Obesity is globally prevalent and highly heritable, but the underlying
genetic factors remain largely elusive. To identify genetic loci for
obesity-susceptibility, we examined associations between body mass index (BMI)
and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of
42 SNPs in up to 125,931 additional individuals. We confirmed 14 known
obesity-susceptibility loci and identified 18 new loci associated with BMI
(P<5×10−8), one of which
includes a copy number variant near GPRC5B. Some loci
(MC4R, POMC, SH2B1, BDNF) map near key hypothalamic
regulators of energy balance, and one is near GIPR, an incretin
receptor. Furthermore, genes in other newly-associated loci may provide novel
insights into human body weight regulation.
White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits.
White blood cells (WBCs) are blood cells that mediate immune systems and defend the body against foreign microorganisms. It is well known that WBCs consist of various subtypes of cells with distinct roles, although the genetic background of each of the WBC subtypes has yet to be examined. In this study, we report genome-wide association studies (GWAS) for the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects. We identified 12 significantly associated genetic loci, and 9 of them were novel. Evaluation of the associations of these identified loci in cohorts of Caucasian populations demonstrated both ethnically common and divergent genetic backgrounds of the WBC subtypes. These loci also indicated a variety of patterns of pleiotropic associations within the hematological traits, including the other WBC subtypes, total WBC count, platelet count, or red blood cell-related traits, which suggests unique and common functional roles of these loci in the processes of hematopoiesis.
Rationale and Objectives
Abdominal aortic calcification (AAC) can be quantified using computed tomography (CT), but imaging planes are prescribed based on bony landmarks, so that individual variation between the landmark and the aortoiliac junction can result in variable aortic coverage. In the Framingham CT substudy, we scanned a 15-cm (Z-direction) abdominal segment cranial to the S1 vertebral body. We sought to determine the range and distribution of length of aorta scanned, the distribution of AAC within the abdominal aorta, and to compare burden of AAC measured from fixed-length segments versus AAC from all slices cranial to the aortoiliac bifurcation.
Materials and Methods
AAC was quantified by modified Agatston score (AS) in 100 Framingham Heart Study participants (60±13 years, 51 men). We compared AS measured from 5-cm and 8-cm segments to ASALL (total visualized aorta).
73/100 participants had AAC > 0. The total length of aorta imaged was ≥ 8 cm in 84% of participants. Qualitatively, 5-cm and 8-cm segments correctly identified 96% and 99%, respectively, of participants as having or not having AAC. Quantitatively, AS8cm was within 20% of ASALL in four-fifths and within 30% of ASALL in nine-tenths of participants. AS5cm more severely underestimated ASALL.
Using S1 as the caudal imaging landmark in a 15-cm slab yields ≥ 8 cm aortic coverage in most adults. Both 5-cm and 8-cm analysis strategies are comparable to analyzing the total visualized abdominal aorta for prevalent AAC, but only 8-cm segment analysis yields quantitatively similar measures of AAC.
abdominal aorta; calcium; population study; segment length; computed tomography
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
Fibrinogen; cardiovascular disease; genome-wide association study
Current screening and detection of asymptomatic aortic aneurysms is largely based on uniform cut-point diameters. Our objective was to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease (CVD).Measurements of the diameter of the ascending aorta(AA), descending thoracic aorta (DTA), infrarenal abdominal (IRA) and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study participants. Mean diameters were stratified by sex, age, and body surface area (BSA). Univariate associations with risk factor levels were examined and multivariable linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameter was 34.1 mm for AA, 25.8 mm for DTA, 19.3 mm for IRA and 18.7 mm for LAA.For women, the average diameter was 31.9 mm for AA, 23.1 mm for DTA, 16.7 mm for IRA, and 16.0 mm for LAA. The mean aorticdiameters were strongly correlated (p<0.0001) with age and BSA in age-adjusted analyses, and these relations remained significant in multivariable regression analyses. Positive associations of diastolic BP with AA and DTA in both sexes and pack years of cigarette smoking with DTA in women and with IRA in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by CT are larger in men compared with women, vary significantly with age and BSA, and are associated with modifiable CVD risk factors including diastolic blood pressure and cigarette smoking.
Aortic diameter; computed tomography; sex; age; body surface area
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
Vascular calcium is well studied in the coronary and peripheral arteries although there is limited data focusing on calcium deposits specific to renal arteries. The associations between renal artery calcium (RAC), cardiovascular disease (CVD) risk factors, and indices of renal function are unknown. We examined 2699 Framingham Heart Study participants who were part of a multidetector computed tomography substudy from 2008–2011. RAC was measured as a calcified plaque of >130 Hounsfield units and an area of >3 contiguous pixels. Detectable RAC was defined as an Agatston score >0. Chronic kidney disease (CKD) was defined as an eGFR <60 mL/min/1.73m2. Microalbuminuria was defined as ACR ≥17 mg/g for men and ≥25 mg/g for women. Multivariable adjusted logistic regression models were used to evaluate the associations between RAC, CVD risk factors, and renal function. The associations were secondarily adjusted for coronary artery calcium (CAC) that was used as a marker of non-renal systemic vascular calcium. The prevalence of RAC was 28.2%; this was similar in women (28.8%) and men (27.5%). Individuals with RAC had a higher odds of microalbuminuria (OR 1.79, 95% CI 1.22–2.61, p=0.003), hypertension (OR 2.11, 95% CI 1.69–2.64, p<0.001) and diabetes (OR 1.60, 95% CI 1.14–2.24, p=0.01) but not CKD (OR 0.87, 95% CI 0.58–1.32). After adjustment for CAC, the association with microalbuminuria and hypertension persisted but the association with diabetes became non-significant. In conclusion, RAC is common and independently associated with microalbuminuria and hypertension after adjustment for non-renal vascular calcium. RAC may be uniquely associated with these markers of renal end-organ damage.
cardiovascular risk factors; microalbuminuria; renal artery calcium
The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC).
Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans.
We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 ± 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS ≥90th percentile for age and sex), as well as sex-stratified analyses.
In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men.
In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease.
abdominal aortic calcification; computed tomography; coronary artery calcification; diet; Framingham Heart Study; magnesium
Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that “aggregate” tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute’s Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.
Exome sequencing study; approximate inference; von Willebrand Factor genetics
Background and Purpose
Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each have a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
Genome-wide association data were obtained from the METASTROKE, CARDIoGRAM, and C4D consortia. We first analyzed common variants reaching a nominal threshold of significance (p<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2,167 individuals with the ischemic large artery stroke (LAS) subtype.
Common variants associated with CAD at p<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, three and five loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (p<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Since these loci had prior evidence for genome-wide significance for CAD we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (pIS=1.62×10-07) and ABO (pIS =2.6×10-4) as well as at HDAC9 (pLAS=2.32×10-12), 9p21 (pLAS =3.70×10-6), RAI1-PEMT-RASD1 (pLAS =2.69×10-5), EDNRA (pLAS =7.29×10-4), and CYP17A1-CNNM2-NT5C2 (pLAS =4.9×10-4).
Our results demonstrate substantial overlap in the genetic risk of ischemic stroke and particularly the large artery stroke subtype with coronary artery disease.
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10−8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis.
Atherosclerosis is a slowly progressive disorder influenced by suboptimal lipid levels. Long-term versus contemporary lipid levels may more strongly impact the development of coronary artery calcium (CAC).
Framingham Heart Study (FHS) Offspring Cohort participants (n=1156, 44%M, 63±9 years) underwent serial fasting lipids [low-density lipoprotein (LDL-C), high-density lipoprotein, and triglycerides], Exam 1 (1971–1975) – Exam 7 (1998–2001). FHS Third Generation Cohort participants (n=1954, 55%M, 45±6 years) had fasting lipid profiles assessed, 2002–2005. Computed tomography (2002–2005) measured CAC. Lipid GRSs were computed from significantly associated single nucleotide polymorphisms. The association between early, long-term average, and contemporary lipids, and lipid GRS, with elevated CAC was assessed using logistic regression.
In FHS Offspring, Exam 1 and long-term average versus Exam 7 lipid measurements, including untreated lipid levels, were strongly associated with elevated CAC. In the FHS Third Generation, contemporary lipids were associated with CAC. The LDL-C GRS was associated with CAC (age/sex-adjusted OR 1.14, 95%CI 1.00–1.29, p=0.04). However, addition of the GRS to the lipid models did not result in a significant increase in the OR or C-statistic for any lipid measure.
Early and long-term average lipid levels, as compared with contemporary measures, are more strongly associated with elevated CAC. Lipid GRS was associated with lipid levels but did not predict elevated CAC. Adult early and long-term average lipid levels provide important information when assessing subclinical atherosclerosis and cardiovascular risk.
Lipids; Genetic risk score; Coronary artery calcium
Abdominal aortic calcium (AAC) is associated with incident cardiovascular disease but the age and sex-related distribution of AAC in a community-dwelling population free of standard cardiovascular disease risk factors has not been described. A total of 3285 participants (aged 50.2±9.9 years) in the Framingham Heart Study Offspring and Third Generation cohorts underwent abdominal multidetector computed tomography (MDCT) scanning during 1998-2005. The presence and amount of AAC was quantified (Agatston score) by an experienced reader using standardized criteria. A healthy referent subsample (N=1656, 803 men) free of hypertension, hyperlipidemia, diabetes, obesity and smoking was identified, and participants were stratified by sex and age group (<45, 45-54, 55-64, 65-74, ≥75 years). The prevalence and burden of AAC increased monotonically and supralinearly with age in both sexes but was greater in men than women in each age group. Below age 45 <16% of referent-subsample participants had any quantifiable AAC, while above age 65 nearly 90% of referent participants had >0 AAC. Across the entire study sample, AAC prevalence and burden similarly increased with greater age. Defining the 90th percentile of referent group AAC as “high,” the prevalence of high AAC was 19% for each sex in the overall study sample. AAC also increased across categories of 10-year coronary heart disease risk, as calculated using the Framingham Risk Score, in the entire study sample. We found AAC to be widely prevalent, with the burden of AAC associated with 10-year coronary risk, in a white, free-living adult cohort.
atherosclerosis; aorta; calcification; computed tomography; epidemiology
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
Incorporation of novel plasma protein biomarkers may improve current models for prediction of atherosclerotic cardiovascular disease (ASCVD) risk.
Approach and Results
We utilized discovery mass spectrometry (MS) to determine plasma concentrations of 861 proteins in 135 myocardial infarction (MI) cases and 135 matched controls. We then measured 59markers by targeted MS in 336 ASCVD case-control pairs. Associations with MI or ASCVD were tested in single marker and multimarker analyses adjusted for established ASCVD risk factors.
Twelve single markers from discovery MS were associated with MI incidence (at p<0.01) adjusting for clinical risk factors. Seven proteins in aggregate (cyclophilin A, CD5 antigen-like, cell surface glycoprotein MUC18, collagen-alpha 1 [XVIII] chain, salivary alpha-amylase 1, C-reactive protein, and multimerin-2) were highly associated with MI (p<0.0001) and significantly improved its prediction compared to a model with clinical risk factors alone (C-statistic of 0.71 vs. 0.84). Through targeted MS, twelve single proteins were predictors of ASCVD (at p<0.05) after adjusting for established risk factors. In multimarker analyses, four proteins in combination (alpha-1-acid glycoprotein 1, paraoxonase 1, tetranectin, and CD5 antigen-like, predicted incident ASCVD (p<0.0001) and moderately improved the C-statistic from the model with clinical covariates alone (C-statistic of 0.69 vs. 0.73).
Proteomics profiling identified single and multimarker protein panels that are associated with new onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD.
Biomarker; cardiovascular disease; epidemiology; myocardial infarction; proteomics
9p21.3 is among the most strongly replicated regions for cardiovascular disease (CVD). There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical CVD and its risk factors, and with copy number variation and gene expression, in the Framingham Heart Study (FHS).
Methods and Results
We sequenced 281 individuals (n=94 with myocardial infarction, n=94 with high coronary artery calcium levels, and n=93controls free of elevated coronary artery calcium or myocardial infarction) followed by genotyping and association in >7,000 additional FHS individuals. We assessed genetic associations with clinical and subclinical CVD, risk factor phenotypes, and gene expression levels of protein-coding genes CDKN2A and CDKN2B as well as the non-coding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters, and no evidence for association with traditional CVD risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or CNV events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B.
Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations, and provide further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.
genetics; myocardial infarction; risk factors; atherosclerosis; calcium
The cardiac sodium channel SCN5A regulates atrioventricular
and ventricular conduction. Genetic variants in this gene are associated with PR and QRS
intervals. We sought to further characterize the contribution of rare and common coding
variation in SCN5A to cardiac conduction.
Methods and Results
In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted
Sequencing Study (CHARGE), we performed targeted exonic sequencing of
SCN5A (n=3699, European-ancestry individuals) and identified 4 common
(minor allele frequency >1%) and 157 rare variants. Common and rare
SCN5A coding variants were examined for association with PR and QRS intervals through
meta-analysis of European ancestry participants from CHARGE, NHLBI’s Exome
Sequencing Project (ESP, n=607) and the UK10K (n=1275) and by examining ESP
African-ancestry participants (N=972). Rare coding SCN5A variants in
aggregate were associated with PR interval in European and African-ancestry participants
(P=1.3×10−3). Three common variants were associated with PR
and/or QRS interval duration among European-ancestry participants and one among
African-ancestry participants. These included two well-known missense variants;
rs1805124 (H558R) was associated with PR and QRS shortening in European-ancestry
participants (P=6.25×10−4 and
P=5.2×10−3 respectively) and rs7626962 (S1102Y) was
associated with PR shortening in those of African ancestry
(P=2.82×10−3). Among European-ancestry participants, two
novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac
conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening
(P=3.35×10−7 and P=2.69×10−4
respectively), and rs6599230 was associated with PR shortening
By sequencing SCN5A, we identified novel common and rare
coding variants associated with cardiac conduction.
PR interval; QRS interval; genetics; sequencing; cohort
In humans, vWF levels predict the risk of myocardial infarction and thrombosis; however,
the factors that influence vWF levels are not completely understood. Recent genome-wide
association studies (GWAS) have identified syntaxin-binding protein 5
(STXBP5) as a candidate gene linked to changes in vWF plasma levels,
though the functional relationship between STXBP5 and vWF is unknown. We
hypothesized that STXBP5 inhibits endothelial cell exocytosis. We found that STXBP5 is
expressed in human endothelial cells and colocalizes with and interacts with syntaxin 4.
In human endothelial cells reduction of STXBP5 increased exocytosis of vWF and P-selectin.
Mice lacking Stxbp5 had higher levels of vWF in the plasma, increased
P-selectin translocation, and more platelet-endothelial interactions, which suggests that
STXBP5 inhibits endothelial exocytosis. However, Stxbp5 KO mice also
displayed hemostasis defects, including prolonged tail bleeding times and impaired
mesenteric arteriole and carotid artery thrombosis. Furthermore, platelets from
Stxbp5 KO mice had defects in platelet secretion and activation; thus,
STXBP5 inhibits endothelial exocytosis but promotes platelet secretion. Our study reveals
a vascular function for STXBP5, validates the functional relevance of a candidate gene
identified by GWAS, and suggests that variation within STXBP5 is a
genetic risk for venous thromboembolic disease.
The SRY-related HMG-box 5 (SOX5) gene encodes a member of the SOX family of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiac-related endophenotypes: higher resting heart rate (HR), the electrocardiographic PR interval, atrial fibrillation and left ventricular mass. We have determined that human SOX5 has a highly conserved Drosophila ortholog, Sox102F, and have employed transgenic Drosophila models to quantitatively measure cardiac function in adult flies. For this purpose, we have developed a high-speed and ultrahigh-resolution optical coherence tomography imaging system, which enables rapid cross-sectional imaging of the heart tube over various cardiac cycles for the measurement of cardiac structural and dynamical parameters such as HR, dimensions and areas of heart chambers, cardiac wall thickness and wall velocities. We have found that the silencing of Sox102F resulted in a significant decrease in HR, heart chamber size and cardiac wall velocities, and a significant increase in cardiac wall thickness that was accompanied by disrupted myofibril structure in adult flies. In addition, the silencing of Sox102F in the wing led to increased L2, L3 and wing marginal veins and increased and disorganized expression of wingless, the central component of the Wnt signaling pathway. Collectively, the silencing of Sox102F resulted in severe cardiac dysfunction and structural defects with disrupted Wnt signaling transduction in flies. This implicates an important functional role for SOX5 in heart and suggests that the alterations in SOX5 levels may contribute to the pathogenesis of multiple cardiac diseases or traits.
The association of familial as compared to genetic factors in the current obesogenic environment, compared to earlier, leaner time periods, is uncertain.
Design and Methods
Participants from the Framingham Heart Study were classified according to parental obesity status in the Original, Offspring, and Third Generation cohorts; mean BMI levels were estimated and we compared the association of parental history across generations. Finally, a genetic risk score comprised of 32 well-replicated single nucleotide polymorphisms for BMI was examined in association with BMI levels in 1948, 1971, and 2002.
BMI was 1.49 kg/m2 higher per each affected parent among the Offspring, and increased to 2.09 kg/m2 higher among the Third Generation participants (p-value for the cohort comparison=0.007). Parental history of obesity was associated with increased weight gain (p<0.0001) and incident obesity (p=0.009). Despite a stronger association of parental obesity with offspring BMI in more contemporary time periods, we observed no change in the effect size of a BMI genetic risk score from 1948 to 2002 (p=0.11 for test of trend across the time periods).
The association of parental obesity has become stronger in more contemporary time period, whereas the association of a BMI genetic risk score has not changed.
obesity; epidemiology; weight change; family history; Framingham Heart Study
Limited data exist regarding the use of a genetic risk score for predicting risk of incident cardiovascular disease (CVD) in US based samples.
Methods and Results
Using findings from recent GWAS, we constructed genetic risk scores (GRS) comprised of 13 genetic variants associated with myocardial infarction (MI) or other manifestations of CHD and 102 genetic variants associated with CHD or its major risk factors. We also updated the 13 SNP GRS with 16 SNPs recently discovered by GWAS. We estimated the association, discrimination and risk reclassification of each GRS for incident cardiovascular events and for prevalent coronary artery calcium (CAC).
In analyses adjusted for age, sex, CVD risk factors and parental history of CVD, the 13 SNP GRS was significantly associated with incident hard CHD (HR 1.07, 95% CI 1.00-1.15, p=0.04), CVD (hazard ratio [HR] per-allele 1.05, 95% confidence interval [CI] 1.01-1.09; p=0.03), and high CAC (defined as >75th age and sex-specific percentile; odds ratio [OR] per-allele 1.18, 95% CI 1.11-1.26, p=3.4 × 10-7). The GRS did not improve discrimination for incident CHD or CVD but led to modest improvements in risk reclassification. However, significant improvements in discrimination and risk reclassification were observed for the prediction of high CAC. The addition of 16 newly discovered SNPs to the 13 SNP GRS did not significantly modify these results.
A GRS comprised of 13 SNPs associated with coronary disease is an independent predictor of cardiovascular events and of high CAC, modestly improves risk reclassification for incident CHD and significant improves discrimination for high CAC. The addition of recently discovered SNPs did not significantly improve the performance of this GRS.
Genetics; single nucleotide polymorphisms; cardiovascular disease; coronary heart disease; risk prediction; reclassification