Abstract Background Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene ...angiopoietin-like 3 ( ANGPTL3 ). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. Objectives The study goal was to leverage 3 distinct lines of evidence—a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)—to test whether ANGPTL3 deficiency is associated with lower risk for CAD. Methods We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. Results The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). Conclusions ANGPTL3 deficiency is associated with protection from CAD.
Nomograms to predict normal aortic root diameter for body surface area (BSA) in broad ranges of age have been widely used but are limited by lack of consideration of gender effects, jumps in upper ...limits of aortic diameter among age strata, and data from older teenagers. Sinus of Valsalva diameter was measured by American Society of Echocardiography convention in normal-weight, nonhypertensive, nondiabetic subjects ≥15 years old without aortic valve disease from clinical or population-based samples. Analyses of covariance and linear regression with assessment of residuals identified determinants and developed predictive models for normal aortic root diameter. In 1,207 apparently normal subjects ≥15 years old (54% women), aortic root diameter was 2.1 to 4.3 cm. Aortic root diameter was strongly related to BSA and height (r = 0.48 for the 2 comparisons), age (r = 0.36), and male gender (+2.7 mm adjusted for BSA and age, p <0.001 for all comparisons). Multivariable equations using age, gender, and BSA or height predicted aortic diameter strongly (R = 0.674 for the 2 comparisons, p <0.001) with minimal relation of residuals to age or body size: for BSA 2.423 + (age years × 0.009) + (BSA square meters × 0.461) − (gender 1 = man, 2 = woman × 0.267), SEE 0.261 cm; for height 1.519 + (age years × 0.010) + (height centimeters × 0.010) − (gender 1 = man, 2 = woman × 0.247), SEE 0.215 cm. In conclusion, aortic root diameter is larger in men and increases with body size and age. Regression models incorporating body size, age, and gender are applicable to adolescents and adults without limitations of previous nomograms.
Summary Background Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Methods ...Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5·0×10−8 ) or the Rotterdam cohort (p<1·0×10−7 ) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10−168 and 2·9×10−18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10−60 and 9·8×10−4 ), and rs1165205 in SLC17A3 (p=3·3×10−26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95% CI 0·52–0·68, p=7·0×10−14 ), rs2231142 (1·74, 1·51–1·99, p=3·3×10−15 ), and rs1165205 (0·85, 0·77–0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06–2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272–351 μmol/L in the Framingham cohort, 269–386 μmol/L in the Rotterdam cohort, and 303–426 μmol/L in white participants of the ARIC study) and gout (frequency 2–13% in the Framingham cohort, 2–8% in the Rotterdam cohort, and 1–18% in white participants in the ARIC study). Interpretation We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout. Funding Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.
Background Selection of antihypertensive therapy is often empiric, and use of genetic information to guide drug therapy selection holds future promise. Trial design The objective of this trial is to ...identify the genetic determinants of the antihypertensive and adverse metabolic responses to a thiazide diuretic (hydrochlorothiazide), a β-blocker (atenolol), and their combination. This will be accomplished through candidate gene and genome-wide association approaches. Individuals with uncomplicated hypertension (N = 800), with ages 17 and 65 years, are being enrolled. Current antihypertensive therapy is discontinued, and hypertension is confirmed, along with collection of other baseline data. Subjects are then randomized to either hydrochlorothiazide or atenolol, with 1 dose titration step, followed by assessment of response to therapy after at least 6 weeks on the target dose. Those with blood pressure >120/70 mm Hg have the second drug added, with similar dose titration and response assessment procedures. Data collected include home, office, and 24-hour ambulatory blood pressure. Biological samples collected in the fasting state include plasma, serum, DNA (buffy coat), and urine. Epstein-Barr virus transformed lymphocyte cell lines are also being created. Conclusions Pharmacogenetic-guided therapy holds clinical potential for hypertension, but the literature in the field is limited. This trial will add substantially to our understanding of the genetic determinants of antihypertensive and adverse metabolic responses to 2 commonly used antihypertensive drug classes.
Background Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk ...for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. Methods and Results We examined 2 dichotomous phenotypes of ideal CV health—clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical + behavioral (clinical plus: not a current smoker, body mass index <25 kg/m2 )—among white participants aged 50 ± 5 years. We performed a meta-analysis of 4 genome-wide association studies (total n = 11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance ( P < 2.0 × 10−9 ). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. Conclusion A common single-nucleotide polymorphism in the APOC1 /APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.
Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated ...by such GWAS confer additional risk of AF.
To study the association of genetic variants with AF at GWAS top loci.
In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.
One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).
We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
We aimed to determine whether polymorphisms in chromosome 4q25 are associated with postoperative atrial fibrillation (AF), long-term AF, postoperative or long-term stroke, and long-term survival ...after coronary artery bypass grafting. We performed genotyping for rs2200733 and rs10033464 in white participants (n = 1,166) from the TexGen genetic registry. The development of postoperative or long-term AF, postoperative or long-term stroke, and long-term mortality were ascertained. Both rs2200733 and rs10033464 were associated with postoperative AF (odds ratio OR 1.41, 95% confidence interval CI 1.04 to 1.91, and OR 1.47, 95% CI 1.05 to 2.06, respectively). Carriers of the risk allele (T) had an increased risk of postoperative AF with preoperative β blocker (BB) (for rs2200733, OR 1.47, 95% CI 1.004 to 2.16 for those taking a BB, and OR 1.13, 95% CI 0.73 to 1.73 for those not taking a BB; for rs10033464, OR 1.89, 95% CI 1.22 to 2.93 for those taking preoperative a BB, and OR 1.04, 95% CI 0.65 to 1.65 for those not taking a BB). Both rs2200733 and rs10033464 were also associated with long-term AF (hazard ratio 1.32, 95% CI 1.05 to 1.67, and hazard ratio 1.28, 95% CI 1.00 to 1.66, respectively). Carriers of rs2200733 had increased long-term mortality (hazard ratio 1.57, 95% CI 1.10 to 2.24). These variants were not associated with postoperative or long-term stroke. In conclusion, variants in 4q25 are associated with an increased risk of postoperative or long-term AF and, possibly, mortality in whites undergoing coronary artery bypass grafting, and could potentially affect the choice of therapy used to decrease postoperative AF.
Purpose In this study we examined whether high glycemic index (GI) and glycemic load (GL) diets are associated with increased risk of developing coronary heart disease (CHD) in Whites and African ...Americans with and without type 2 diabetes. Methods Data on 13,051 patients ages 45 to 64 years from the Atherosclerosis Risk in Communities study were analyzed. The ARIC food frequency questionnaire baseline data provided GI and GL indices. A propensity score was created to estimate the effect of a patient's covariates on energy-adjusted GI or GL. During a maximum of 17 years of follow-up, 1683 cases of CHD (371 with diabetes and 1312 without diabetes) were recorded. Results For every 5-units increase in GI, there was a 1.16-fold (95% confidence interval 95% CI, 1.01−1.33) increased risk of incident CHD in African Americans. For every 30-units increase in GL, there was a 1.11-fold (95% CI, 1.01−1.21) increased risk of incident CHD in Whites. High GL was an especially important CHD risk factor for Whites without diabetes (per 30-units increase; hazard ratio, 1.14; 95% CI, 1.02−1.26). However, these relationships were not seen in individuals with diabetes. Conclusions Nutritional advice to reduce the GI and GL in diets of African Americans and Whites subjects (without diabetes) may play a role in reducing CHD risk.
Purpose To investigate the potential interaction between folate intake and the paraoxonase 1 (PON1) Q192R polymorphism with the risk of incident coronary heart disease (CHD) and ischemic stroke in ...the Atherosclerosis Risk in Communities study, a population-based prospective cohort of cardiovascular disease in 15,792 white and African-American subject. Methods Race-stratified Cox proportional hazards models were performed to examine the interaction between folate intake and the PON1 Q192R polymorphism. Results A significant inverse association between folate intake and risk of incident CHD among white subjects was found (hazard rate ratio, 1.30; 95% confidence interval, 1.09–1.56; P = .004; folate intake ≤155 μg vs ≥279 μg, reference group). An interaction effect was observed between the dominant genetic model and folate intake with regards to incident ischemic stroke in white subjects (hazard rate ratio, 0.68; 95% confidence interval, 0.91–0.99; and 1.24 from 1st-4th quartile, respectively; P -trend = .05). Conclusions There was an interaction between folate intake and PON1 Q192 polymorphism with regard to the risk of ischemic stroke in white subjects. Future studies should investigate the interaction between additional polymorphisms within the PON1 gene and genetic variants in other folate metabolizing genes with folate intake on the risk of incident CHD and stroke.
Purpose Alcohol consumption has been shown to contribute to a favorable lipid profile, and most studies have reported a reduction in coronary heart disease risk with low-to-moderate consumption of ...alcohol that is generally attributed to the beneficial effects of alcohol on lipids. The influence of different types of alcoholic beverages on plasma lipid levels has been investigated to a lesser extent and in limited populations. Methods We investigated the effect of overall alcohol consumption, as well as the type of alcoholic beverage consumed, on multiple lipid measures in the large bi-ethnic population of the Atherosclerosis Risk in Communities study. Results We found both low-to-moderate and heavy alcohol consumption, regardless of the type of alcoholic beverage consumed, to result in significantly greater levels of high-density lipoprotein (HDL) cholesterol, HDL3 cholesterol, and apolipoprotein A-I in both white and African-American males and females. Associations with other lipid measures contrasted between whites and African Americans, with greater levels of alcohol consumption resulting in significantly greater triglyceride levels in African Americans. Conclusions Our results confirm previous studies associating alcohol consumption, regardless of beverage type, with greater HDL cholesterol levels, with additional consistent associations detected for the major HDL cholesterol density subfraction, HDL3 cholesterol, and the major HDL cholesterol structural apolipoprotein, apolipoprotein A-I.
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