Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk. We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

Rapid over-activation of β-adrenergic receptor (β-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute β-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon β-AR insult. Male C57BL/6 mice were injected with a single dose of β-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon β-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1β, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced β₁-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis. Inflammasome-dependent activation of IL-18 within the myocardium upon acute β-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of β-AR insult can successfully prevent inflammatory responses and cardiac injuries.

Aims: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. Methods and results: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43–3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20–80%) PRS. Conclusion: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.

A meta-analysis of exome-wide association studies for blood lipid levels in East Asian populations identifies a novel coding variant. Exome array data from the Global Lipids Genetics Consortium were integrated and led to the discovery of novel and population-specific variants associated with cholesterol and triglycerides. Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian–specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

The aim of this study was to investigate the effects of telemonitored exercise rehabilitation on patients with coronary heart disease (CHD) in China. Ninety-six patients with stable CHD were included and analyzed (48 in telemonitored group and 48 in control group). All patients received routine follow-up, and patients in telemonitored group participated in smartphone-based telemonitored cardiac rehabilitation. Patients’ demographic information, medical history, diagnosis and treatment of CHD, and laboratory results were collected. The difference of cardiopulmonary exercise testing (CPET), blood test, and echocardiographic parameters; exercise habits; control rate of blood lipid and blood glucose; and incidence of adverse events between the two groups during 6 months of follow-up was analyzed. After intervention, the subjects in the telemonitored group performed significantly better in VO_2peak, exercise compliance, and some other parameters than those in the control group. Telemonitored exercise rehabilitation is an effective rehabilitation mode for CHD patients in China.

Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10⁻⁷), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci—PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser—also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.