A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study.

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.

Integrated transcriptome and hormonal analysis of naphthalene acetic acid-induced adventitious root formation of tea cuttings (Camellia sinensis).

BACKGROUND: Tea plant breeding or cultivation mainly involves propagation via cuttings, which not only ensures the inheritance of the excellent characteristics of the mother plant but also facilitates mechanized management. The formation of adventitious root (AR) determines the success of cutting-based propagation, and auxin is an essential factor involved in this process. To understand the molecular mechanism underlying AR formation in nodal tea cuttings, transcriptome and endogenous hormone analysis was performed on the stem bases of red (mature)- and green (immature)-stem cuttings of 'Echa 1 hao' tea plant as affected by a pulse treatment with naphthalene acetic acid (NAA). RESULTS: In this study, NAA significantly promoted AR formation in both red- and green-stem cuttings but slightly reduced callus formation. External application of NAA reduced the levels of endogenous indole-3-acetic acid (IAA) and cytokinin (TZR, trans-zeatin riboside). The number of DEGs (NAA vs. CK) identified in the green-stem cuttings was significantly higher than that in the red-stem cuttings, which corresponded to a higher rooting rate of green-stem cuttings under the NAA treatment. A total of 82 common DEGs were identified as being hormone-related and involved in the auxin, cytokinin, abscisic acid, ethylene, salicylic acid, brassinosteroid, and jasmonic acid pathways. The negative regulation of NAA-induced IAA and GH3 genes may explain the decrease of endogenous IAA. NAA reduced endogenous cytokinin levels and further downregulated the expression of cytokinin signalling-related genes. By the use of weighted gene co-expression network analysis (WGCNA), several hub genes, including three [cellulose synthase (CSLD2), SHAVEN3-like 1 (SVL1), SMALL AUXIN UP RNA (SAUR21)] that are highly related to root development in other crops, were identified that might play important roles in AR formation in tea cuttings. CONCLUSIONS: NAA promotes the formation of AR of tea cuttings in coordination with endogenous hormones. The most important endogenous AR inductor, IAA, was reduced in response to NAA. DEGs potentially involved in NAA-mediated AR formation of tea plant stem cuttings were identified via comparative transcriptome analysis. Several hub genes, such as CSLD2, SVL1 and SAUR21, were identified that might play important roles in AR formation in tea cuttings.

Integrating polygenic and clinical risks to improve stroke risk stratification in prospective Chinese cohorts.

The utility of the polygenic risk score (PRS) to identify individuals at higher risk of stroke beyond clinical risk remains unclear, and we clarified this using Chinese population-based prospective cohorts. Cox proportional hazards models were used to estimate the 10-year risk, and Fine and Gray's models were used for hazard ratios (HRs), their 95% confidence intervals (CIs), and the lifetime risk according to PRS and clinical risk categories. A total of 41,006 individuals aged 30-75 years with a mean follow-up of 9.0 years were included. Comparing the top versus bottom 5% of the PRS, the HR was 3.01 (95%CI 2.03-4.45) in the total population, and similar findings were observed within clinical risk strata. Marked gradients in the 10-year and lifetime risk across PRS categories were also found within clinical risk categories. Notably, among individuals with intermediate clinical risk, the 10-year risk for those in the top 5% of the PRS (7.3%, 95%CI 7.1%-7.5%) reached the threshold of high clinical risk (⩾7.0%) for initiating preventive treatment, and this effect of the PRS on refining risk stratification was evident for ischemic stroke. Even among those in the top 10% and 20% of the PRS, the 10-year risk would also exceed this level when aged ⩾50 and ⩾60 years, respectively. Overall, the combination of the PRS with the clinical risk score improved the risk stratification within clinical risk strata and distinguished actual high-risk individuals with intermediate clinical risk.

Prevalence of familial hypercholesterolemia and its association with coronary artery disease: A Chinese cohort study.

Background: Familial hypercholesterolemia (FH) is underrecognized, and its association with coronary artery disease (CAD) remains limited, especially in China. We aimed to investigate the prevalence of FH and its relationship with CAD in a large Chinese cohort. Methods: FH was defined using the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria. The crude and age-sex standardized prevalence of FH were calculated based on surveys of the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project during 2007-2008. The associations of FH with incident CAD and its major subtypes were estimated with the cohort-stratified multivariate Cox proportional hazard models based on the data from the baseline to the last follow-up (2018-2020). Results: Among 98,885 included participants, 190 participants were defined as FH. Crude and age-sex standardized prevalence and 95% confidence interval (CI) of FH were 0.19% (0.17%-0.22%) and 0.13% (0.10%-0.16%), respectively. The prevalence varied across age groups and peaked in the group of 60-<70 years (0.28%), and the peak prevalence (0.18%) in males was earlier, yet lower than the peak crude prevalence in females (0.41%). During a mean follow-up of 10.7 years, 2493 cases of incident CAD were identified. After multivariate adjustment, FH patients had a 2.03-fold greater risk of developing CAD compared to non-FH participants. Conclusions: The prevalence of FH was estimated to be 0.19% in the participants, and it was associated with an elevated risk of incident CAD. Our study suggests that early screening of FH has certain public health significance for the prevention of CAD.

Impact of cardiovascular health and genetic risk on coronary artery disease in Chinese adults.

OBJECTIVE: To examine whether adherence to ideal cardiovascular health (CVH) can mitigate the genetic risk of coronary artery disease (CAD) in non-European populations. METHODS: Fine and Grey's models were used to calculate HRs and their corresponding 95% CIs, as well as the lifetime risk of CVH metrics across Polygenic Risk Score (PRS) categories. RESULTS: We included 39 755 individuals aged 30-75 years in Chinese prospective cohorts. 1275 CAD cases were recorded over a mean follow-up of 12.9 years. Compared with unfavourable CVH profile (zero to three ideal CVH metrics), favourable CVH profile (six to seven ideal CVH metrics) demonstrated similar relative effects across PRS categories, with the HRs of 0.40 (95% CI 0.24 to 0.67), 0.41 (95% CI 0.32 to 0.52) and 0.36 (95% CI 0.26 to 0.52) in low (bottom quintile of PRS), intermediate (two to four quintiles of PRS) and high (top quintile of PRS) PRS categories, respectively. For the absolute risk reduction (ARR), individuals with high PRS achieved the greatest benefit from favourable CVH, mitigating the risk to the average level of population (from 21.1% to 8.7%), and the gradient was strengthened in individuals at the top 5% of PRS. Moreover, compared with individuals at low PRS, those at high PRS obtained longer CAD-free years (2.6 vs 1.1) from favourable CVH at the index age of 35 years. CONCLUSION: Favourable CVH profile reduced the CAD relative risk by similar magnitude across PRS categories, while the ARR from favourable CVH was most pronounced in high PRS category. Attaining favourable CVH should be encouraged for all individuals, especially in individuals with high genetic susceptibility.

Floral transcriptome sequencing for SSR marker development and linkage map construction in the tea plant (Camellia sinensis).

Despite the worldwide consumption and high economic importance of tea, the plant (Camellia sinensis) is not well studied in molecular biology. Under the few circumstances in which the plant is studied, C. sinensis flowers, which are important for reproduction and cross-breeding, receive less emphasis than investigation of its leaves or roots. Using high-throughput Illumina RNA sequencing, we analyzed a C. sinensis floral transcriptome, and 26.9 million clean reads were assembled into 75,531 unigenes averaging 402 bp. Among them, 50,792 (67.2%) unigenes were annotated with a BLAST search against the NCBI Non-Redundant (NR) database and 10,290 (16.67%) were detected that contained one or more simple sequence repeats (SSRs). From these SSR-containing sequences, 2,439 candidate SSR markers were developed and 720 were experimentally tested, validating 431 (59.9%) novel polymorphic SSR markers for C. sinensis. Then, a consensus SSR-based linkage map was constructed that covered 1,156.9 cM with 237 SSR markers distributed in 15 linkage groups. Both transcriptome information and the genetic map of C. sinensis presented here offer a valuable foundation for molecular biology investigations such as functional gene isolation, quantitative trait loci mapping, and marker-assisted selection breeding in this important species.