-
[show abstract]
[hide abstract]
ABSTRACT: Reliable quantification of the burden of stroke in low- and middle-income (LMI) countries is difficult as population-based surveillance reports are scarce and may vary considerably in methodology. We aimed to evaluate all available primary stroke surveillance studies by applying components of a benchmark protocol (WHO STEPwise approach to stroke surveillance) and quantify the reported burden of stroke in LMI settings.
Electronic databases Medline, Embase, Scopus, and Web of Knowledge were searched for population-based surveillance studies. Studies conducted in the LMI countries that reported on incident stroke were included. Data were extracted from each study using a prestructured format. Information on epidemiologic measures including crude and age-adjusted incidence rates, person-years, admission rates, case fatality rates, death certification, autopsy rates, measures of disability, and other study-specific information, in line with WHO STEPS stroke protocol, were recorded. Age-adjusted incidence rate data of stroke were combined using random-effects meta-analyses.
We identified 7 studies that reported on burden of stroke in 9 LMI countries, including aggregate information from 1,711,372 participants collected over 5,240,923 person-years. The age-adjusted incidence rates across the LMI countries varied widely, with the burden of total first-ever strokes ranging from 41 to 909 events per 100,000 person-years.
Systematic evaluation of all available primary surveillance studies, particularly in the context of WHO STEPS guidelines, indicates inadequate adherence to standardized surveillance methodology in LMI countries. Incorporation of standardized approaches is essential to enhance generalizability and estimate stroke burden accurately in these resource-poor settings.
Neurology 02/2013; 80(7):677-84. · 8.31 Impact Factor
-
David R Crosslin,
Andrew McDavid,
Noah Weston,
Xiuwen Zheng,
Eugene Hart,
Mariza de Andrade,
Iftikhar J Kullo,
Catherine A McCarty,
Kimberly F Doheny,
Elizabeth Pugh, [......],
Dan L Longo,
Jacqueline C M Witteman,
Bruce M Psaty,
Luigi Ferrucci,
Tamara B Harris,
Christopher J O'Donnell,
Santhi K Ganesh,
Eric B Larson,
Chris S Carlson,
Gail P Jarvik
[show abstract]
[hide abstract]
ABSTRACT: With white blood cell count (WBC) emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases, such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11,014 subjects in the electronic Medical Records and Genomics (eMERGE) Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (p-value=2.78e-16, β=-0.22). Other monocyte associations include novel missense variants in the chemokine binding protein 2 (CCBP2) gene (p-value=1.88e-7, β=0.30) and a region of replication found in ribophorin I (RPN1) (p-value=2.63e-16, β=-0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA2 gene, which has been previously shown to be associated with coronary heart disease. On chromosome 9 we found a novel association in the prostaglandin reductase 1 (PTGR1) gene (p-value=2.29e-7, β=0.16), which is downstream from lysophosphatidic acid receptor 1 (LPAR1). This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (p-value=5.68e-17, β=-0.23) at the ITGA4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
Human Molecular Genetics 01/2013; · 7.64 Impact Factor
-
Nora Franceschini,
Frank J A van Rooij,
Bram P Prins,
Mary F Feitosa,
Mahir Karakas,
John H Eckfeldt,
Aaron R Folsom,
Jeffrey Kopp,
Ahmad Vaez,
Jeanette S Andrews, [......],
Alan F Wright,
Qingyu Wu,
Yongmei Liu,
Nancy S Jenny,
Kari E North, Janine F Felix,
Behrooz Z Alizadeh,
L Adrienne Cupples,
John R B Perry,
Andrew P Morris
[show abstract]
[hide abstract]
ABSTRACT: Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.
The American Journal of Human Genetics 09/2012; 91(4):744-753. · 10.60 Impact Factor
-
Maarten J G Leening,
Suzette E Elias-Smale,
Maryam Kavousi, Janine F Felix,
Jaap W Deckers,
Rozemarijn Vliegenthart,
Matthijs Oudkerk,
Albert Hofman,
Ewout W Steyerberg,
Bruno H Ch Stricker,
Jacqueline C M Witteman
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to determine the association of coronary artery calcification (CAC) with incident heart failure in the elderly and examine its independence of overt coronary heart disease (CHD).
Heart failure is often observed as a first manifestation of coronary atherosclerosis rather than a sequela of overt CHD. Although numerous studies have shown that CAC, an established measure of coronary atherosclerosis, is a strong predictor of CHD, the association between CAC and future heart failure has not been studied prospectively.
In the Rotterdam Study, a population-based cohort, 1,897 asymptomatic participants (mean age, 69.9 years; 58% women) underwent CAC scoring and were followed for the occurrence of heart failure and CHD.
During a median follow-up of 6.8 years, there were 78 cases of heart failure and 76 cases of nonfatal CHD. After adjustment for cardiovascular risk factors, increasing CAC scores were associated with heart failure (p for trend = 0.001), with a hazard ratio of 4.1 (95% confidence interval [CI]: 1.7 to 10.1) for CAC scores >400 compared with CAC scores of 0 to 10. After censoring participants for incident nonfatal CHD, increasing extent of CAC remained associated with heart failure (p for trend = 0.046), with a hazard ratio of 2.9 (95% CI: 1.1 to 7.4) for CAC scores >400. Moreover, adding CAC to cardiovascular risk factors resulted in an optimism-corrected increase in the c-statistic by 0.030 (95% CI: 0.001 to 0.050) to 0.734 (95% CI: 0.698 to 0.770) and substantially improved the risk classification of subjects (continuous net reclassification index = 34.0%).
CAC has a clear association with the risk of heart failure, independent of overt CHD. Because heart failure is highly prevalent in the elderly, it might be worthwhile to include heart failure as an outcome in future risk assessment programs incorporating CAC.
JACC. Cardiovascular imaging 09/2012; 5(9):874-80. · 14.29 Impact Factor
-
Gary F Mitchell,
Germaine C Verwoert,
Kirill V Tarasov,
Aaron Isaacs,
Albert V Smith,
Yasmin,
Ernst R Rietzschel,
Toshiko Tanaka,
Yongmei Liu,
Afshin Parsa, [......],
John R Cockcroft,
Vilmundur Gudnason,
Guy G De Backer,
Luigi Ferrucci,
Tamara B Harris,
Alan R Shuldiner,
Cornelia M van Duijn,
Daniel Levy,
Edward G Lakatta,
Jacqueline C M Witteman
[show abstract]
[hide abstract]
ABSTRACT: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.
We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004).
Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
Circulation Cardiovascular Genetics 11/2011; 5(1):81-90. · 6.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To clarify the association between cholesterol and noncardiovascular mortality and to evaluate how this association varies across age groups.
Prospective population-based cohort study.
Rotterdam, the Netherlands.
Adults aged 55 to 99 (N = 5,750).
Participants were evaluated for total cholesterol and subfractions and followed for mortality for a median of 13.9 years. Total cholesterol and its subfractions were evaluated in relation to noncardiovascular mortality. Cox regression analyses were conducted in the total sample and within age-groups (55-64, 65-74, 75-84, ≥85).
Age- and sex-adjusted analyses showed that each 1-mmol/L increase in total cholesterol was associated with an approximately 12% lower risk of noncardiovascular mortality (hazard ratio (HR) = 0.88, 95% confidence interval (CI) = 0.84-0.92, P < .001). Age group-specific analyses demonstrated that this association reached significance after the age of 65 and increased in magnitude across each subsequent decade. This was driven largely by non-high-density lipoprotein cholesterol (non-HDL-C) (HR = 0.89, 95% CI 0.85-0.93, P < .001) and was partly attributable to cancer mortality. Conversely, HDL-C was not significantly associated with noncardiovascular mortality (HR = 0.92, 95% CI 0.79-1.07, P = .26).
Higher total cholesterol was associated with a lower risk of noncardiovascular mortality in older adults. This association varied across the late-life span and was stronger in older age groups. Further research is required to examine the mechanisms underlying this association.
Journal of the American Geriatrics Society 10/2011; 59(10):1779-85. · 3.74 Impact Factor
-
Sonia Shah,
Christopher P Nelson,
Tom R Gaunt,
Pim van der Harst,
Timothy Barnes,
Peter S Braund,
Debbie A Lawlor,
Juan-Pablo Casas,
Sandosh Padmanabhan,
Fotios Drenos, [......],
Rudolf A de Boer,
Gerjan Navis,
Wiek H van Gilst,
Bongani M Mayosi,
John R Thompson,
Meena Kumari,
Peter W MacFarlane,
Ian N M Day,
Aroon D Hingorani,
Nilesh J Samani
[show abstract]
[hide abstract]
ABSTRACT: Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH.
We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in ≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22 × 10(-7)) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74 × 10(-8)), 15q25.2 (NMB, rs2292462, P=3.23 × 10(-9)), and 15q26.3 (IGF1R, rs4966014, P=1.26 × 10(-7)) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes.
These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.
Circulation Cardiovascular Genetics 09/2011; 4(6):626-35. · 6.11 Impact Factor
-
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
[show abstract]
[hide abstract]
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
-
Michael A Nalls,
David J Couper,
Toshiko Tanaka,
Frank J A van Rooij,
Ming-Huei Chen,
Albert V Smith,
Daniela Toniolo,
Neil A Zakai,
Qiong Yang,
Andreas Greinacher, [......],
Andrew B Singleton,
Dena G Hernandez,
Dan L Longo,
Nicole Soranzo,
Jacqueline C M Witteman,
Bruce M Psaty,
Luigi Ferrucci,
Tamara B Harris,
Christopher J O'Donnell,
Santhi K Ganesh
[show abstract]
[hide abstract]
ABSTRACT: White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
PLoS Genetics 06/2011; 7(6):e1002113. · 8.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tracheal agenesis (TA) is a rare congenital anomaly of the respiratory tract. Many patients have associated anomalies, suggesting a syndromal phenotype. In a cohort of 12 patients, we aimed to detect copy number variations. In addition to routine cytogenetic analysis, we applied oligonucleotide array comparative genomic hybridization. Our patient cohort showed various copy number variations, of which many were parentally inherited variants. One patient had, in addition to an inherited 16p12.1 deletion, a 3.6 Mb deletion on chromosomal locus 5q11.2. This patient had a syndromic phenotype, including vertebral, anal, cardiovascular and tracheo-oesophageal associated anomalies, and other foregut-related anomalies, such as cartilage rings in the oesophagus and an aberrant right bronchus. No common deletions or duplications are found in our cohort, suggesting that TA is a genetically heterogeneous disorder.
European journal of human genetics: EJHG 11/2010; 18(11):1265-8. · 3.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To examine the association between unrecognised myocardial infarction (MI) as detected by electrocardiography and the long-term risk of heart failure.
The Rotterdam Study is a prospective population-based cohort study of the general population of a suburb of the city of Rotterdam, The Netherlands.
At baseline 2581 men and 3724 women aged > or =55 years were classified on the basis of electrocardiography, interview and clinical data into those with recognised MI, those with ECG-based unrecognised MI and those without MI. The participants were followed-up for incident heart failure, death or end of the study period on 12 October 2006.
During a median follow-up time of 13.2 years, 823 cases of heart failure occurred, of which 403 in men. Independently of cardiovascular risk factors, recognised and unrecognised MIs yielded HRs of developing heart failure in men of 2.6 (95% CI 2.0 to 3.3) and 2.1 (95% CI 1.5 to 2.9), respectively. In women, recognised MI was associated with heart failure (HR=2.8; 95% CI 1.9 to 4.1), whereas unrecognised MI was not significantly related to the risk of heart failure (HR=1.1; 95% CI 0.7 to 1.7).
Unrecognised MI detected by electrocardiography yields a long-term risk of heart failure equivalent to recognised MI in men, but is not significantly related to heart failure in women. In the light of the high incidence of both unrecognised MI and heart failure in the elderly, it may be worthwhile for both doctors and patients to improve responsiveness to typical and atypical symptoms of MI.
Heart (British Cardiac Society) 09/2010; 96(18):1458-62. · 4.22 Impact Factor
-
Tamra E Meyer,
Germaine C Verwoert,
Shih-Jen Hwang,
Nicole L Glazer,
Albert V Smith,
Frank J A van Rooij,
Georg B Ehret,
Eric Boerwinkle, Janine F Felix,
Tennille S Leak, [......],
André G Uitterlinden,
Aravinda Chakravarti,
Bruce M Psaty,
Cornelia M van Duijn,
W H Linda Kao,
Jacqueline C M Witteman,
Vilmundur Gudnason,
David S Siscovick,
Caroline S Fox,
Anna Köttgen
[show abstract]
[hide abstract]
ABSTRACT: Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.
PLoS Genetics 08/2010; 6(8). · 8.69 Impact Factor
-
Bryan Kestenbaum,
Nicole L Glazer,
Anna Köttgen, Janine F Felix,
Shih-Jen Hwang,
Yongmei Liu,
Kurt Lohman,
Stephen B Kritchevsky,
Dorothy B Hausman,
Ann-Kristin Petersen, [......],
Abbas Dehghan,
Fernando Rivadeneira,
André G Uitterlinden,
Albert Hofman,
Cornelia M van Duijn,
Michael G Shlipak,
W H Linda Kao,
Jacqueline C M Witteman,
David S Siscovick,
Caroline S Fox
[show abstract]
[hide abstract]
ABSTRACT: Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
Journal of the American Society of Nephrology 07/2010; 21(7):1223-32. · 9.66 Impact Factor
-
Nicholas L Smith, Janine F Felix,
Alanna C Morrison,
Serkalem Demissie,
Nicole L Glazer,
Laura R Loehr,
L Adrienne Cupples,
Abbas Dehghan,
Thomas Lumley,
Wayne D Rosamond, [......],
Christopher J O'Donnell,
Andre G Uitterlinden,
Jerome I Rotter,
James T Willerson,
Daniel Levy,
Cornelia M van Duijn,
Bruce M Psaty,
Jacqueline C M Witteman,
Eric Boerwinkle,
Ramachandran S Vasan
[show abstract]
[hide abstract]
ABSTRACT: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.
We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
Circulation Cardiovascular Genetics 06/2010; 3(3):256-66. · 6.11 Impact Factor
-
Alanna C Morrison, Janine F Felix,
L Adrienne Cupples,
Nicole L Glazer,
Laura R Loehr,
Abbas Dehghan,
Serkalem Demissie,
Joshua C Bis,
Wayne D Rosamond,
Yurii S Aulchenko, [......],
Ervin R Fox,
Andre G Uitterlinden,
Thomas J Wang,
Bruce M Psaty,
James T Willerson,
Cornelia M van Duijn,
Eric Boerwinkle,
Jacqueline C M Witteman,
Ramachandran S Vasan,
Nicholas L Smith
[show abstract]
[hide abstract]
ABSTRACT: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.
This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.
Circulation Cardiovascular Genetics 06/2010; 3(3):248-55. · 6.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Esophageal atresia and tracheoesophageal fistula (EA/TEF) are major congenital malformations affecting 1:3500 live births. Current research efforts are focused on understanding the etiology of these defects. We describe well-known animal models, human syndromes, and associations involving EA/TEF, indicating its etiologically heterogeneous nature. Recent advances in genotyping technology and in knowledge of human genetic variation will improve clinical counseling on etiologic factors. This review provides a clinical summary of environmental and genetic factors involved in EA/TEF.
Current Gastroenterology Reports 06/2010; 12(3):215-22.
-
Anna,
Cristian Pattaro,
Carsten A,
Christian Fuchsberger,
Matthias Olden,
Nicole L Glazer,
Afshin Parsa,
Xiaoyi Gao,
Qiong Yang,
Albert V Smith, [......],
Ulf Gyllensten,
James F Wilson,
Jacqueline C Witteman,
Peter P Pramstaller,
Rainer Rettig,
Nick Hastie,
Daniel I Chasman,
W H Kao,
Iris M Heid,
Caroline S Fox
Nature Genetics 04/2010; 42(5):376-384. · 35.53 Impact Factor
-
Anna Köttgen,
Cristian Pattaro,
Carsten A Böger,
Christian Fuchsberger,
Matthias Olden,
Nicole L Glazer,
Afshin Parsa,
Xiaoyi Gao,
Qiong Yang,
Albert V Smith, [......],
Ulf Gyllensten,
James F Wilson,
Jacqueline C Witteman,
Peter P Pramstaller,
Rainer Rettig,
Nick Hastie,
Daniel I Chasman,
W H Kao,
Iris M Heid,
Caroline S Fox
[show abstract]
[hide abstract]
ABSTRACT: Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
Nature Genetics 04/2010; 42(5):376-84. · 35.53 Impact Factor
-
Santhi K Ganesh,
Neil A Zakai,
Frank J A van Rooij,
Nicole Soranzo,
Albert V Smith,
Michael A Nalls,
Ming-Huei Chen,
Anna Kottgen,
Nicole L Glazer,
Abbas Dehghan, [......],
Bruce M Psaty,
Luigi Ferrucci,
Aravinda Chakravarti,
Andreas Greinacher,
Christopher J O'Donnell,
Jacqueline C M Witteman,
Susan Furth,
Mary Cushman,
Tamara B Harris,
Jing-Ping Lin
[show abstract]
[hide abstract]
ABSTRACT: Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
Nature Genetics 11/2009; 41(11):1191-8. · 35.53 Impact Factor
-
Ramachandran S Vasan,
Nicole L Glazer, Janine F Felix,
Wolfgang Lieb,
Philipp S Wild,
Stephan B Felix,
Norbert Watzinger,
Martin G Larson,
Nicholas L Smith,
Abbas Dehghan, [......],
H-Erich Wichmann,
Thomas F Munzel,
Heyo K Kroemer,
Emelia J Benjamin,
Jerome I Rotter,
Jacqueline C Witteman,
Heribert Schunkert,
Helena Schmidt,
Henry Völzke,
Stefan Blankenberg
[show abstract]
[hide abstract]
ABSTRACT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
JAMA The Journal of the American Medical Association 08/2009; 302(2):168-78. · 30.03 Impact Factor
