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Alvaro Alonso,
Bouwe P Krijthe,
Thor Aspelund,
Katherine A Stepas,
Michael J Pencina,
Carlee B Moser,
Moritz F Sinner,
Nona Sotoodehnia,
João D Fontes,
A Cecile J W Janssens, [......],
Daniel Levy,
John S Gottdiener,
Stefan Kääb, David Couper,
Tamara B Harris,
Elsayed Z Soliman,
Bruno H C Stricker,
Vilmundur Gudnason,
Susan R Heckbert,
Emelia J Benjamin
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ABSTRACT: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.
Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.
A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.
Journal of the American Heart Association. 01/2013; 2(2):e000102.
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Sarah M Hartz,
Susan E Short,
Nancy L Saccone,
Robert Culverhouse,
LiShiun Chen,
Tae-Hwi Schwantes-An,
Hilary Coon,
Younghun Han,
Sarah H Stephens,
Juzhong Sun, [......],
Andrew Heath,
Eric O Johnson,
Jaakko Kaprio,
Pamela Madden,
Nicholas G Martin,
Victoria L Stevens,
Jerry A Stitzel,
Robert B Weiss,
Peter Kraft,
Laura J Bierut
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ABSTRACT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Primary data.
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01).
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
Archives of general psychiatry 08/2012; 69(8):854-60. · 12.26 Impact Factor
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Jemma B Wilk,
Nick R G Shrine,
Laura R Loehr,
Jing Hua Zhao,
Ani Manichaikul,
Lorna M Lopez,
Albert Vernon Smith,
Susan R Heckbert,
Joanna Smolonska,
Wenbo Tang, [......],
Ruth J F Loos,
David P Strachan,
Stephanie J London,
H Marike Boezen,
Nicole Probst-Hensch,
Sina A Gharib,
Ian P Hall,
George T O'Connor,
Martin D Tobin,
Bruno H Stricker
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ABSTRACT: Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
American Journal of Respiratory and Critical Care Medicine 07/2012; 186(7):622-32. · 11.08 Impact Factor
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ABSTRACT: Objective To determine if antenatal treatment of maternal periodontitis affects early childhood neurodevelopment.Study Design We evaluated neurodevelopment of 331 24-month-old children born to women who participated in a randomized trial of antenatal (167) or postpartum (164) treatment of periodontitis. Children within groups defined by maternal treatment were designated as high risk for abnormal neurodevelopment (n = 96; birth at ≤346/7 weeks' gestation or small for gestational age following birth at term) or low risk (n = 235; appropriate birth weight and ≥37 weeks' gestation). We measured neurodevelopment using the Bayley Scale of Infant and Toddler Development III (BSID III) and neurological examination. Treatment effect was analyzed using a chi-square or Fisher exact test. Between-group mean scores were compared using Student t test.Results There were no differences in the incidence of neuromotor or sensory (visual or hearing) impairment or scores on the BSID III between groups. Low-risk children in the antenatal treatment group had higher language scores than those in the postpartum treatment group (92.9 versus 89.2; p = 0.05).Conclusion Antenatal treatment of maternal periodontitis does not appear to affect neurodevelopment at 24 months of age. The slight improvement in language development in low-risk children may be an artifact or not clinically relevant.
American Journal of Perinatology 07/2012; 29(10):815-22. · 1.32 Impact Factor
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ABSTRACT: Elevated plasma interleukin-18 (IL-18) has been linked to onset of diabetes mellitus (DM) and its complications. However, so far this association has been shown only in predominantly white populations. We examined IL-18 levels and their association with incident DM in a racially heterogeneous population.
In a nested case-cohort design representing a 9-year follow-up of 9,740 middle-aged, initially healthy, nondiabetic white and African American participants of the Atherosclerosis Risk in Communities Study, we selected and measured analytes on race-stratified (50% white, 50% African American) random samples of both cases of incident diabetes (n = 548) and eligible members of the full cohort (n = 536). RESULTS Baseline IL-18 levels were significantly higher in white participants compared with African American participants (P < 0.001). Although white participants in the fourth (versus first) quartile of IL-18 levels had a significant hazard ratio (HR) for developing DM (HR: 2.1, 95% CI: 1.3-3.4), after adjustment for age, sex, and study center, no difference was seen among African Americans (HR: 1.0, 95% CI: 0.6-1.7). Unlike those in African Americans, IL-18 levels in whites had a significant correlation with age (P < 0.01); anthropometric characteristics such as waist circumference (P < 0.001), height (P = 0.04), waist-to-hip ratio (P < 0.001), and BMI (P < 0.01); and total (P < 0.001) and high-molecular-weight (P < 0.001) adiponectin.
There are racial differences in levels of IL-18 and the association of IL-18 with risk factors and incident type 2 DM. In addition, there seems to be a complex interplay of inflammation and adiposity in the development of DM.
Diabetes care 05/2012; 35(7):1513-8. · 8.09 Impact Factor
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Alisa K Manning,
Marie-France Hivert,
Robert A Scott,
Jonna L Grimsby,
Nabila Bouatia-Naji,
Han Chen,
Denis Rybin,
Ching-Ti Liu,
Lawrence F Bielak,
Inga Prokopenko, [......],
Tatijana Zemunik,
Lina Zgaga,
Nicholas J Wareham,
Mark I McCarthy,
Ines Barroso,
Richard M Watanabe,
Jose C Florez,
Josée Dupuis,
James B Meigs,
Claudia Langenberg
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ABSTRACT: Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Nature Genetics 05/2012; 44(6):659-69. · 35.53 Impact Factor
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Artur Fedorowski,
Nora Franceschini,
Jennifer Brody,
Chunyu Liu,
Germaine C Verwoert,
Eric Boerwinkle, David Couper,
Kenneth M Rice,
Jerome I Rotter,
Francesco Mattace-Raso, [......],
Marketa Sjögren,
Bo Hedblad,
Martin G Larson,
Christopher Newton-Cheh,
Thomas J Wang,
Kathryn M Rose,
Bruce M Psaty,
Daniel Levy,
Jacqueline Witteman,
Olle Melander
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ABSTRACT: Aims Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. Methods and results A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85-0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75-0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87-0.98; P= 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02-1.24; P = 0.02, rs198358: 1.10, 1.01-1.20; P = 0.04, and rs5068: 1.22, 1.04-1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04). Conclusion The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.
European Heart Journal 04/2012; 33(18):2331-41. · 10.48 Impact Factor
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ABSTRACT: Prospective epidemiologic studies have characterized major risk factors for incident diabetes by a variety of diabetes case definitions. Whether different definitions alter the association of diabetes with risk factors is largely unknown. Using 1987-1998 data from the ongoing Atherosclerosis Risk in Communities (ARIC) Study, the authors assessed the relation of traditional risk factors with 3 different diabetes case definitions and 4 fasting glucose categories. They compared the study protocol case definition with 2 nested case definitions, self-reported diabetes and a multiple-evidence definition. Significant differences in risk factor associations by case definition and by screening cutpoints were observed. Specifically, the magnitude of the association between the risk factors (baseline metabolic syndrome, fasting glucose, blood pressure, body mass index, and serum insulin) and incident diabetes differed by case definition. Associations with these risk factors were weaker with a case definition based on self-report compared with other definitions. These results illustrate the potential limitations of case definitions that rely solely on self-report or those that incorporate measured glucose values to ascertain undiagnosed cases. Although the ability to identify risk factors of diabetes was consistent for the case definitions studied, tests of novel risk factors may result in different estimates of effect sizes depending on the definition used.
American journal of epidemiology 03/2012; 175(5):466-72. · 5.59 Impact Factor
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Adam S Butterworth,
Peter S Braund,
Martin Farrall,
Robert J Hardwick,
Danish Saleheen,
John F Peden,
Nicole Soranzo,
John C Chambers,
Suthesh Sivapalaratnam,
Marcus E Kleber, [......],
Anders Hamsten,
Alistair S Hall,
Jaspal S Kooner,
Simon G Thompson,
John R Thompson,
Panos Deloukas,
Willem H Ouwehand,
Hugh Watkins,
John Danesh,
Nilesh J Samani
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ABSTRACT: Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.
PLoS Genetics 09/2011; 7(9):e1002260. · 8.69 Impact Factor
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ABSTRACT: African Americans have the highest rate of mortality due to coronary heart disease (CHD). Although multiple loci have been identified influencing CHD risk in European-Americans using a genome-wide association (GWAS) approach, no GWAS of incident CHD has been reported for African Americans. We performed a GWAS for incident CHD events collected during 19 years of follow-up in 2,905 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. We identified a genome-wide significant SNP (rs1859023, MAF = 31%) located at 7q21 near the PFTK1 gene (HR = 0.57, 95% CI 0.46 to 0.69, p = 1.86×10(-08)), which replicated in an independent sample of over 8,000 African American women from the Women's Health Initiative (WHI) (HR = 0.81, 95% CI 0.70 to 0.93, p = 0.005). PFTK1 encodes a serine/threonine-protein kinase, PFTAIRE-1, that acts as a cyclin-dependent kinase regulating cell cycle progression and cell proliferation. This is the first finding of incident CHD locus identified by GWAS in African Americans.
PLoS Genetics 08/2011; 7(8):e1002199. · 8.69 Impact Factor
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Stefan Walter,
Gil Atzmon,
Ellen W Demerath,
Melissa E Garcia,
Robert C Kaplan,
Meena Kumari,
Kathryn L Lunetta,
Yuri Milaneschi,
Toshiko Tanaka,
Gregory J Tranah, [......],
Sebastian E Baumeister,
David A Bennett,
Luigi Ferrucci,
Vilmundur Gudnason,
Mika Kivimaki,
Yongmei Liu,
Joanne M Murabito,
Anne B Newman,
Henning Tiemeier,
Nora Franceschini
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ABSTRACT: Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.
Neurobiology of aging 07/2011; 32(11):2109.e15-28. · 5.94 Impact Factor
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Alexander P Reiner,
Guillaume Lettre,
Michael A Nalls,
Santhi K Ganesh,
Rasika Mathias,
Melissa A Austin,
Eric Dean,
Sampath Arepalli,
Angela Britton,
Zhao Chen, [......],
Lisa R Yanek,
Lingyao Yang,
Elad Ziv,
Alan B Zonderman,
Aaron R Folsom,
Michele K Evans,
Yongmei Liu,
Diane M Becker,
Beverly M Snively,
James G Wilson
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ABSTRACT: Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10(-8)). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.
PLoS Genetics 06/2011; 7(6):e1002108. · 8.69 Impact Factor
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Marilyn C Cornelis,
Keri L Monda,
Kai Yu,
Nina Paynter,
Elizabeth M Azzato,
Siiri N Bennett,
Sonja I Berndt,
Eric Boerwinkle,
Stephen Chanock,
Nilanjan Chatterjee, [......],
Eric B Rimm,
Lynda M Rose,
Nathaniel Rothman,
Debra Silverman,
Rachael Stolzenberg-Solomon,
Amy Subar,
Meredith Yeager,
Daniel I Chasman,
Rob M van Dam,
Neil E Caporaso
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ABSTRACT: We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4 × 10(-19)), near AHR, and 15q24 (P = 5.2 × 10(-14)), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2.
PLoS Genetics 04/2011; 7(4):e1002033. · 8.69 Impact Factor
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Cathy E Elks,
John R B Perry,
Patrick Sulem,
Daniel I Chasman,
Nora Franceschini,
Chunyan He,
Kathryn L Lunetta,
Jenny A Visser,
Enda M Byrne,
Diana L Cousminer, [......],
Paul M Ridker,
Tim D Spector,
Elizabeth A Streeten,
Kari Stefansson,
Unnur Thorsteinsdottir,
André G Uitterlinden,
Elisabeth Widen,
Joanne M Murabito,
Ken K Ong,
Anna Murray
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ABSTRACT: To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
Nature Genetics 12/2010; 42(12):1077-85. · 35.53 Impact Factor
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ABSTRACT: Orthostatic hypotension is associated with cardiovascular disease and mortality, but little is known of its association with incident chronic kidney disease. We evaluated this association in the Atherosclerosis Risk in Communities study. Orthostatic hypotension was defined as a decrease in systolic blood pressure ≥ 20 mm Hg or a decrease in diastolic blood pressure ≥ 10 mm Hg within 2 minutes of standing. Incident chronic kidney disease was defined using an estimated glomerular filtration rate < 60 mL/min/1.73 m², or a coded hospitalization (discharge) or death for chronic kidney disease through 2005, after exclusion of chronic kidney disease at baseline. The associations between orthostatic hypotension and chronic kidney disease were modeled using Cox proportional hazard while adjusting for confounders including resting blood pressure and medications. Among 12 593 participants, 1326 developed chronic kidney disease (6.3 cases per 1000 person-years; median follow-up of 16 years), with higher rates in blacks than whites. An increased risk of chronic kidney disease was observed among persons with orthostatic hypotension compared with those without it (blacks hazard ratio 2.0, 95% CI, 1.5 to 2.8; whites hazard ratio 1.2, 95% CI, 1.0 to 1.6; P for race interaction = 0.02). An alternative chronic kidney disease classification, based on an increase in serum creatinine at the 3- or 9-year follow-up visits, showed significant associations with orthostatic hypotension in both whites and blacks. These findings suggest that orthostatic hypotension increases the risk of chronic kidney disease in middle-aged persons, but race effects vary by choice of chronic kidney disease definition.
Hypertension 11/2010; 56(6):1054-9. · 6.21 Impact Factor
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ABSTRACT: Adiponectin, synthesized by adipocytes, has been shown to be a predictor of type 2 diabetes. Adiponectin circulates in plasma as three oligomeric isoforms. High-molecular-weight (HMW) adiponectin is thought to be the most biologically active form of adiponectin in terms of glucose homeostasis.
Our objective was to investigate whether HMW adiponectin is more strongly associated with incident diabetes than is total adiponectin.
A nested case-cohort study was conducted in a population-based cohort of 9740 middle-aged, initially healthy, white and African-American participants of the Atherosclerosis Risk in Communities (ARIC) study followed for up to 9 yr. Plasma total and HMW adiponectin were measured by ELISA in 550 incident diabetes cases and 540 noncases.
Overall hazard ratios (95% confidence intervals) for developing diabetes for those in the fourth (vs. the first) quartile of total adiponectin, HMW adiponectin, and the ratio of HMW to total were 0.40 (0.25-0.64), 0.38 (0.23-0.63), and 0.65 (0.42-0.99), respectively, after adjustment for age, sex, ethnicity, study center, parental history of diabetes, hypertension, body mass index, and waist-to-hip ratio and 0.52 (0.32-0.85), 0.51 (0.31-0.86), and 0.77 (0.50-1.20), respectively, after additional adjustment for inflammation score (a score composed of six inflammation markers) and fasting insulin. When further adjusting for baseline fasting glucose, the graded associations were attenuated substantially and lost their gradation.
In this community-based sample of U.S. adults, higher total and HMW adiponectin concentrations were similarly associated with a lower incidence of diabetes over 9 yr of follow-up.
The Journal of clinical endocrinology and metabolism 11/2010; 95(11):5097-104. · 6.50 Impact Factor
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ABSTRACT: Although genome-wide association studies (GWAS) have been performed in longitudinal studies, most used only a single trait measure. GWAS of fasting glucose have generally included only normoglycemic individuals. We examined the impact of both repeated measures and sample selection on GWAS in Atherosclerosis Risk In Communities (ARIC), a study which obtained four longitudinal measures of fasting glucose and included both individuals with and without prevalent diabetes. The sample included Caucasians and the Affymetrix 6.0 chip was used for genotyping. Sample sizes for GWAS analyses ranged from 8,372 (first study visit) to 5,782 (average fasting glucose). Candidate SNP analyses with SNPs identified through fasting glucose or diabetes GWAS were conducted in 9,133 individuals, including 761 with prevalent diabetes. For a constant sample size, smaller P-values were obtained for the average measure of fasting glucose compared to values at any single visit, and two additional significant GWAS signals were detected. For four candidate SNPs (rs780094, rs10830963, rs7903146, and rs4607517), the strength of association between genotype and glucose was significantly (P-interaction<0.05) different in those with and without prevalent diabetes, and for all five fasting glucose candidate SNPs (rs780094, rs10830963, rs560887, rs4607517, and rs13266634) the association with measured fasting glucose was more significant in the smaller sample without prevalent diabetes than in the larger combined sample of those with and without diabetes. This analysis demonstrates the potential utility of averaging trait values in GWAS studies and explores the advantage of using only individuals without prevalent diabetes in GWAS of fasting glucose.
Genetic Epidemiology 11/2010; 34(7):665-73. · 3.44 Impact Factor
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Mark Eijgelsheim,
Christopher Newton-Cheh,
Nona Sotoodehnia,
Paul I W de Bakker,
Martina Müller,
Alanna C Morrison,
Albert V Smith,
Aaron Isaacs,
Serena Sanna,
Marcus Dörr, [......],
Peter P Pramstaller,
Cornelia M van Duijn,
Edward G Lakatta,
Stephan B Felix,
Vilmundur Gudnason,
Arne Pfeufer,
Susan R Heckbert,
Bruno H Ch Stricker,
Eric Boerwinkle,
Christopher J O'Donnell
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ABSTRACT: Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
Human Molecular Genetics 10/2010; 19(19):3885-94. · 7.64 Impact Factor
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ABSTRACT: Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT), a measure of subclinical atherosclerosis. It is unclear if this association is causal. Using the principle of Mendelian randomization, we sought to explore the causal association between circulating glucose and IMT by examining the association of a genetic risk score with IMT.
The sample was drawn from the Atherosclerosis Risk in Communities (ARIC) study and included 7,260 nondiabetic Caucasian individuals with IMT measurements and relevant genotyping. Components of the fasting glucose genetic risk score (FGGRS) were selected from a fasting glucose genome-wide association study in ARIC. The score was created by combining five single nucleotide polymorphisms (SNPs) (rs780094 [GCKR], rs560887 [G6PC2], rs4607517 [GCK], rs13266634 [SLC30A8], and rs10830963 [MTNR1B]) and weighting each SNP by its strength of association with fasting glucose. IMT was measured through bilateral carotid ultrasound. Mean IMT was regressed on the FGGRS and on the component SNPs, individually.
The FGGRS was significantly associated (P = 0.009) with mean IMT. The difference in IMT predicted by a 1 SD increment in the FGGRS (0.0048 mm) was not clinically relevant but was larger than would have been predicted based on observed associations between the FFGRS, fasting glucose, and IMT. Additional adjustment for baseline measured glucose in regression models attenuated the association by about one third.
The significant association of the FGGRS with IMT suggests a possible causal association of elevated fasting glucose with atherosclerosis, although it may be that these loci influence IMT through nonglucose pathways.
Diabetes 10/2010; 60(1):331-5. · 8.29 Impact Factor
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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
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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
