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Original Contribution |

Genetic Variants Associated With Cardiac Structure and Function:  A Meta-analysis and Replication of Genome-wide Association Data FREE

Ramachandran S. Vasan, MD; Nicole L. Glazer, PhD; Janine F. Felix, MD, PhD; Wolfgang Lieb, MD; Philipp S. Wild, MD; Stephan B Felix, MD; Norbert Watzinger, MD; Martin G. Larson, ScD; Nicholas L. Smith, PhD; Abbas Dehghan, MD, DSc; Anika Großhennig, PhD; Arne Schillert, PhD; Alexander Teumer, Dipl-Math; Reinhold Schmidt, MD; Sekar Kathiresan, MD; Thomas Lumley, PhD; Yurii S. Aulchenko, PhD; Inke R. König, PhD; Tanja Zeller, PhD; Georg Homuth, PhD; Maksim Struchalin; Jayashri Aragam, MD; Joshua C. Bis, PhD; Fernando Rivadeneira, MD, PhD; Jeanette Erdmann, PhD; Renate B. Schnabel, MD; Marcus Dörr, MD; Robert Zweiker, MD; Lars Lind, MD, PhD; Richard J. Rodeheffer, MD; Karin Halina Greiser, MD; Daniel Levy, MD; Talin Haritunians, PhD; Jaap W. Deckers, MD, PhD; Jan Stritzke, MD; Karl J. Lackner, PhD; Uwe Völker, PhD; Erik Ingelsson, MD, PhD; Iftikhar Kullo, MD; Johannes Haerting, PhD; Christopher J. O’Donnell, MD; Susan R. Heckbert, MD, PhD; Bruno H. Stricker, MB, PhD; Andreas Ziegler, PhD; Thorsten Reffelmann, MD; Margaret M. Redfield, MD; Karl Werdan, MD; Gary F. Mitchell, MD; Kenneth Rice, PhD; Donna K. Arnett, PhD; Albert Hofman, MD, PhD; John S. Gottdiener, MD; Andre G. Uitterlinden, PhD; Thomas Meitinger, MD; Maria Blettner, PhD; Nele Friedrich, PhD; Thomas J. Wang, MD; Bruce M. Psaty, MD; Cornelia M. van Duijn, PhD; H.-Erich Wichmann, MD, PhD; Thomas F. Munzel, MD; Heyo K. Kroemer, PhD; Emelia J. Benjamin, MD, ScM; Jerome I. Rotter, MD; Jacqueline C. Witteman, PhD; Heribert Schunkert, MD; Helena Schmidt, MD, PhD; Henry Völzke, MD; Stefan Blankenberg, MD
[+] Author Affiliations

Author Affiliations:Framingham Heart Study: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham (Drs Vasan, Larson, Kathiresan, Aragam, Levy, O’Donnell, Mitchell, Wang, and Benjamin); Departments of Medicine, Preventive Medicine and Cardiology Sections, Boston University School of Medicine (Drs Vasan and Benjamin) and Department of Mathematics and Statistics, Boston University (Dr Larson), Boston, Massachusetts; and National Heart, Lung, and Blood Institute (Drs O’Donnell and Levy), Bethesda, Maryland. The Cardiovascular Health Study: Cardiovascular Health Research Unit and Department of Medicine (Drs Glazer, Bis, and Psaty), Departments of Biostatistics (Drs Lumley and Rice), Epidemiology (Drs Heckbert, Smith, and Psaty), and Health Services (Dr Psaty), University of Washington, Seattle; Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development (Dr Smith) and Center for Health Studies, Group Health (Dr Psaty), Seattle; Department of Epidemiology, University of Alabama at Birmingham (Dr Arnett); Division of Cardiology, University of Maryland Hospital, Baltimore (Dr Gottdiener); and Medical Genetics Institute, Cedars-Sinai Medical Center, West Los Angeles, California (Drs Haritunians and Rotter). Rotterdam Study: Departments of Epidemiology (Drs J. Felix, Dehghan, Aulchenko, Struchalin, Stricker, Hofman, van Duijn, and Witteman), Internal Medicine (Drs Rivadeneira and Uitterlinden), Cardiology (Dr Deckers), Erasmus MC Rotterdam, the Netherlands; Member of the Netherlands Consortium on Healthy Aging (Drs J. Felix and Witteman). MONICA/KORA: Medical Clinic 2 (Drs Lieb, Großhennig, Erdmann, Stritzke, and Schunkert) and Institute of Medical Biometry and Statistics (Drs Großhennig, König), University of Lübeck, Lübeck; Institutes of Epidemiology (Dr Wichmann) and Human Genetics (Dr Meitinger), Helmholtz Zentrum München, München; German Research Center for Environmental Health, Neuherberg and Ludwig Maximilians University (Dr Wichmann) and German Research Center for Environmental Health, Neuherberg, Technische Universität München (Dr Meitinger), Munich, Germany. Gutenberg Heart Study: Departments of Medicine II (Drs Wild, Zeller, Schnabel, Münzel, and Blankenberg), Clinical Chemistry and Laboratory Medicine (Dr Lackner), Institute of Medical Biometry, Epidemiology, and Informatics (Dr Blettner), Johannes Gutenberg-University, Mainz, and Institute for Medical Biometry and Statistics (Drs Schillert and Ziegler), University Lübeck, Germany. Study of Health in Pomerania: Department of Internal Medicine B (Drs S. Felix, Dörr, and Reffelmann), Interfaculty Institute for Genetics and Functional Genomics (Drs Teumer, Homuth, and Völker), Institute of Pharmacology (Dr Kroemer), and Institute for Community Medicine (Drs Friedrich and Völzke), Ernst-Moritz-Arndt-Universität, Greifswald, Germany (Drs S. Felix, Homuth, Dörr, Völker, Reffelmann, Friedrich, Kroemer, and Völzke and Mr Teumer). Austrian Stroke Prevention Study: Department of Internal Medicine, Division of Cardiology (Drs Watzinger and Zweiker), Department of Neurology (Dr R. Schmidt), and Institute for Molecular Biology and Biochemistry (Dr H. Schmidt), Medical University Graz, Graz, Austria. PIVUS Study: Department of Medical Sciences, Uppsala University, Uppsala (Dr Lind) and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm (Dr Ingelsson). Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota (Drs Rodeheffer, Kullo, and Redfield). CARLA Study: Institute of Medical Epidemiology, Biostatistics and Informatics (Drs Greiser and Haerting) and Martin-Luther-University, Halle-Wittenberg, Halle (Saale), Germany; and Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland (Dr Levy).


JAMA. 2009;302(2):168-178. doi:10.1001/jama.2009.978-a.
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Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

Objective 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.

Design, Setting, and Participants 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 × 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.

Main Outcome Measures Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

Results 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).

Conclusions 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.

Figures in this Article

Alterations in cardiac structure and function adversely affect the prognosis of individuals in the general population. In community-based cohorts, the presence of left ventricular (LV) hypertrophy and increased LV mass predict the development of coronary heart disease,1,2 congestive heart failure (CHF),2 stroke,2,3 cardiovascular disease (CVD), and all-cause mortality.2,4 Likewise, increased LV wall thickness predicts CVD events,5 LV dilation predicts CHF,6 and asymptomatic LV systolic dysfunction predicts CHF and death.7 Left atrial size is related to incidence of atrial fibrillation,5 stroke, and death.8 Aortic root size is associated with risk of CHF, stroke, and mortality.8,9 Thus, traits obtained from echocardiography serve not only as measures of cardiac structure and function but also as intermediate phenotypes for clinical CVD outcomes.

These echocardiographic phenotypes are heritable1018 and have been linked to genetic loci.1921 Candidate gene studies have identified several single-nucleotide polymorphisms (SNPs) in genes such as ACE (GenBank J04144),2224PPARA (GenBank L02932),25GNB3 (RefSeq NM_002075),26 and CYP11B2 (GenBank X54741)27 that may contribute to variability in LV mass. However, many of the studies suggesting specific genetic associations were small, based on selected samples, failed to adjust for key confounders and were not replicated.2832

Genome-wide association analyses have led to the discovery of previously unsuspected common variants underlying risk for complex diseases unconstrained by prior knowledge.33 The present investigation uses a 2-stage approach and leverages the availability of whole genome scans in 5 community-based samples to perform a prospective combined meta-analysis of findings from these studies to identify genomic variation associated with echocardiographic traits (stage 1), followed by replication in 2 other population-based samples (stage 2).

EchoGen Consortium Organization

The EchoGen consortium includes 7 cohort studies that enrolled participants of European ancestry and had both genome-wide variation data and echocardiographic measurements (see below for details of the cohorts); 3 of these cohorts (Cardiovascular Health Study, Rotterdam Study, and Framingham Heart Study) are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.34 All participating studies approved guidelines for collaboration and arrived at a consensus not only on phenotype definitions including harmonization, covariate selection, and analytic plans for within-study analyses but also on a prospective meta-analysis of results. The institutional review boards at the parent institutions for each cohort study approved the informed consent procedures, examination and surveillance components (including DNA collection), the data access and security processes, genotyping protocols, and the genome-wide association design. All participants provided written informed consent and gave permission to have their DNA used for research purposes.

Five studies contributed genome-wide association data to the discovery (stage 1) phase, and 2 studies contributed data to the replication (stage 2) phase. A description of these samples follows.

Stage 1 Cohorts

Cardiovascular Health Study. The Cardiovascular Health Study is a population-based cohort study of risk factors for coronary heart disease and stroke in adults aged 65 years or older conducted at 4 field centers.35 The original cohort of 5201 persons of primarily European ancestry was recruited in 1989-1990 from random samples of the Medicare eligibility lists and an additional 687 individuals of African ancestry were enrolled subsequently for a total sample of 5888. Those with prevalent coronary heart disease (n = 1195), CHF (n = 86), peripheral vascular disease (n = 93), valvular heart disease (n = 20), stroke (n = 166), or transient ischemic attack (n = 56) at baseline were excluded from the genome-wide associations. Because the other cohorts were predominantly of European descent, the African American participants were excluded from this analysis. Participants were eligible for the present investigation if their genotyping was complete and they had available echocardiographic phenotype information at their first (1989-1990) or second (1994-1995) examinations (n = 3279).

Rotterdam Study. The community-based Rotterdam Study was founded in 1990 to examine the determinants of disease and health in the elderly with a focus on neurogeriatric, cardiovascular, bone, and eye diseases.36 Inhabitants of a suburb of Rotterdam, the Netherlands (n = 7983), aged 55 years or older were included. Participants were visited at home for a standardized questionnaire and were subsequently examined at the research center in 1990-1993 and every 3 to 4 years thereafter. For the present investigation, data from the fourth round of examination (2002-2004) were used. Of 3550 eligible participants, 2199 were free of myocardial infarction (MI) and CHF and had both echocardiographic and genome-wide association data available.

Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study. In 1984, the World Health Organization instituted a Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, which was continued since 1996 in the Southern German region of the Augsburg (KORA).37 The MONICA-KORA study investigated the CVD risk factor profile of randomly selected individuals of the Augsburg population (Bavaria, Germany) in cross-sectional surveys. The study design, sampling frame, and data collection have been described elsewhere.37 A total of 4856 men and women participated in the study, of which only 2376 participants residing within or close to the city of Augsburg were offered an echocardiographic examination for logistical reasons. Participants (n = 3006) had a follow-up examination (KORA F3) in 2004-2005, of whom 1644 participants between 35 and 79 years of age had genome-wide associations conducted.38 Of these, 589 had available echocardiograms and were free of prevalent MI and CHF.

Framingham Heart Study. The Framingham Heart Study is a longitudinal observational, community-based cohort initiated in 1948 in Framingham, Massachusetts, to prospectively investigate CVD and its risk factors. The children (and spouses of the children) of the original cohort, labeled the Offspring cohort, were recruited in 1971, and have been examined approximately every 4 years since.39 At each clinic examination, participants receive routine questionnaires, a physical examination, anthropometry, electrocardiograms, and blood tests. At the second (1978-1982), fourth (1987-1990), fifth (1991-1995), and sixth (1996-1998) examination cycles participants underwent transthoracic echocardiography (see supplementary material). The offspring cohort participants with available echocardiographic information at any of these 4 examinations and who were free of MI and CHF at these examinations (n = 3245) were eligible for the present investigation.

Gutenberg Heart Study. The Gutenberg Heart Study was initiated in 2006 to achieve a contemporary German sex-specific cardiovascular risk score. It is a community-based, prospective cohort study including approximately 17 000 participants, aged 35 to 74 years from the city of Mainz and the district Mainz-Bingen. The sample is stratified according to sex (50% women) and decade of age. A large variety of noninvasive cardiovascular phenotypes have been assessed including 2-dimensional echocardiography. By September 2008, 5000 individuals have been enrolled; 3300 study participants with genome-wide association data and echocardiographic measurements and who were free of prevalent MI and CHF were eligible for the present investigation.

Stage 2 Cohorts

Study of Health in Pomerania. The Study of Health in Pomerania (SHIP) is a longitudinal population-based cohort study conducted in West Pomerania, the northeast area of Germany.40 For the baseline examinations, a sample of 6267 eligible persons aged 20 to 79 years was drawn from population registries. Only individuals with German citizenship and main residency in the study area were included. Selected persons received a maximum of 3 written invitations. In case of nonresponse, letters were followed by a telephone call or by home visits if contact by telephone was not possible. The SHIP population finally comprised 4310 participants (response, 68.8%). Baseline examinations were conducted between 1997 and 2001. Between 2002 and 2006 all participants were re-invited for an examination follow-up, in which 3300 participants (83.5% of eligible persons) took part. Echocardiography at baseline was conducted only in those 45 years or older but had no age restriction at follow-up. A total of 3212 individuals who were free of prevalent MI and CHF were eligible for the present study.

Austrian Stroke Prevention Study. The Austrian Stroke Prevention Study is a community-based prospective cohort study on the cerebral effects of vascular risk factors in the normal elderly population of the city of Graz, Austria.41 From 1991-1994, 509 persons without neuropsychiatric disease were randomly selected from the official community register (stratified by sex and 5-year age groups) to undergo neuroimaging, cognitive testing, and echocardiography. In 1999-2003, an additional 567 individuals were randomly selected to undergo the same imaging procedures, thereby increasing the size of the baseline cohort to 1076 individuals aged 45 to 85 years. Blood was drawn from all study participants for DNA extraction and all consented to genetic testing. Of the 996 study participants from whom DNA was extracted, 908 underwent transthoracic echocardiography. We excluded 26 individuals because of prevalent MI or CHF, leaving 882 eligible for the present analysis.

Echocardiographic Methods

In each cohort, participants underwent routine transthoracic echocardiography at selected examinations (1 each for the Rotterdam and Gutenberg studies; 2 for the Cardiovascular Health Study, MONICA-KORA, SHIP, and Austrian Stroke Prevention Study, and 4 for the Framingham Heart Study; data from all available echocardiographic examinations of each cohort [including the most recent ones] were included). Measurements of LV internal dimension, the thicknesses of the posterior wall and interventricular septum, and the diameter of the aortic root (all measured at end-diastole) and the left atrium at end-systole were obtained by using a leading edge technique and averaging measurements in 3 cardiac cycles according to the American Society of Echocardiography guidelines.42 Left ventricular wall thickness was calculated as the sum of posterior wall and interventricular septum measurements. The LV mass was calculated by using the formula 0.8 [1.04{(LV diastolic internal dimension + interventricular septum + posterior wall)3 −(LV diastolic internal dimension)3}] + 0.6.43 The LV systolic dysfunction was defined as the presence of reduced fractional shortening (<0.29, which corresponds to an ejection fraction of 50%) on M-mode or a diminished ejection fraction (<50%) on 2-dimensional echocardiography.44 Details of ultrasonographic instrumentation are provided in the “Echocardiographic Methods” section and in eTable 1). The present investigation focused on 6 echocardiographic traits: LV mass, LV diastolic internal dimension, LV wall thickness, aortic root, and left atrial size (continuous traits), and LV systolic dysfunction (a binary trait). For cohorts with multiple echocardiographic examinations, we used the average of all available measurements obtained at the eligible examinations for our analyses.

Genotyping Methods and Imputation

The 7 studies included in this meta-analysis used different genotyping platforms: the Illumina HumanCNV370-Duo for the Cardiovascular Health Study, the Illumina Infinium HumanHap550-chip v3.0 for the Rotterdam Study, Illumina Human610-Quad BeadChip for the Austrian Stroke Prevention Study, Affymetrix Human Mapping 500K Array Set for MONICA-KORA, Affymetrix Human Mapping 500K Array Set and 50K Human Gene Focused Panel for the Framingham Heart Study, and the Affymetrix Human SNP Array 6.0 for the Gutenberg Study and SHIP. Therefore, to facilitate meta-analyses, all studies used their genotype data to impute to the 2.5 million nonmonomorphic, autosomal, SNPs described in HapMap (CEU population, release 22, build 36; http://hapmap.org).45,46 Imputation of unmeasured genotypes in order to combine results data across genotyping platforms is an essential and accepted tool in the conduct of genome-wide association studies.34 Stated simply, the application of imputation techniques on each specific genotyping platform allowed us to estimate the association of all 2.5 million polymorphic HapMap SNPs in each study. The Cardiovascular Health Study used the BIMBAM algorithm software for imputation (available at http://stephenslab.uchicago.edu/software.html),47 whereas the Rotterdam, Framingham, Gutenberg, Austrian Stroke and Prevention, and MONICA-KORA studies used the MACH algorithm software (http://www.sph.umich.edu/csg/abecasis/MaCH). SHIP used the IMPUTE algorithm software (http://www.stats.ox.ac.uk/~marchini/software/gwas/impute.html). All studies imputed the genotype dosage, from 0 to 2, which is the expected number of minor alleles. Extensive quality control analyses were performed in each cohort. Imputation methods and quality control filters are described in the “Genotyping Methods” section of the supplementary material.

Statistical Methods

We chose a 2-stage design with a larger stage 1 (followed by joint analysis) to combine statistical efficiency with power for detecting variants with modest effects.48 For stage 1, separate within-cohort analyses (n = 5 cohorts) were performed for each echocardiographic trait using an additive genetic model relating the trait to genotype dosage (0-2 copies of the minor allele) for each SNP, adjusting for age, sex, height, and weight. The Cardiovascular Health Study additionally adjusted for study site. For continuous phenotypes, linear regression was used. For LV systolic dysfunction, we used a log-additive model in unconditional logistic regression to compare those with and without the condition. In the Framingham Heart Study alone, we used mixed-effects models (linear or logistic depending on trait) to account for familial correlations. The association of each echocardiographic trait to each genotype was quantified by the regression slope (β), its standard error [SE(β)], and P value. Genomic control correction was applied in each study prior to the meta-analysis.49

After verifying strand alignment across studies, we conducted a prospective meta-analysis of results from within-cohort analysis (n = 5 cohorts) for each echocardiographic trait. We combined the results from individual studies with inverse-variance weighting for each SNP using the R software (http://www.r-project.org). The approach did not pool raw participant-specific data, which could induce problems associated with phenotypic heterogeneity or population structure/admixture; hence, the approach is robust. We selected an a priori genome-wide statistical significance threshold of 5 × 10−7, the threshold used by the Wellcome Trust Case-control Consortium.50 For 2.5 million tests, this threshold provides an expectation of less than 1.25 false-positive results across the genome. Post–meta-analytic filters were an average weighted minor allele frequency of more than 0.005 for continuous traits and more than 0.03 for the binary trait of LV systolic dysfunction.

For stage 2, we selected the top SNP at each genetic locus that was associated with an echocardiographic trait and achieved genome-wide significance in stage 1 (as defined above); a locus was defined as a set of HapMap SNPs associated with the most significantly associated SNP with an R2 of 0.5 or greater. We related the top SNPs to corresponding echocardiographic traits in the 2 replication samples. To be considered replication, we required that the direction of the β (for a SNP) must be in the same direction in the replication study as in the discovery analysis. Using a 1-sided P value is therefore necessary in order for the P value distribution to be correct under the null hypothesis. Accordingly, we only calculated replication P values for SNPs with βs in the appropriate direction and defined statistical significance based on a 1-sided P value less than .05 (uncorrected). We queried HapMap for evaluating if any of the replicated SNPs at a locus was correlated with a nonsynonymous SNP (R2>0.5). We estimated that our stage 2 sample size of 4094 individuals yielded more than 80% power to detect associations of a magnitude similar to that observed in stage 1 for each trait at a 1-sided α of .05 (eTable 2).

Table 1 displays the clinical and echocardiographic characteristics of the 7 samples contributing to the 2 stages of the present investigation. The genomic inflation factor (λ) was small in each of the 5 studies contributing to stage 1 (<1.09 for all traits in all cohorts). The quantile-quantile (Q-Q) plots of observed against expected P value distributions are shown in eFigure 1 [panels A-F]) and the meta-analytic λ for all traits was 1.02 or less. The Q-Q plots show a marked excess of statistically significant associations over that expected by chance alone for LV diastolic dimensions and aortic root size (eFigure 1, panels B and E, respectively).

Table Graphic Jump LocationTable 1. Study Sample Characteristics
SNPs Related to Echocardiographic Traits Meeting Threshold for Genome-wide Significance in Stage 1

Figure 1 illustrates the primary findings from the stage 1 meta-analysis and displays the genome-wide P values for interrogated SNPs across the 22 autosomal chromosomes separately for each of the 6 echocardiographic traits. Table 2 lists the 16 genetic loci (and the SNP with the lowest P value at each locus) associated with echocardiographic traits that were marked by 1 or more SNPs with P < 5×10−7, the prespecified genome-wide significance threshold: 3 loci each for LV mass and LV wall thickness, 1 locus each for LV diastolic internal dimension and LV systolic dysfunction, and 8 loci for aortic root diameter. There are 18 SNPs representing the 16 loci because 2 LV diastolic internal dimensions SNPs are correlated, as are 2 SNPs on chromosome 17 that are related to aortic root size (R2≥0.5). No SNP was associated with left atrial size at the genome-wide significance threshold. The section “Loci Associated With Echocardiographic Traits in Stage 1” of the supplementary material provides a description of these genetic loci and eTable 3 amplifies the details of the SNPs listed in Table 2 with regard to their imputation status and the quality of imputation. We provide in eTables 4 through 9 a list of all SNPs associated with each of the echocardiographic traits at a meta-analytic P < 1×10−5level. (See supplemental material.)

Place holder to copy figure label and caption
Figure 1. Genome-wide Signal Intensity Plots
Graphic Jump Location

The plots show the single-nucleotide polymorphism–wise log P values (based on the fixed-effects meta-analysis) against their genomic position for left ventricular mass, internal dimensions, wall thickness, and systolic dysfunction and for the aortic root diameter and left atrial size. Within each chromosome, shown on the x-axis, the results are plotted from the p-terminal end. The horizontal dotted lines indicate the significance threshold of P = 5 × 10−7.

Table Graphic Jump LocationTable 2. Genetic Loci in Which Single-Nucleotide Polymorphisms Associated With Echocardiographic Traits With P < 5 x 10−7 (Stage 1) and Replication of These SNPs (Stage 2)
SNPs Related to Echocardiographic Traits in Stage 2 (Replication)

Table 2 shows the association and 1-sided P value for each stage 1 locus in the stage 2 replication samples. Seven of the 17 SNPs (representing 15 loci; 1 LV mass SNP was not subjected to replication, given very low minor allele frequency) tested in Table 2 replicated, including 2 for LV diastolic dimensions, and 5 for aortic root dimensions. Five of these 7 replicated SNPs were genotyped in at least 1 of the replication cohorts (eTable 3).

The replicated SNPs explained only a modest proportion in the variance of LV diastolic dimensions (increments in R2 attributable to SNPs were 0.0 in the Rotterdam Study, 0.002 in the Cardiovascular Health Study, 0.004 in the Gutenberg Heart Study, and 0.005 in KORA and the Framingham Heart Study) and aortic root size (increments in R2 attributable to SNPs were 0.01 in the Cardiovascular Health Study and KORA, 0.02 in the Rotterdam Study, and 0.03 in the Framingham Heart Study; eTable 10). Figure 2 displays the stage 1 forest plots for each of these 7 SNPs. eFigure 2 (Panels A-B) shows the regional plots for the associations centered on these 7 SNPs.

Place holder to copy figure label and caption
Figure 2. Seven Single-Nucleotide Polymorphisms Associated With Select Echocardiographic Traits in Stage 1 and Replicated in Stage 2
Graphic Jump Location

Individual studies are plotted against the individual effect sizes (β coefficients for continuous traits). The size of the box is inversely proportional to the estimated variance of the effect-size estimator. Horizontal lines are the confidence intervals corresponding to the P value threshold of 5×10−7. The vertical line indicates the value is consistent with no association. If a single-nucleotide polymorphism was not available in a study, there is no data point for that study. The diamond represents the meta-analytic effect size.

Table 2 also displays the P values for combined meta-analysis of the 17 SNPs in stages 1 and 2.

We identified novel findings for 5 genetic loci that are associated with LV structure (1 locus) and aortic root diameter (4 loci). The effect sizes for the observed associations were generally very modest, and the proportion of variance explained was 1% to 3% for aortic root size, and 0.2% to 0.5% for LV diastolic dimensions. However, since the causal variants have not been identified, our investigation may underestimate the proportion of variance explained by these loci. Four of the replicated SNPs (2 each that were associated with LV diastolic dimensions and aortic root size) were within genes.

Novel Loci Associated With LV Structure and Function

Left ventricular diastolic dimension was associated with 2 SNPs presumably marking the same 6q22 locus and that included the SLC35F1 (GenBank BC028615) and C6orf204 (GenBank AF308284) genes. SLC35F1 codes a membrane protein that belongs to the solute transporter family. Its role in cardiac physiology is unknown, although the protein is expressed in cardiac tissue. Some of the associated SNPs at the 6q22 locus are in C6orf204, which is expressed in cardiac tissue and encodes a protein (coiled-coil domain containing protein C6orf204) whose function is unclear. One of the top SNPs in this gene (rs11968176), is about 100 kb from PLN (RefSeq NM_002667, which encodes phospholamban, a protein that inhibits cardiac muscle sarcoplasmic reticulum Ca2+-ATPase and regulates diastolic function.51 Mutations in PLN have been implicated in the pathogenesis of dilated cardiomyopathy.52

Novel Loci Associated With Aortic Root Diameter

Aortic root size was associated with 5 SNPs presumably representing 4 genetic loci. The SNP at 17p13, rs10852932, is in the gene SMG6 ([GenBank AB018275] Smg-6 homologue, nonsense mediated mRNA decay factor). SMG6 is expressed in aortic tissue and encodes a component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.53 This protein may have a general role in telomere regulation, including promoting the ability of telomerase reverse transcriptase to elongate telomeres.53 Of note, telomerase activity is up-regulated in the aorta of spontaneous hypertensive rats, and down-regulation of telomerase activity is associated with arrest of the proliferation of vascular smooth muscle cells and induction of apoptosis.54 Thus, regulation of telomerase activity may play a critical role in vascular remodeling in hypertension.

Aortic root diameter was also associated with SNPs at 3 genetic loci that were intergenic, located at variable distances from CCDC100 ([GenBank AK095646] centrosomal protein 120kDa [also referred to as CEP120]; 149 kb), HMGA2 ([GenBank U28754] high mobility group AT-hook 2; 35 kb), and PDE3A ([RefSeq NM_000921] phosphodiesterase 3A, cGMP-inhibited; 291 kb), all 3 genes are expressed in aortic tissue. CCDC100 encodes a centrosomal protein that has a role in development of the neocortex55; its function in cardiac or vascular tissue remains unclear. HMGA2 encodes a protein with structural DNA-binding domains that acts as a transcriptional regulating factor. It is expressed largely during embryogenesis and has been linked to vascular tumors including angiomyxomas and pulmonary hamartomas.56 The gene has also been related to adult stature,57 which could be another potential basis for its association with aortic diameter. A mutation in the gene results in the “pygmy” mouse,58 suggesting that the gene may have a vital role in growth and development and body size; our data raise the possibility that variation in the gene may be associated with the size of the aorta. PDE3A is expressed in aortic smooth muscle cells, and alterations in activity levels have been associated with phenotypic alterations of the smooth muscle cells in experimental animals.59 It is unclear, however, how such altered activity may contribute to variation in aortic root size in humans.

Strengths and Limitations

The large community-based studies, the common method of M-mode echocardiography; and the implementation of quality control procedures in individual imaging laboratories in each study cohort (see “Echocardiographic Methods” section of the supplementary material) and the harmonization of imputation strategies and analytical methods into a prospective meta-analysis strengthen the present investigation (eTable 3 provides the details regarding the imputation status of these SNPs).

Several limitations of our investigation merit comment. First, phenotypic and study design heterogeneity diminished statistical power to detect modest genetic effects in genome-wide association. Measurement errors would bias the estimates toward the null hypothesis of no association of SNPs. In this context, it should be noted that M-mode measurements of the aortic root may be less accurate and can result in underestimation of aortic diameter (compared with 2-dimensional images). Furthermore, our approach has limited statistical power to evaluate associations of traits with rare SNPs or with poorly imputed SNPs. We evaluated additive models using pooled sex analyses; additional investigations are required to detect sex-specific associations and nonadditive genetic effects. Also, we acknowledge that genome-wide association data may establish significant genomic regions without identifying the mechanisms of association or establishing causality. The cohorts studied were all of European descent, limiting the generalizability of our findings to individuals of non-European ancestry.

Our prospective meta-analysis of echocardiographic data from more than 12 000 participants in 5 community-based cohorts with replication in more than 4000 people from 2 other cohorts identified 5 genetic loci that are associated with interindividual variation in cardiac dimensions and aortic root size. These findings are novel, but the loci explained a very small proportion of the variance of the traits. Additional investigations are required to replicate our findings, to identify the underlying causal variants and characterize their functional importance, to understand the biological mechanisms underlying the observed associations, and to determine whether they are related to overt cardiovascular disease.

Corresponding Author: Ramachandran S. Vasan, MD, Framingham Heart Study, 73 Mt Wayte Ave, Ste 2, Framingham, MA 01702-5827 (vasan@bu.edu).

Author Contributions: Dr Vasan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The following authors contributed equally to the manuscript; Drs Ramachandran S. Vasan, Nicole L. Glazer, Janine F. Felix, Wolfgang Lieb, Philipp Wild, Stephan B. Felix, Norbert Watzinger, Emelia J. Benjamin, Jerome I. Rotter, Jacqueline C. Witteman, Heribert Schunkert, Helena Schmidt, Henry Völzke, and Stefan Blankenberg.

Study concept and design: Vasan, Glazer, J. Felix, Lieb, S. Felix, Larson, Smith, Lumley, Lackner, Völker, O’Donnell, Redfield, Mitchell, Arnett, Hofman, Blettner, Psaty, Duijn, Kroemer, Benjamin, Rotter, Witteman, Blankenberg.

Acquisition of data: Vasan, Wild, Watzinger, Schmidt, Zeller, Homuth, Aragam, Rivadeneira, Erdmann, Schnabel, Dörr, Zweiker, Rodeheffer, Levy, Haritunians, Deckers, Stritzke, Lackner, Heckbert, Stricker, Mitchell, Arnett, Gottdiener, Uitterlinden, Meitinger, Friedrich, Psaty, Wichmann, Kroemer, Benjamin, Rotter, Schunkert, Schmidt, Völzke, Blankenberg.

Analysis and interpretation of data: Vasan, Glazer, J. Felix, Lieb, Wild, S. Felix, Watzinger, Larson, Dehghan, Großhennig, Schillert, Teumer, Schmidt, Kathiresan, Lumley, Aulchenko, König, Struchalin, Bis, Rivadeneira, Schnabel, Dörr, Lind, Greiser, Stritzke, Ingelsson, Kullo, Haerting, Heckbert, Stricker, Ziegler, Reffelmann, Werdan, Mitchell, Rice, Arnett, Meitinger, Wang, Munzel, Benjamin, Rotter, Witteman, Schmidt, Völzke, Blankenberg.

Drafting of the manuscript: Vasan, Glazer, Arnett, Meitinger, Schunkert.

Critical revision of the manuscript for important intellectual content: Vasan, Glazer, J. Felix, Lieb, Wild, S. Felix, Watzinger, Larson, Smith, Dehghan, Großhennig, Schillert, Teumer, Schmidt, Kathiresan, Lumley, Aulchenko, König, Zeller, Homuth, Struchalin, Aragam, Bis, Rivadeneira, Erdmann, Schnabel, Dörr, Zweiker, Lind, Rodeheffer, Greiser, Levy, Haritunians, Deckers, Stritzke, Lackner, Völker, Ingelsson, Kullo, Haerting, O’Donnell, Heckbert, Stricker, Ziegler, Reffelmann, Redfield, Werdan, Mitchell, Rice, Arnett, Hofman, Gottdiener, Uitterlinden, Meitinger, Blettner, Friedrich, Wang, Psaty, Duijn, Wichmann, Munzel, Kroemer, Benjamin, Rotter, Witteman, Schmidt, Völzke, Blankenberg.

Statistical analysis: Vasan, Glazer, J. Felix, Lieb, Wild, Larson, Dehghan, Großhennig, Schillert, Teumer, Kathiresan, Lumley, Aulchenko, König, Zeller, Struchalin, Rivadeneira, Dörr, Stricker, Ziegler, Reffelmann, Rice, Arnett, Gottdiener, Schunkert, Schmidt.

Obtained funding: Vasan, S. Felix, Schmidt, Zeller, Rodeheffer, Levy, Lackner, Völker, J. Felix, Arnett, Hofman, Gottdiener, Uitterlinden, Meitinger, Psaty, Wichmann, Kroemer, Benjamin, Rotter, Schmidt, Völzke, Blankenberg.

Administrative, technical, or material support: Vasan, Glazer, Lieb, Wild, Watzinger, Teumer, Schmidt, Zeller, Homuth, Bis, Rivadeneira, Erdmann, Schnabel, Zweiker, Lind, Völker, O’Donnell, Ziegler, Arnett, Gottdiener, Uitterlinden, Meitinger, Psaty, Wichmann, Kroemer, Rotter, Schmidt, Blankenberg.

Study supervision: Vasan, S. Felix, Watzinger, Zeller, Homuth, Aragam, Dörr, Deckers, Völker, Heckbert, Stricker, Ziegler, Mitchell, Arnett, Hofman, Gottdiener, Uitterlinden, Blettner, Psaty, Duijn, Munzel, Rotter, Witteman, Schmidt, Blankenberg.

Financial Disclosures: None reported.

Funding/Support: Support for research reported in this article is listed by study.

Cardiovascular Health Study: Contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00069 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

Rotterdam Study: The genome-wide associations database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (nr. 175.010.2005.011, 911.03.012) and the Research Institute for Diseases in the Elderly (RIDE). This study was supported by the Netherlands Genomics Initiative (NGI)/NWO project number 050 60 810. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands organization for scientific research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Netherlands Heart Foundation, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We thank Michael Moorhouse, PhD, Department of Bioinformatics, and Pascal Arp, BSc, Mila Jhamai, BSc, Marijn Verkerk, BSc, and Sander Bervoets, BSc, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands, for their help in creating the database.

MONICA-KORA: The study was funded by the European Union sponsored project Cardiogenics (LSHM-CT 2006-037593), by the National Genome Network (01GS0418 to Drs Schunkert and Erdmann; 01GR0466 to Dr Ziegler) and by the National Genome Network Plus sponsored by the German Federal Ministry of Education and Research (BMBF). The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München (former GSF)–National Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the BMBF and Munich Center of Health Sciences (MC Health) as part of LMUinnovativ.

Framingham Heart Study: This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278), and by grants from the National Heart, Lung, and Blood Institute 2K24HL04334, RO1HL080124, RO1HL077477, and R01HL093328 (all to Dr Vasan).

Gutenberg Heart Study: The Gutenberg Heart Study is funded through the government of Rheinland-Pfalz (“Stiftung Rheinland Pfalz für Innovation,” contract number AZ 961-386261/733), the research programs “Wissen schafft Zukunft” and “Schwerpunkt Vaskuläre Prävention” of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems including an unrestricted grant for the Gutenberg Heart Study. Specifically, the research reported in this article was supported by the National Genome Network “NGFNplus” (contract number project A3 01GS0833) by the Federal Ministry of Education and Research, Germany.

Study of Health in Pomerania (SHIP): SHIP is funded by the Federal Ministry of Education and Research (grants No. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Echocardiography in the 5-year follow-up was funded by the Competence Network Heart Failure of the Federal Ministry of Education and Research, and statistical analyses were supported by Deutsche Forschungsgemeinschaft (by grant SFB TR 19). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and by the Federal State of Mecklenburg- West Pomerania.

Austrian Stroke Prevention Study: Current analyses of the Austrian Stroke Prevention Study are funded by the Austrian Science Fund Project P20545_P05 Genetics of cerebral small vessel disease (Dr H. Schmidt).

Mayo Clinic, Olmsted County: Dr Rodheffer was supported in part by RO1 HL55502.

Role of the Sponsors: The funding sources had no role in the study design, analyses, or drafting of the manuscript. The National Heart, Lung, and Blood Institute reviews all manuscripts submitted for publication, but it was not involved in the decision to publish.

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Figures

Place holder to copy figure label and caption
Figure 1. Genome-wide Signal Intensity Plots
Graphic Jump Location

The plots show the single-nucleotide polymorphism–wise log P values (based on the fixed-effects meta-analysis) against their genomic position for left ventricular mass, internal dimensions, wall thickness, and systolic dysfunction and for the aortic root diameter and left atrial size. Within each chromosome, shown on the x-axis, the results are plotted from the p-terminal end. The horizontal dotted lines indicate the significance threshold of P = 5 × 10−7.

Place holder to copy figure label and caption
Figure 2. Seven Single-Nucleotide Polymorphisms Associated With Select Echocardiographic Traits in Stage 1 and Replicated in Stage 2
Graphic Jump Location

Individual studies are plotted against the individual effect sizes (β coefficients for continuous traits). The size of the box is inversely proportional to the estimated variance of the effect-size estimator. Horizontal lines are the confidence intervals corresponding to the P value threshold of 5×10−7. The vertical line indicates the value is consistent with no association. If a single-nucleotide polymorphism was not available in a study, there is no data point for that study. The diamond represents the meta-analytic effect size.

Tables

Table Graphic Jump LocationTable 1. Study Sample Characteristics
Table Graphic Jump LocationTable 2. Genetic Loci in Which Single-Nucleotide Polymorphisms Associated With Echocardiographic Traits With P < 5 x 10−7 (Stage 1) and Replication of These SNPs (Stage 2)

References

Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Left ventricular mass and incidence of coronary heart disease in an elderly cohort: the Framingham Heart Study.  Ann Intern Med. 1989;110(2):101-107
PubMed   |  Link to Article
Gardin JM, McClelland R, Kitzman D,  et al.  M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the Cardiovascular Health Study).  Am J Cardiol. 2001;87(9):1051-1057
PubMed   |  Link to Article
Bikkina M, Levy D, Evans JC,  et al.  Left ventricular mass and risk of stroke in an elderly cohort: the Framingham Heart Study.  JAMA. 1994;272(1):33-36
PubMed   |  Link to Article
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study.  N Engl J Med. 1990;322(22):1561-1566
PubMed   |  Link to Article
Vasan RS, Larson MG, Levy D, Evans JC, Benjamin EJ. Distribution and categorization of echocardiographic measurements in relation to reference limits: the Framingham Heart Study: formulation of a height- and sex-specific classification and its prospective validation.  Circulation. 1997;96(6):1863-1873
PubMed   |  Link to Article
Vasan RS, Larson MG, Benjamin EJ, Evans JC, Levy D. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction.  N Engl J Med. 1997;336(19):1350-1355
PubMed   |  Link to Article
Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history of asymptomatic left ventricular systolic dysfunction in the community.  Circulation. 2003;108(8):977-982
PubMed   |  Link to Article
Benjamin EJ, D'Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke and death: the Framingham Heart Study.  Circulation. 1995;92(4):835-841
PubMed   |  Link to Article
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