D900 or palpatorily by the OMRON HEM-705CP device.
Results
Serum TSH concentrations were not significantly associated with ABI values in any of the three studies. Likewise, groups of individuals with a TSH <0.3 mIU/l or with a TSH ≥3.0 mIU/l had no significantly different ABI values in comparison with individuals with a TSH in the reference range. Analyses regarding TSH within the reference range or serum 3,5-T2 concentrations did not reveal consistent significant associations with the ABI. No sex-specific associations were detected.
Conclusions
The results of our study do not substantiate evidence for an association between thyroid function and PAD, but further studies are needed to investigate the associations of overt forms of thyroid dysfunction with PAD.
doi:10.1159/000381309
PMCID: PMC4640292  PMID: 26601080
Epidemiology; Population-based study; Thyrotropin; Thyroid; Peripheral arterial disease; Ankle-brachial index
6.  Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans 
European Thyroid Journal  2015;4(Suppl 1):92-100.
Context
3,5-Diiodo-L-thyronine (3,5-T2) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T2 and glucose but not lipid metabolism.
Objective
The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T2 concentrations in healthy individuals.
Study Design and Methods
Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by 1H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T2 concentrations.
Results
Serum 3,5-T2 concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T2 concentrations doubled owing to a 1-standard deviation (SD) decrease in urine trigonelline levels, or increased by 29-50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels.
Conclusion
Our findings in humans confirmed the metabolic effects of circulating 3,5-T2 on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T2 exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones.
doi:10.1159/000381308
PMCID: PMC4640298  PMID: 26601079
3,5-Diiodothyronine; Trigonelline; Urine metabolome; NMR spectroscopy; Thyroid hormone
7.  Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian’an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R.B.
Nature communications  2015;6:7756.
More than one hundred loci have been identified for age at menarche by genome-wide association studies (GWAS), but collectively these explain only ~3% of the trait variance. Here, we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08%-4.6%; effect sizes 0.08-1.25 years/allele; P<5×10−8). Additionally, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4×10−13) and FAAH2 (rs5914101, P=4.9×10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-years later menarche (P=2.8×10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively these novel variants explain ~0.5% variance, indicating these overlooked sources of variation do not substantially explain the ‘missing heritability’ of this complex trait.
doi:10.1038/ncomms8756
PMCID: PMC4538850  PMID: 26239645
8.  Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration 
Background
Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.
Methods
Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.
Results
Mean baseline CCA-IMT amounted to 0.74mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072mm for fibrinogen (p < 0.001); and 0.0025mm for leucocyte count (p = 0.033). ‘Inflammatory load’, defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest ‘inflammatory load’ had a greater CCA-IMT progression (p = 0.015).
Conclusion
Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for ‘inflammatory load’ suggest important combined effects of the three inflammatory markers on early atherosclerosis.
doi:10.1177/2047487314560664
PMCID: PMC4544641  PMID: 25416041
Inflammation; atherosclerosis; meta-analysis
9.  Association of PNPLA3 rs738409 and TM6SF2 rs58542926 with health services utilization in a population-based study 
Background
Hepatic steatosis confers an increased risk of metabolic and cardiovascular disease and higher health services use. Associations of the single nucleotide polymorphisms (SNP) PNPLA3 rs738409 and TM6SF2 rs58542926 with hepatic steatosis have recently been established. This study investigates the association between rs738409 and rs58542926 with health services utilization in a general population.
Methods
Data of 3759 participants from Study of Health in Pomerania (SHIP), a population-based study in Germany, were obtained. The annual number of outpatient visits, hospitalization and length of hospital stay was regressed on rs738409 and rs58542926 and adjusted for socio-economic factors, lifestyle habits, clinical factors, and health status.
Results
Minor allele homozygous subjects of rs738409 had an increased odds of hospitalization as compared to major allele homozygous subjects (odds ratio [OR] 1.51; 95 % confidence interval [CI], 1.02 to 2.15). Heterozygous subjects did not differ from major allele homozygous subjects with respect to their odds of hospitalization. The three genotype groups of rs738409 were similar with respect to the number of outpatient visits and inpatient days. Minor allele homozygous and heterozygous subjects of rs58542926 had higher outpatient utilization (+53.04 % and +67.56 %, p < 0.05, respectively) and inpatient days than major allele homozygous subjects.
Conclusions
After adjustment for several confounding factors, PNPLA3 rs738409 and TM6SF2 rs58542926 were associated with the number of outpatient visits, hospitalization, and inpatient days. Further studies are warranted to replicate our findings and to evaluate whether genetic data can be used to identify subjects with excess health services utilization.
doi:10.1186/s12913-016-1289-6
PMCID: PMC4741011  PMID: 26847197
Genotype information; Hepatic steatosis; Costs Health Services Utilization
10.  Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2? 
Thyroid  2015;25(2):188-197.
Background: During the last two decades, it has become obvious that 3,5-diiodothyronine (3,5-T2), a well-known endogenous metabolite of the thyroid hormones thyroxine (T4) or triiodothyronine (T3), not only represents a simple degradation intermediate of the former but also exhibits specific metabolic activities. Administration of 3,5-T2 to hypothyroid rodents rapidly stimulated their basal metabolic rate, prevented high-fat diet-induced obesity as well as steatosis, and increased oxidation of long-chain fatty acids.
Objective: The aim of the present study was to analyze associations between circulating 3,5-T2 in human serum and different epidemiological parameters, including age, sex, or smoking, as well as measures of anthropometry, glucose, and lipid metabolism.
Methods: 3,5-T2 concentrations were measured by a recently developed immunoassay in sera of 761 euthyroid participants of the population-based Study of Health in Pomerania. Subsequently, analysis of variance and multivariate linear regression analysis were performed.
Results: Serum 3,5-T2 concentrations exhibited a right-skewed distribution, resulting in a median serum concentration of 0.24 nM (1st quartile: 0.20 nM; 3rd quartile: 0.37 nM). Significant associations between 3,5-T2 and serum fasting glucose, thyrotropin (TSH), as well as leptin concentrations were detected (p<0.05). Interestingly, the association to leptin concentrations seemed to be mediated by TSH. Age, sex, smoking, and blood lipid profile parameters did not show significant associations with circulating 3,5-T2.
Conclusion: Our findings from a healthy euthyroid population may point toward a physiological link between circulating 3,5-T2 and glucose metabolism.
doi:10.1089/thy.2014.0262
PMCID: PMC4322092  PMID: 25343227
11.  LOng-term follow-up after liVE kidney donation (LOVE) study: a longitudinal comparison study protocol 
BMC Nephrology  2016;17:14.
Background
The benefits of live donor kidney transplantation must be balanced against the potential harm to the donor. Well-designed prospective studies are needed to study the long-term consequences of kidney donation.
Methods
The “LOng-term follow-up after liVE kidney donation” (LOVE) study is a single center longitudinal cohort study on long-term consequences after living kidney donation. We will study individuals who have donated a kidney from 1981 through 2010 in the Erasmus University Medical Center in Rotterdam, The Netherlands. In this time period, 1092 individuals donated a kidney and contact information is available for all individuals. Each participating donor will be matched (1:4) to non-donors derived from the population-based cohort studies of the Rotterdam Study and the Study of Health in Pomerania. Matching will be based on baseline age, gender, BMI, ethnicity, kidney function, blood pressure, pre-existing co-morbidity, smoking, the use of alcohol and highest education degree. Follow-up data is collected on kidney function, kidney-related comorbidity, mortality, quality of life and psychological outcomes in all participants.
Discussion
This study will provide evidence on the long-term consequences of live kidney donation for the donor compared to matched non-donors and evaluate the current donor eligibility criteria.
Trial registration
Dutch Trial Register NTR3795.
doi:10.1186/s12882-016-0227-5
PMCID: PMC4736233  PMID: 26830198
Living donors; Nephrectomy; Kidney transplantation; Follow-up studies; Cohort studies
12.  Genome-Wide Meta-Analyses of Plasma Renin Activity and Concentration Reveal Association with the Kininogen 1 and Prekallikrein Genes 
Background
The renin-angiotensin-aldosterone-system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood.
Methods and Results
We meta-analyzed genome-wide association data for plasma renin activity (n=5,275), plasma renin concentrations (n=8,014) and circulating aldosterone (n=13,289) from up to four population-based cohorts of European and European-American ancestry, and assessed replication of the top results in an independent sample (n=6,487).
Single nucleotide polymorphisms (SNPs) in two independent loci displayed associations with plasma renin activity atgenome-wide significance (p<5×10-8). A third locus was close to this threshold (rs4253311 in kallikrein B [KLKB1], p=5.5×10-8). Two of these loci replicated in an independent sample for both plasma renin and aldosterone concentrations (SNP rs5030062 in kininogen 1 [KNG1]: p=0.001 for plasma renin, p=0.024 for plasma aldosterone concentration; rs4253311 with p<0.001 for both plasma renin and aldosterone concentration). SNPs in the NEBL gene reached genome-wide significance for plasma renin concentration in the discovery sample (top SNP rs3915911, p= 8.81×10-9), but did not replicate (p=0.81). No locus reached genome-wide significance for aldosterone. SNPs rs5030062 and rs4253311 were not related to blood pressure or renal traits; in a companion study, variants in the kallikrein B locus were associated with B-type natriuretic peptide concentrations in African-Americans.
Conclusions
We identified two genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS.
doi:10.1161/CIRCGENETICS.114.000613
PMCID: PMC4354880  PMID: 25477429
renin angiotensin system; aldosterone; Genome Wide Association Study
13.  New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk 
Lu, Yingchang | Day, Felix R. | Gustafsson, Stefan | Buchkovich, Martin L. | Na, Jianbo | Bataille, Veronique | Cousminer, Diana L. | Dastani, Zari | Drong, Alexander W. | Esko, Tõnu | Evans, David M. | Falchi, Mario | Feitosa, Mary F. | Ferreira, Teresa | Hedman, Åsa K. | Haring, Robin | Hysi, Pirro G. | Iles, Mark M. | Justice, Anne E. | Kanoni, Stavroula | Lagou, Vasiliki | Li, Rui | Li, Xin | Locke, Adam | Lu, Chen | Mägi, Reedik | Perry, John R. B. | Pers, Tune H. | Qi, Qibin | Sanna, Marianna | Schmidt, Ellen M. | Scott, William R. | Shungin, Dmitry | Teumer, Alexander | Vinkhuyzen, Anna A. E. | Walker, Ryan W. | Westra, Harm-Jan | Zhang, Mingfeng | Zhang, Weihua | Zhao, Jing Hua | Zhu, Zhihong | Afzal, Uzma | Ahluwalia, Tarunveer Singh | Bakker, Stephan J. L. | Bellis, Claire | Bonnefond, Amélie | Borodulin, Katja | Buchman, Aron S. | Cederholm, Tommy | Choh, Audrey C. | Choi, Hyung Jin | Curran, Joanne E. | de Groot, Lisette C. P. G. M. | De Jager, Philip L. | Dhonukshe-Rutten, Rosalie A. M. | Enneman, Anke W. | Eury, Elodie | Evans, Daniel S. | Forsen, Tom | Friedrich, Nele | Fumeron, Frédéric | Garcia, Melissa E. | Gärtner, Simone | Han, Bok-Ghee | Havulinna, Aki S. | Hayward, Caroline | Hernandez, Dena | Hillege, Hans | Ittermann, Till | Kent, Jack W. | Kolcic, Ivana | Laatikainen, Tiina | Lahti, Jari | Leach, Irene Mateo | Lee, Christine G. | Lee, Jong-Young | Liu, Tian | Liu, Youfang | Lobbens, Stéphane | Loh, Marie | Lyytikäinen, Leo-Pekka | Medina-Gomez, Carolina | Michaëlsson, Karl | Nalls, Mike A. | Nielson, Carrie M. | Oozageer, Laticia | Pascoe, Laura | Paternoster, Lavinia | Polašek, Ozren | Ripatti, Samuli | Sarzynski, Mark A. | Shin, Chan Soo | Narančić, Nina Smolej | Spira, Dominik | Srikanth, Priya | Steinhagen-Thiessen, Elisabeth | Sung, Yun Ju | Swart, Karin M. A. | Taittonen, Leena | Tanaka, Toshiko | Tikkanen, Emmi | van der Velde, Nathalie | van Schoor, Natasja M. | Verweij, Niek | Wright, Alan F. | Yu, Lei | Zmuda, Joseph M. | Eklund, Niina | Forrester, Terrence | Grarup, Niels | Jackson, Anne U. | Kristiansson, Kati | Kuulasmaa, Teemu | Kuusisto, Johanna | Lichtner, Peter | Luan, Jian'an | Mahajan, Anubha | Männistö, Satu | Palmer, Cameron D. | Ried, Janina S. | Scott, Robert A. | Stancáková, Alena | Wagner, Peter J. | Demirkan, Ayse | Döring, Angela | Gudnason, Vilmundur | Kiel, Douglas P. | Kühnel, Brigitte | Mangino, Massimo | Mcknight, Barbara | Menni, Cristina | O'Connell, Jeffrey R. | Oostra, Ben A. | Shuldiner, Alan R. | Song, Kijoung | Vandenput, Liesbeth | van Duijn, Cornelia M. | Vollenweider, Peter | White, Charles C. | Boehnke, Michael | Boettcher, Yvonne | Cooper, Richard S. | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Hingorani, Aroon | Jørgensen, Torben | Jousilahti, Pekka | Kivimaki, Mika | Kumari, Meena | Laakso, Markku | Langenberg, Claudia | Linneberg, Allan | Luke, Amy | Mckenzie, Colin A. | Palotie, Aarno | Pedersen, Oluf | Peters, Annette | Strauch, Konstantin | Tayo, Bamidele O. | Wareham, Nicholas J. | Bennett, David A. | Bertram, Lars | Blangero, John | Blüher, Matthias | Bouchard, Claude | Campbell, Harry | Cho, Nam H. | Cummings, Steven R. | Czerwinski, Stefan A. | Demuth, Ilja | Eckardt, Rahel | Eriksson, Johan G. | Ferrucci, Luigi | Franco, Oscar H. | Froguel, Philippe | Gansevoort, Ron T. | Hansen, Torben | Harris, Tamara B. | Hastie, Nicholas | Heliövaara, Markku | Hofman, Albert | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Knekt, Paul B. | Koskinen, Seppo | Kovacs, Peter | Lehtimäki, Terho | Lind, Lars | Liu, Yongmei | Orwoll, Eric S. | Osmond, Clive | Perola, Markus | Pérusse, Louis | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Rivadeneira, Fernando | Rudan, Igor | Salomaa, Veikko | Sørensen, Thorkild I. A. | Stumvoll, Michael | Tönjes, Anke | Towne, Bradford | Tranah, Gregory J. | Tremblay, Angelo | Uitterlinden, André G. | van der Harst, Pim | Vartiainen, Erkki | Viikari, Jorma S. | Vitart, Veronique | Vohl, Marie-Claude | Völzke, Henry | Walker, Mark | Wallaschofski, Henri | Wild, Sarah | Wilson, James F. | Yengo, Loïc | Bishop, D. Timothy | Borecki, Ingrid B. | Chambers, John C. | Cupples, L. Adrienne | Dehghan, Abbas | Deloukas, Panos | Fatemifar, Ghazaleh | Fox, Caroline | Furey, Terrence S. | Franke, Lude | Han, Jiali | Hunter, David J. | Karjalainen, Juha | Karpe, Fredrik | Kaplan, Robert C. | Kooner, Jaspal S. | McCarthy, Mark I. | Murabito, Joanne M. | Morris, Andrew P. | Bishop, Julia A. N. | North, Kari E. | Ohlsson, Claes | Ong, Ken K. | Prokopenko, Inga | Richards, J. Brent | Schadt, Eric E. | Spector, Tim D. | Widén, Elisabeth | Willer, Cristen J. | Yang, Jian | Ingelsson, Erik | Mohlke, Karen L. | Hirschhorn, Joel N. | Pospisilik, John Andrew | Zillikens, M. Carola | Lindgren, Cecilia | Kilpeläinen, Tuomas Oskari | Loos, Ruth J. F.
Nature Communications  2016;7:10495.
To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.
doi:10.1038/ncomms10495
PMCID: PMC4740398  PMID: 26833246
14.  Anthropometric markers and their association with incident type 2 diabetes mellitus: which marker is best for prediction? Pooled analysis of four German population-based cohort studies and comparison with a nationwide cohort study 
BMJ Open  2016;6(1):e009266.
Objective
To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany.
Methods
Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison.
Results
Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups (<65 vs ≥65 years).
Conclusions
We found stronger associations between anthropometric markers that reflect abdominal obesity (ie, WC and WHtR) and incident T2DM than for BMI and weight. The use of these measurements in risk prediction should be encouraged.
doi:10.1136/bmjopen-2015-009266
PMCID: PMC4735317  PMID: 26792214
EPIDEMIOLOGY; PUBLIC HEALTH
15.  Corrigendum: Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E. | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian'an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R. B.
Nature Communications  2015;6:10257.
doi:10.1038/ncomms10257
PMCID: PMC4703878  PMID: 26674845
16.  Changes of individual perception in psychosocial stressors related to German reunification in 1989/1990 and cardiovascular risk factors and cardiovascular diseases in a population-based study in East Germany 
BMJ Open  2016;6(1):e008703.
Objectives
Aim was to examine the relationship between individually perceived changes in psychosocial stressors associated with German reunification and cardiovascular effects. We hypothesised that higher levels of psychosocial stress related to German reunification were associated with an increase in cardiovascular risk factors and cardiovascular diseases (CVDs).
Design
Cross-sectional data from 2 cohort studies in East Germany were used: Cardiovascular Disease, Living and Ageing in Halle Study (CARLA), and Study of Health in Pomerania (SHIP).
Setting
2 populations in East Germany.
Participants
CARLA study: 1779 participants, aged 45–83 years at baseline (812 women), SHIP study: 4308 participants, aged 20–79 years at baseline (2193 women).
Primary and secondary outcome measures
Psychosocial stressors related to reunification were operationalised by the Reunification Stress Index (RSI; scale from 0 to 10). This index was composed of questions that were related to individually perceived changes in psychosocial stressors (occupational, financial and personal) after reunification. To examine the associations between the RSI and each stressor separately with cardiovascular risk factors and CVD, regression models were used.
Results
RSI was associated with CVD in women (RR=1.15, 95% CI 1.00 to 1.33). Cardiovascular risk factors were associated with RSI for both men and women, with strongest associations between RSI and diabetes in women (RR=1.10, 95% CI 1.01 to 1.20) and depressive disorders in men (RR=1.15, 95% CI 1.07 to 2.77). The change in occupational situation related to reunification was the major contributing psychosocial stressor. We observed a strong association with CVD in women who experienced occupational deterioration after reunification (RR=4.04, 95% CI 1.21 to 13.43).
Conclusions
Individually perceived deterioration of psychosocial stressors (occupational, financial and personal) related to German reunification was associated with cardiovascular risk factors and CVD. The associations were stronger for women than for men. An explanation for these findings could be that women were more often affected by unemployment after reunification. Morbidity and mortality follow-up of both cohorts could enhance the results.
doi:10.1136/bmjopen-2015-008703
PMCID: PMC4716160  PMID: 26729378
EPIDEMIOLOGY; SOCIAL MEDICINE
17.  Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation 
Artigas, María Soler | Wain, Louise V. | Miller, Suzanne | Kheirallah, Abdul Kader | Huffman, Jennifer E. | Ntalla, Ioanna | Shrine, Nick | Obeidat, Ma'en | Trochet, Holly | McArdle, Wendy L. | Alves, Alexessander Couto | Hui, Jennie | Zhao, Jing Hua | Joshi, Peter K. | Teumer, Alexander | Albrecht, Eva | Imboden, Medea | Rawal, Rajesh | Lopez, Lorna M. | Marten, Jonathan | Enroth, Stefan | Surakka, Ida | Polasek, Ozren | Lyytikäinen, Leo-Pekka | Granell, Raquel | Hysi, Pirro G. | Flexeder, Claudia | Mahajan, Anubha | Beilby, John | Bossé, Yohan | Brandsma, Corry-Anke | Campbell, Harry | Gieger, Christian | Gläser, Sven | González, Juan R. | Grallert, Harald | Hammond, Chris J. | Harris, Sarah E. | Hartikainen, Anna-Liisa | Heliövaara, Markku | Henderson, John | Hocking, Lynne | Horikoshi, Momoko | Hutri-Kähönen, Nina | Ingelsson, Erik | Johansson, Åsa | Kemp, John P. | Kolcic, Ivana | Kumar, Ashish | Lind, Lars | Melén, Erik | Musk, Arthur W. | Navarro, Pau | Nickle, David C. | Padmanabhan, Sandosh | Raitakari, Olli T. | Ried, Janina S. | Ripatti, Samuli | Schulz, Holger | Scott, Robert A. | Sin, Don D. | Starr, John M. | Viñuela, Ana | Völzke, Henry | Wild, Sarah H. | Wright, Alan F. | Zemunik, Tatijana | Jarvis, Deborah L. | Spector, Tim D. | Evans, David M. | Lehtimäki, Terho | Vitart, Veronique | Kähönen, Mika | Gyllensten, Ulf | Rudan, Igor | Deary, Ian J. | Karrasch, Stefan | Probst-Hensch, Nicole M. | Heinrich, Joachim | Stubbe, Beate | Wilson, James F. | Wareham, Nicholas J. | James, Alan L. | Morris, Andrew P. | Jarvelin, Marjo-Riitta | Hayward, Caroline | Sayers, Ian | Strachan, David P. | Hall, Ian P. | Tobin, Martin D.
Nature Communications  2015;6:8658.
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
doi:10.1038/ncomms9658
PMCID: PMC4686825  PMID: 26635082
18.  Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes 
EMBO Molecular Medicine  2015;7(12):1565-1579.
Abstract
Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high‐ versus low‐risk constellation regarding the accumulation model. Thereby, the brain‐expressed miR‐181 species emerged as potential “umbrella regulator”, with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.
doi:10.15252/emmm.201505696
PMCID: PMC4693501  PMID: 26612855
FMR1; FMR2; FXR1; FXR2; miR‐181; PGAS; Genetics, Gene Therapy & Genetic Disease; Neuroscience
19.  The transcriptional landscape of age in human peripheral blood 
Peters, Marjolein J. | Joehanes, Roby | Pilling, Luke C. | Schurmann, Claudia | Conneely, Karen N. | Powell, Joseph | Reinmaa, Eva | Sutphin, George L. | Zhernakova, Alexandra | Schramm, Katharina | Wilson, Yana A. | Kobes, Sayuko | Tukiainen, Taru | Ramos, Yolande F. | Göring, Harald H. H. | Fornage, Myriam | Liu, Yongmei | Gharib, Sina A. | Stranger, Barbara E. | De Jager, Philip L. | Aviv, Abraham | Levy, Daniel | Murabito, Joanne M. | Munson, Peter J. | Huan, Tianxiao | Hofman, Albert | Uitterlinden, André G. | Rivadeneira, Fernando | van Rooij, Jeroen | Stolk, Lisette | Broer, Linda | Verbiest, Michael M. P. J. | Jhamai, Mila | Arp, Pascal | Metspalu, Andres | Tserel, Liina | Milani, Lili | Samani, Nilesh J. | Peterson, Pärt | Kasela, Silva | Codd, Veryan | Peters, Annette | Ward-Caviness, Cavin K. | Herder, Christian | Waldenberger, Melanie | Roden, Michael | Singmann, Paula | Zeilinger, Sonja | Illig, Thomas | Homuth, Georg | Grabe, Hans-Jörgen | Völzke, Henry | Steil, Leif | Kocher, Thomas | Murray, Anna | Melzer, David | Yaghootkar, Hanieh | Bandinelli, Stefania | Moses, Eric K. | Kent, Jack W. | Curran, Joanne E. | Johnson, Matthew P. | Williams-Blangero, Sarah | Westra, Harm-Jan | McRae, Allan F. | Smith, Jennifer A. | Kardia, Sharon L. R. | Hovatta, Iiris | Perola, Markus | Ripatti, Samuli | Salomaa, Veikko | Henders, Anjali K. | Martin, Nicholas G. | Smith, Alicia K. | Mehta, Divya | Binder, Elisabeth B. | Nylocks, K Maria | Kennedy, Elizabeth M. | Klengel, Torsten | Ding, Jingzhong | Suchy-Dicey, Astrid M. | Enquobahrie, Daniel A. | Brody, Jennifer | Rotter, Jerome I. | Chen, Yii-Der I. | Houwing-Duistermaat, Jeanine | Kloppenburg, Margreet | Slagboom, P. Eline | Helmer, Quinta | den Hollander, Wouter | Bean, Shannon | Raj, Towfique | Bakhshi, Noman | Wang, Qiao Ping | Oyston, Lisa J. | Psaty, Bruce M. | Tracy, Russell P. | Montgomery, Grant W. | Turner, Stephen T. | Blangero, John | Meulenbelt, Ingrid | Ressler, Kerry J. | Yang, Jian | Franke, Lude | Kettunen, Johannes | Visscher, Peter M. | Neely, G. Gregory | Korstanje, Ron | Hanson, Robert L. | Prokisch, Holger | Ferrucci, Luigi | Esko, Tonu | Teumer, Alexander | van Meurs, Joyce B. J. | Johnson, Andrew D.
Nature Communications  2015;6:8570.
Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
Ageing increases the risk of many diseases. Here the authors compare blood cell transcriptomes of over 14,000 individuals and identify a set of about 1,500 genes that are differently expressed with age, shedding light on transcriptional programs linked to the ageing process and age-associated diseases.
doi:10.1038/ncomms9570
PMCID: PMC4639797  PMID: 26490707
20.  Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts 
BMC Medical Genomics  2015;8:65.
Background
Obesity, defined as pathologically increased body mass index (BMI), is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed.
Methods
Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals.
Results
Extensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS).
Conclusions
Whereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0141-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12920-015-0141-x
PMCID: PMC4608219  PMID: 26470795
Transcriptomics; Transcriptome-wide association study (TWAS); BMI; Obesity; Insulin resistance; Type 2 diabetes; Oxidative stress; Insulin signaling
21.  Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E. | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian'an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R. B.
Nature Communications  2015;6:7756.
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08–4.6%; effect sizes 0.08–1.25 years per allele; P<5 × 10−8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10−13) and FAAH2 (rs5914101, P=4.9 × 10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability' of this complex trait.
Previous studies have linked over 100 genomic loci to age-at-menarche but that work was restricted to common autosomal variation. Here, Lunetta et al. identify associations with rare protein-coding and X-linked variants, implicating new mechanisms that regulate puberty timing.
doi:10.1038/ncomms8756
PMCID: PMC4538850  PMID: 26239645
22.  Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis 
Gastroenterology  2015;149(3):765-776.e10.
Background & Aims
Little is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients.
Methods
Chronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling.
Results
During the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood.
Conclusions
In mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis.
doi:10.1053/j.gastro.2015.05.012
PMCID: PMC4560830  PMID: 26001927
Pancreatic Stellate Cells; Transcriptome Analysis; Complement System; αSMA; C5, complement component 5; HSC, hepatic stellate cell; IL, interleukin; IP, intraperitoneal; MPO, myeloperoxidase; PSC, pancreatic stellate cell; αSMA, α smooth muscle actin; SNP, single-nucleotide polymorphism; TGFβ, transforming growth factor β; TNFα, tumor necrosis factor α
23.  Association of Change of Anthropometric Measurements With Incident Type 2 Diabetes Mellitus 
Medicine  2015;94(34):e1394.
Abstract
Our objective was to investigate the association of change of anthropometric measurements and the incidence of type 2 diabetes mellitus (T2DM) within a pooled sample of 2 population-based cohorts.
A final sample of 1324 women and 1278 men aged 31 to 83 years from 2 prospective cohorts in Germany, the CARLA (Cardiovascular Disease - Living and Ageing in Halle) and the SHIP study (Study of Health in Pomerania), were pooled. The association of change of body weight and waist circumference (WC) with incidence of T2DM was assessed by calculating sex-specific hazard ratios (HRs). We investigated the absolute change of markers of obesity as well as change relative to the baseline value and estimated crude and adjusted HRs. Furthermore, we conducted the analyses stratified by obesity status and age (<60 vs ≥60 years) at baseline.
Associations were found for both change of body weight and WC and incidence of T2DM in the crude and adjusted analyses. In the stratified study sample, those participants with a body mass index of <30 kg/m2 at baseline showed considerably lower HRs compared with obese women and men for both weight and WC. In the age-stratified analysis, we still found associations between change of weight and WC and incident T2DM with only marginal differences between the age groups.
Our study showed associations of change of weight and WC as markers of obesity with incidence of T2DM. Keeping a healthy and primarily stable weight should be the goal for preventing the development of T2DM.
doi:10.1097/MD.0000000000001394
PMCID: PMC4602920  PMID: 26313783
24.  Blood Pressure Control Has Improved in People with and without Type 2 Diabetes but Remains Suboptimal: A Longitudinal Study Based on the German DIAB-CORE Consortium 
PLoS ONE  2015;10(7):e0133493.
Background
Hypertension is a very common comorbidity and major risk factor for cardiovascular complications, especially in people with Type 2 Diabetes (T2D). Nevertheless, studies in the past have shown that blood pressure is often insufficiently controlled in medical practice. For the DIAB-CARE study, we used longitudinal data based on the German DIAB-CORE Consortium to assess whether health care regarding hypertension has improved during the last decade in our participants.
Methods
Data of the three regional population-based studies CARLA (baseline 2002-2006 and follow-up 2007-2010), KORA (baseline 1999-2001 and follow-up 2006-2008) and SHIP (baseline 1997-2001 and follow-up 2002-2006) were pooled. Stratified by T2D status we analysed changes in frequencies, degrees of awareness, treatment and control. Linear mixed models were conducted to assess the influence of sex, age, study, and T2D status on changes of systolic blood pressure between the baseline and follow-up examinations (mean observation time 5.7 years). We included 4,683 participants aged 45 to 74 years with complete data and accounted for 1,256 participants who were lost to follow-up by inverse probability weighting.
Results
Mean systolic blood pressure decreased in all groups from baseline to follow-up (e.g. – 8.5 mmHg in those with incident T2D). Pulse pressure (PP) was markedly higher in persons with T2D than in persons without T2D (64.14 mmHg in prevalent T2D compared to 52.87 mmHg in non-T2D at baseline) and did not change much between the two examinations. Awareness, treatment and control increased considerably in all subgroups however, the percentage of those with insufficiently controlled hypertension remained high (at about 50% of those with hypertension) especially in prevalent T2D. Particularly elderly people with T2D often had both, high blood pressure ≥140/90 mmHg and a PP of ≥60 mmHg. Blood pressure in men had improved more than in women at follow-up, however, men still had higher mean SBP than women at follow-up.
Conclusion
Blood pressure management has developed positively during past years in Germany. While hypertension prevalence, awareness and treatment were substantially higher in participants with T2D than in those without T2D at follow-up, hypertension control was achieved only in about half the number of people in each T2D group leaving much room for further improvement.
doi:10.1371/journal.pone.0133493
PMCID: PMC4519307  PMID: 26221962
25.  Methodology used in studies reporting chronic kidney disease prevalence: a systematic literature review 
Nephrology Dialysis Transplantation  2015;30(Suppl 4):iv6-iv16.
Background
Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced by study population characteristics and laboratory methods.
Methods
For this systematic review, two researchers independently searched PubMed, MEDLINE and EMBASE to identify all original research articles that were published between 1 January 2003 and 1 November 2014 reporting the prevalence of CKD in the European adult general population. Data on study methodology and reporting of CKD prevalence results were independently extracted by two researchers.
Results
We identified 82 eligible publications and included 48 publications of individual studies for the data extraction. There was considerable variation in population sample selection. The majority of studies did not report the sampling frame used, and the response ranged from 10 to 87%. With regard to the assessment of kidney function, 67% used a Jaffe assay, whereas 13% used the enzymatic assay for creatinine determination. Isotope dilution mass spectrometry calibration was used in 29%. The CKD-EPI (52%) and MDRD (75%) equations were most often used to estimate glomerular filtration rate (GFR). CKD was defined as estimated GFR (eGFR) <60 mL/min/1.73 m2 in 92% of studies. Urinary markers of CKD were assessed in 60% of the studies. CKD prevalence was reported by sex and age strata in 54 and 50% of the studies, respectively. In publications with a primary objective of reporting CKD prevalence, 39% reported a 95% confidence interval.
Conclusions
The findings from this systematic review showed considerable variation in methods for sampling the general population and assessment of kidney function across studies reporting CKD prevalence. These results are utilized to provide recommendations to help optimize both the design and the reporting of future CKD prevalence studies, which will enhance comparability of study results.
doi:10.1093/ndt/gfv131
PMCID: PMC4514069  PMID: 26209739
CKD; CKD-EPI equation; epidemiology; MDRD; systematic review

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