L-GATOR: Genetic Association Testing for a Longitudinally Measured Quantitative Trait in Samples with Related Individuals.

In complex-trait mapping, when each subject has multiple measurements of a quantitative trait over time, power for detecting genetic association can be gained by the inclusion of all measurements and not just single time points or averages in the analysis. To increase power and control type 1 error, one should account for dependence among observations for a single individual as well as dependence between observations of related individuals if they are present in the sample. We propose L-GATOR, a retrospective, mixed-effects method for association mapping of longitudinally measured traits in samples with related individuals. L-GATOR allows arbitrary time points for different individuals, incorporates both time-varying and static covariates, and properly addresses various types of dependence. In simulations, we show that L-GATOR outperforms existing prospective methods in terms of both type 1 error and power when there is phenotype model misspecification or missing data. Compared with the previously proposed longGWAS method, L-GATOR was more than ten times faster for association testing in our simulations and almost 100 times faster for parameter estimation. L-GATOR is applicable to essentially arbitrary combinations of related and unrelated individuals, including small families as well as large, complex pedigrees. We apply the method to data from the Framingham Heart Study to identify association between longitudinal systolic blood pressure measurements and genome-wide SNPs. Of the smallest p values, one-third occur in or near genes that have been previously identified as associated with pulse pressure (such as PIK3CG) and systolic and diastolic blood pressure (such as C10orf107), showing that L-GATOR is able to prioritize relevant loci in a genome screen.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Mechanisms of Systolic Cardiac Dysfunction in PP2A, PP5 and PP2AxPP5 Double Transgenic Mice.

As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated transgenic mice with cardiac muscle cell-specific overexpression of PP2Acα (PP2A) and PP5 (PP5). For further studies we crossbred PP2A and PP5 mice to obtain PP2AxPP5 double transgenic mice (PP2AxPP5, DT) and compared them with littermate wild-type mice (WT) serving as a control. The mortality of DT mice was greatly enhanced vs. other genotypes. Cardiac fibrosis was noted histologically and mRNA levels of collagen 1α, collagen 3α and fibronectin 1 were augmented in DT. DT and PP2A mice exhibited an increase in relative heart weight. The ejection fraction (EF) was reduced in PP2A and DT but while the EF of PP2A was nearly normalized after ß-adrenergic stimulation by isoproterenol, it was almost unchanged in DT. Moreover, left atrial preparations from DT were less sensitive to isoproterenol treatment both under normoxic conditions and after hypoxia. In addition, levels of the hypertrophy markers atrial natriuretic peptide and B-type natriuretic peptide as well as the inflammation markers interleukin 6 and nuclear factor kappa B were increased in DT. PP2A enzyme activity was enhanced in PP2A vs. WT but similar to DT. This was accompanied by a reduced phosphorylation state of phospholamban at serine-16. Fittingly, the relaxation times in left atria from DT were prolonged. In summary, cardiac co-overexpression of PP2A and PP5 were detrimental to animal survival and cardiac function, and the mechanism may involve dephosphorylation of important regulatory proteins but also fibrosis and inflammation.

Novel polymorphisms in PDLIM3 and PDLIM5 gene encoding Z-line proteins increase risk of idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (IDCM), characterized by ventricular dilation and impaired systolic function, is a primary cardiomyopathy resulting in heart failure. During heart contraction, the Z-line is responsible for transmitting force between sarcomeres and is also a hot spot for muscle cell signalling. Mutations in Z-line proteins have been linked to cardiomyopathies in both humans and mice. Actinin-associated LIM protein (ALP) and enigma homolog protein (ENH), encoded by PDLIM3 and PDLIM5, are components of the muscle cytoskeleton and localize to the Z-line. A PDLIM3 or PDLIM5 deficiency in mice leads to dilated cardiomyopathy. Since PDLIM3 and PDLIM5 are candidate IDCM susceptibility genes, the current study aims to investigate whether polymorphisms within PDLIM3 and PDLIM5 could be correlated with IDCM. We designed a case-control study, and exons of the PDLIM3 and PDLIM5 were amplified by polymerase chain reactions in 111 IDCM patients and 137 healthy controls. We found that five synonymous polymorphisms had statistical distribution differences between IDCM patients and controls, including rs4861669, rs4862543, c.731 + 131 T > G, c.1789-3 C > T and rs7690296, according to genotype and allele distribution. Haplotype G-C-C-C and A-T-C-T (rs2306705, rs10866276, rs12644280 and rs4635850 synthesized) were regarded as risk factors for IDCM patients when compared with carriers of other haplotypes (all P < .05). Furthermore, IDCM patients with two novel polymorphisms (c.731 + 131 T > G and c.1789-3 C > T) had lower systolic blood pressure. In conclusion, these five synonymous polymorphisms might constitute a genetic background that increases the risk of the development of IDCM in the Chinese Han population.

Blood cell transcript levels in 5-year-old children as potential markers of breastfeeding effects in those small for gestational age at birth.

BACKGROUND: Nutrition of the newborn during the early postnatal period seems to be of capital importance and there is clinical evidence showing the protective effect of breastfeeding compared with formula feeding on childhood obesity and its comorbidities. Infants born small for gestation age may be more sensitive to the type of feeding during lactation. Here, we aimed to analyze the impact of birth weight and the type of infant feeding on the expression levels in peripheral blood cells of selected candidate genes involved in energy homeostasis in 5-year-old children, to find out potential early biomarkers of metabolic programming effects during this period of metabolic plasticity. METHODS: Forty subjects were recruited at birth and divided in four groups according to birth weight (adequate or small for gestational age) and type of infant feeding (breastfeeding or formula feeding). They were followed from birth to the age of 5 years. RESULTS: At 5 years, no significant differences regarding anthropometric parameters were found between groups, and all children had normal biochemical values. Expression levels of UCP2 and MC4R in peripheral blood cells were lower and higher, respectively, in formula feeding children compared with breastfeeding ones (P = 0.002 and P = 0.064, two-way ANOVA). Differences were more marked and significant by Student's t test in small for gestation age children (P < 0.001 and P = 0.017, respectively). Transcript levels of FASN and FTO in peripheral blood cells were also different according to the type of infant feeding, but only in small for gestation age children. CONCLUSIONS: Altogether, these results suggest that small for gestation age infants are more sensitive to the type of feeding during lactation, and transcript levels of particular genes in peripheral blood cells, especially the MC4R/UCP2 mRNA ratio, may precisely reflect these effects in the absence of clear differences in phenotypic traits.

Point mutations in the tri-helix bundle of the M-domain of cardiac myosin binding protein-C influence systolic duration and delay cardiac relaxation.

Cardiac myosin binding protein-C (cMyBP-C) is an essential regulatory protein required for proper systolic contraction and diastolic relaxation. We previously showed that N'-terminal domains of cMyBP-C stimulate contraction by binding to actin and activating the thin filament in vitro. In principle, thin filament activating effects of cMyBP-C could influence contraction and relaxation rates, or augment force amplitude in vivo. cMyBP-C binding to actin could also contribute to an internal load that slows muscle shortening velocity as previously hypothesized. However, the functional significance of cMyBP-C binding to actin has not yet been established in vivo. We previously identified an actin binding site in the regulatory M-domain of cMyBP-C and described two missense mutations that either increased (L348P) or decreased (E330K) binding affinity of recombinant cMyBP-C N'-terminal domains for actin in vitro. Here we created transgenic mice with either the L348P or E330K mutations to determine the functional significance of cMyBP-C binding to actin in vivo. Results showed that enhanced binding of cMyBP-C to actin in L348P-Tg mice prolonged the time to end-systole and slowed relaxation rates. Reduced interactions between cMyBP-C and actin in E330K-Tg mice had the opposite effect and significantly shortened the duration of ejection. Neither mouse model displayed overt systolic dysfunction, but L348P-Tg mice showed diastolic dysfunction presumably resulting from delayed relaxation. We conclude that cMyBP-C binding to actin contributes to sustained thin filament activation at the end of systole and during isovolumetric relaxation. These results provide the first functional evidence that cMyBP-C interactions with actin influence cardiac function in vivo.

Associations of methylenetetrahydrofolate reductase C677T genotype with blood pressure levels in Chinese population with essential hypertension.

OBJECTIVE: To confirm the association between baseline blood pressure (BP) levels and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in patients with essential hypertension. METHODS: A total of 347 patients were enrolled from the Dongzhi community in Anhui Province, China. The C677T polymorphism of the MTHFR gene was detected using high-throughput TaqMan allelic discrimination assay. Baseline BP was measured using a standardized mercury-gravity monometer. RESULTS: In the whole sample, the frequency of the MTHFR C677T genotypes CC, CT, and TT were 38.6%, 48.1%, and 13.3%, respectively. In a recessive model (CC+CT versus TT genotypes), baseline diastolic blood pressure (DBP) was significantly higher in patients with the TT genotype compared to those with the CT or CC genotypes (P= 0.013). We also divided all patients into three groups based on the tertiles of the baseline BP distribution. Compared to subjects in the lowest tertile of DBP, the adjusted odds of having the TT genotype among subjects in the highest tertile was 2.6 (95% CI: 1.1 to 6.2). However, no significant associations were observed between baseline systolic blood pressure (SBP) and the MTHFR C677T polymorphism. CONCLUSIONS: The MTHFR gene polymorphism could be an important genetic determinant of baseline DBP levels in Chinese essential hypertensive patients.

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip.

The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structure-function relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α- to ß-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart.

Multivariate modeling of body mass index, pulse pressure, systolic and diastolic blood pressure in Chinese twins.

Systolic and diastolic blood pressure, pulse pressure (PP), and body mass index (BMI) are heritable traits in human metabolic health but their common genetic and environmental backgrounds are not well investigated. The aim of this article was to explore the phenotypic and genetic associations among PP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. The studied sample contained 615 twin pairs (17-84 years) collected in the Qingdao municipality. Univariate and multivariate structural equation models were fitted for assessing the genetic and environmental contributions. The AE model combining additive genetic (A) and unique environmental (E) factors produced the best fit for each four phenotypes. Heritability estimated in univariate analysis ranged from 0.42 to 0.74 with the highest for BMI (95% CI 0.70-0.78), and the lowest for PP (95% CI 0.34-0.49). The multivariate model estimated (1) high genetic correlations for DBP with SBP (0.87), PP with SBP (0.75); (2) low-moderate genetic correlations between PP and DBP (0.32), each BP component and BMI (0.24-0.37); (3) moderate unique environmental correlation for PP with SBP (0.68) and SBP with DBP (0.63); (4) there was no significant unique environmental correlation between PP and BMI. Overall, our multivariate analyses revealed common genetic and environmental backgrounds for PP, BP, and BMI in Chinese twins.

While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIδ-KO mice.

OBJECTIVE: CaMKII contributes to impaired contractility in heart failure by inducing SR Ca(2+)-leak. CaMKII-inhibition in the heart was suggested to be a novel therapeutic principle. Different CaMKII isoforms exist. Specifically targeting CaMKIIδ, the dominant isoform in the heart, could be of therapeutic potential without impairing other CaMKII isoforms. RATIONALE: We investigated whether cardiomyocyte function is affected by isoform-specific knockout (KO) of CaMKIIδ under basal conditions and upon stress, i.e. upon ß-adrenergic stimulation and during acidosis. RESULTS: Systolic cardiac function was largely preserved in the KO in vivo (echocardiography) corresponding to unchanged Ca(2+)-transient amplitudes and isolated myocyte contractility in vitro. CaMKII activity was dramatically reduced while phosphatase-1 inhibitor-1 was significantly increased. Surprisingly, while diastolic Ca(2+)-elimination was slower in KO most likely due to decreased phospholamban Thr-17 phosphorylation, frequency-dependent acceleration of relaxation was still present. Despite decreased SR Ca(2+)-reuptake at lower frequencies, SR Ca(2+)-content was not diminished, which might be due to reduced diastolic SR Ca(2+)-loss in the KO as a consequence of lower RyR Ser-2815 phosphorylation. Challenging KO myocytes with isoproterenol showed intact inotropic and lusitropic responses. During acidosis, SR Ca(2+)-reuptake and SR Ca(2+)-loading were significantly impaired in KO, resulting in an inability to maintain systolic Ca(2+)-transients during acidosis and impaired recovery. CONCLUSIONS: Inhibition of CaMKIIδ appears to be safe under basal physiologic conditions. Specific conditions exist (e.g. during acidosis) under which CaMKII-inhibition might not be helpful or even detrimental. These conditions will have to be more clearly defined before CaMKII inhibition is used therapeutically.

Circulating miRNA as novel markers for diastolic dysfunction.

MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. Though their significance is unclear, pioneer profiling studies have attributed specific serum miRNA signatures to different disease conditions. The diagnostic potential of miRNA detection in human plasma for cardiovascular disorders is beginning to be recognized as important. In this study, we examined miRNA profiling in isolated diastolic dysfunction (DD) with preserved systolic function to identify promising candidate miRNAs. The presence of these miRNAs was tested in stable patients with isolated DD, patients with stable compensated dilated cardiomyopathy (DCM-systolic plus diastolic dysfunction) and those with decompensated congestive heart failure secondary to dilated cardiomyopathy (DCM-CHF-systolic plus diastolic dysfunction). We identified new circulating miRNAs (miR-454, miR-500, miR-1246, miR-142-3p) which showed distinct patterns of expression in patients with diastolic dysfunction. The presence or absence of systolic dysfunction does not seem to affect this trend. MiR-454 and miR-500 are downregulated in diastolic dysfunction. MiR-1246 is upregulated in diastolic dysfunction. MiR-142-3p is downregulated in DCM and DCM-CHF groups but not in the DD group. The expression of miR-124-5p is highly upregulated in DCM but not in DD and DCM-CHF groups. We therefore propose that these circulating miRNAs may serve as novel biomarkers for diastolic dysfunction because in all of these patients the only common factor was diastolic dysfunction.

The CTGF gene -945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes.

BACKGROUND: Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes. METHODS: The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria). RESULTS: The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD. CONCLUSIONS: In Caucasians with type 2 diabetes, genetic variation in the CTGF -945 G/C polymorphism is not associated with cardiac or kidney complications.

Loss of enigma homolog protein results in dilated cardiomyopathy.

RATIONALE: The Z-line, alternatively termed the Z-band or Z-disc, is a highly ordered structure at the border between 2 sarcomeres. Enigma subfamily proteins (Enigma, Enigma homolog protein, and Cypher) of the PDZ-LIM domain protein family are Z-line proteins. Among the Enigma subfamily, Cypher has been demonstrated to play a pivotal role in the structure and function of striated muscle, whereas the role of Enigma homolog protein (ENH) in muscle remains largely unknown. OBJECTIVE: We studied the role of Enigma homolog protein in the heart using global and cardiac-specific ENH knockout mouse models. METHODS AND RESULTS: We identified new exons and splice isoforms for ENH in the mouse heart. Impaired cardiac contraction and dilated cardiomyopathy were observed in ENH null mice. Mice with cardiac specific ENH deletion developed a similar dilated cardiomyopathy. Like Cypher, ENH interacted with Calsarcin-1, another Z-line protein. Moreover, biochemical studies showed that ENH, Cypher short isoform and Calsarcin-1 are within the same protein complex at the Z-line. Cypher short isoform and Calsarcin-1 proteins are specifically downregulated in ENH null hearts. CONCLUSIONS: We have identified an ENH-CypherS-Calsarcin protein complex at the Z-line. Ablation of ENH leads to destabilization of this protein complex and dilated cardiomyopathy.

Genome-wide linkage screen for systolic blood pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and confirmation of a major susceptibility locus on chromosome 6q14.1.

OBJECTIVE: Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). METHODS: Using data from 1,089 individuals distributed across 266 families, we performed a multipoint linkage analysis to localize susceptibility loci for SBP and DBP by applying two models. In model 1, we added a sensible constant to the observed BP values in treated subjects [Tobin et al.; Stat Med 2005;24:2911-2935] to account for antihypertensive use (i.e. 15 and 10 mm Hg to SBP and DBP values, respectively). In model 2, we fixed values of 140 mm Hg for SBP and 90 mm Hg for DBP, if the treated values were less than the standard referenced treatment thresholds of 140/ 90 mm Hg for hypertensive status. However, if the observed treated BP values were found to be above these standard treatment thresholds, the actual observed treated BP values were retained in order not to reduce them by substitution of the treatment threshold values. RESULTS: The multipoint linkage analysis revealed strong linkage signals for SBP compared with DBP. The strongest evidence for linkage of SBP (model 1, LOD = 5.0; model 2, LOD = 3.6) was found on chromosome 6q14.1 near the marker D6S1031 (89 cM) in both models. In addition, some evidence for SBP linkage occurred on chromosomes 1q, 4p, and 16p. Most importantly, our major SBP linkage finding on chromosome 6q near marker D6S1031 was independently confirmed in a Caucasian population (LOD = 3.3). In summary, our study found evidence for a major locus on chromosome 6q influencing SBP levels in Mexican-Americans.

Hypertension subtypes and angiotensin converting enzyme (ACE) gene polymorphism in Indian population.

OBJECTIVE: To find out the association of angiotensin converting enzyme (ACE) gene polymorphism with hypertension subtypes in a population from India. METHODS: Consecutive subjects of either sex, aged > or =18 years attending in temporary field clinics arranged in various localities of Assam and Mizoram were interviewed to record information about socio-demographic characteristics, alcohol consumption and smoking. Three readings of blood pressure, height and weight of all subjects were measured. Hypertension and its subtypes were defined as per JNC-VI criteria. Fasting venous blood samples were collected to estimate blood glucose level and to extract genomic DNA followed by PCR analysis for ACE gene polymorphism. RESULTS: A total of 916 (male=465, female=451) consecutive subjects comprising of 407 (44.4%) hypertensive subjects and 509 (55.6%) normotensive controls were included in the study. Of the hypertensive subjects, majority (69.0%) had systolic diastolic hypertension with male predominance (70.3% vs. 67.6%) which was followed by isolated diastolic hypertension (16.7%) and isolated systolic hypertension (14.3%). The predominant ACE genotype was Ins/Ins (50.0%) and Del/Del genotype showed lowest prevalence (11.4%). After adjusting confounding variables, the Del/Del genotype revealed significant association with isolated systolic hypertension. CONCLUSION: Del/Del polymorphism of ACE gene showed significant association with ISH in our study population.

Association of IL1B polymorphism with left ventricular systolic dysfunction: a relation with the release of interleukin-1ß in stress condition.

OBJECTIVE: Proinflammatory cytokines play a major role in the pathomechanisms of heart failure. Besides this, the influence of mental stress on heart failure is poorly documented despite its effects on sympathetic stimulation of interleukin-1ß (IL-1ß) secretion. We examined whether the polymorphisms of proinflammatory cytokines are predictors of left ventricular systolic dysfunction (LVSD) and if so, whether such associations are related to the secretion of these cytokines, in 572 consecutive patients under mental stress produced by coronary angiography. METHODS: We examined IL-1RN (VNTR), IL1A-889 C>T, IL1B-511 C>T, IL6-174 G>C and TNFA-308 G>A, according to LVSD (left ventricular ejection fraction, <40%). Saliva IL-1ß, serum tumour necrosis factor-α and C-reactive protein were assayed in basal (T0 and T2, before and after coronary angiography) and stress (T1) conditions. MAIN RESULTS: The 42.1% of patients with LVSD had a 1.5-fold higher frequency of IL1B T allele (P<0.001). IL1B-511TT was associated with LVSD (P=0.008) and with a decrease in IL-1ß level in saliva at T1 (P=0.013). IL-1ß was the highest at T1 (P<0.001) and was associated with left ventricular ejection fraction (P=0.002). The IL1B TT genotype and the C-reactive protein were the two independent predictors of LVSD in multivariate analysis, with an odds ratio of 2.7 (95% confidence interval: 1.3-5.5; P=0.008) and 1.1 (95% confidence interval: 1.1-1.2; P<0.001), respectively. CONCLUSION: IL1B was a predictor of LVSD and of the decreased IL-1ß response to stress. This suggests that IL1B exerts an influence on LVSD through its effect on IL-1ß secretion.

Genetic susceptibility, elevated blood pressure, and risk of atrial fibrillation: a Mendelian randomization study.

BACKGROUND: Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual's genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. METHODS: First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. RESULTS: The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mmHg [OR] 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. CONCLUSIONS: The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.

The effects of race on peak oxygen consumption and survival in patients with systolic dysfunction.

BACKGROUND: The relationship of peak exercise oxygen consumption (VO(2)) to survival in black heart failure (HF) patients is not well established. We examined the effects of race on peak VO(2) values and survival in HF patients with systolic dysfunction. METHODS AND RESULTS: This study evaluated consecutive ambulatory HF patients who underwent symptom-limited stress tests with breath-by-breath expired gas analyses using ramped treadmill protocols. The relationship between cardiopulmonary exercise parameters and patient transplant-free survival was assessed by race. This study included 580 HF patients (mean age 52 +/- 12 years; 28% females; 22% blacks; mean left ventricular ejection fraction 26 +/- 12%; mean body mass index 28.7 +/- 5.4; 73% on beta-blocker). Black patients had a significantly lower peak VO(2) than white patients (14.2 +/- 5.2 versus 16.4 +/- 7.0; P < .0001), despite adjusting for identified covariates. However, there was no significant difference in the 1-year transplant-free survival between black and white HF patients (87% versus 85%; P = NS). Peak VO(2) was significantly associated with survival in both racial groups. CONCLUSIONS: Black HF patients had significantly lower peak VO(2), but yet had equivalent survival rates at 1 year. Further study is warranted to clarify the impact of these racial differences on the timing of cardiac transplantation black HF patients.

Lionheart LincRNA alleviates cardiac systolic dysfunction under pressure overload.

Recent high-throughput approaches have revealed a vast number of transcripts with unknown functions. Many of these transcripts are long noncoding RNAs (lncRNAs), and intergenic region-derived lncRNAs are classified as long intergenic noncoding RNAs (lincRNAs). Although Myosin heavy chain 6 (Myh6) encoding primary contractile protein is down-regulated in stressed hearts, the underlying mechanisms are not fully clarified especially in terms of lincRNAs. Here, we screen upregulated lincRNAs in pressure overloaded hearts and identify a muscle-abundant lincRNA termed Lionheart. Compared with controls, deletion of the Lionheart in mice leads to decreased systolic function and a reduction in MYH6 protein levels following pressure overload. We reveal decreased MYH6 results from an interaction between Lionheart and Purine-rich element-binding protein A after pressure overload. Furthermore, human LIONHEART levels in left ventricular biopsy specimens positively correlate with cardiac systolic function. Our results demonstrate Lionheart plays a pivotal role in cardiac remodeling via regulation of MYH6.

Indoleamine 2,3-dioxygenase and ischemic heart disease: a Mendelian Randomization study.

Tryptophan is an essential amino acid. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the tryptophan-kynurenine pathway, is positively associated with cardiac events, and may be relevant to cancer. We used Mendelian Randomization to obtain unconfounded estimates of the association of IDO1 with ischemic heart disease (IHD), ischemic stroke and their risk factors, all-cancer, cancer of the prostate, lung and bronchus, and breast. We obtained genetic instruments independently and strongly (p-value < 5 × 10-8) predicting plasma IDO1 from a proteome genome-wide association study (GWAS), and applied them to consortia GWAS of the outcomes, including the UK Biobank SOFT CAD GWAS (cases < = 76 014, non-cases < = 264 785) for IHD. Estimates were obtained using inverse variance weighting; with MR-Egger, weighted median and MR-PRESSO as sensitivity analyses. IDO1 was inversely associated with IHD (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (CI) 0.93 to 1.00, p-value = 0.04), diabetes (OR 0.91, 95% CI 0.85 to 0.97) and prostate cancer (OR 0.96, 95% CI 0.93 to 0.99) with a directionally consistent estimate for stroke (OR 0.98, 95% CI 0.95 to 1.02) but not with blood pressure, or the other cancers considered. IDO1 might be a potential therapeutic target for IHD, diabetes and prostate cancer.