Association between genetic predisposition and disease burden of stroke in China: a genetic epidemiological study.

Background: Stroke ranks second worldwide and first in China as a leading cause of death and disability. It has a polygenic architecture and is influenced by environmental and lifestyle factors. However, it remains unknown as to whether and how much the genetic predisposition of stroke is associated with disease burden. Methods: Allele frequency from the whole genome sequencing data in the Chinese Millionome Database of 141,418 individuals and trait-specific polygenic risk score models were applied to estimate the provincial genetic predisposition to stroke, stroke-related risk factors and stroke-related drug response. Disease burden including mortality, disability-adjusted life years (DALYs), years of life lost(YLLs), years lived with disability (YLDs) and prevalence in China was collected from the Global Burden Disease study. The association between stroke genetic predisposition and the epidemiological burden was assessed and then quantified in both regression-based models and machine learning-based models at a provincial resolution. Findings: Among the 30 administrative divisions in China, the genetic predisposition of stroke was characterized by a north-higher-than-south gradient (p < 0.0001). Genetic predisposition to stroke, blood pressure, body mass index, and alcohol use were strongly intercorrelated (rho >0.6; p < 0.05 after Bonferroni correction for each comparison). Genetic risk imposed an independent effect of approximately 1-6% on mortality, DALYs and YLLs. Interpretation: The distribution pattern of stroke genetic predisposition is different at a macroscopic level, and it subtly but significantly impacts the epidemiological burden. Further research is warranted to identify the detailed aetiology and potential translation into public health measures. Funding: Beijing Municipal Science and Technology Commission (Z191100006619106), CAMS Innovation Fund for Medical Sciences (CAMS-I2M, 2023-I2M-1-001), the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17), National Natural Science Foundation of China (32000398, 32171441 to X.J.), Natural Science Foundation of Guangdong Province, China (2017A030306026 to X.J.), and National Key R&D Program of China (2022YFC2502402).

The effect of dietary carbohydrate and calorie restriction on weight and metabolic health in overweight/obese individuals: a multi-center randomized controlled trial.

BACKGROUND: Both low-carbohydrate (LC) and calorie-restricted (CR) diets have been shown to have metabolic benefits. However, the two regimens have yet to be thoroughly compared. We conducted a 12-week randomized trial to compare the effects of these diets separately and in combination on both weight loss and metabolic risk factors in overweight/obese individuals. METHODS: A total of 302 participants were randomized to LC diet (n = 76), CR diet (n = 75), LC + CR diet (n = 76), or normal control (NC) diet (n = 75) using a computer-based random number generator. The primary outcome was the change in body mass index (BMI). The secondary outcomes included body weight, waist circumference, waist-to-hip ratio, body fat, and metabolic risk factors. All participants attended health education sessions during the trial. RESULTS: A total of 298 participants were analyzed. BMI change over 12 weeks was - 0.6 (95% CI, - 0.8 to - 0.3) kg/m2 in NC, - 1.3 (95% CI, - 1.5 to - 1.1) kg/m2 in CR, - 2.3 (95% CI, - 2.6 to - 2.1) kg/m2 in LC, and - 2.9 (95% CI, - 3.2 to - 2.6) kg/m2 in LC + CR. LC + CR diet was more effective than LC or CR diet alone at reducing BMI (P = 0.001 and P < 0.001, respectively). Furthermore, compared with the CR diet, the LC + CR diet and LC diet further reduced body weight, waist circumference, and body fat. Serum triglycerides were significantly reduced in the LC + CR diet group compared with the LC or CR diet alone. Plasma glucose, homeostasis model assessment of insulin resistance, and cholesterol concentrations (total, LDL, and HDL) did not change significantly between the groups during the 12-week intervention. CONCLUSIONS: The reduction of carbohydrate intake without restricting caloric intake is more potent to achieve weight loss over 12 weeks when compared to a calorie-restricted diet in overweight/obese adults. The combination of restricting carbohydrate and total calorie intake may augment the beneficial effects of reducing BMI, body weight, and metabolic risk factors among overweight/obese individuals. TRIAL REGISTRATION: The study was approved by the institutional review board of Zhujiang Hospital of Southern Medical University and registered at the China Clinical Trial Registration Center (registration number: ChiCTR1800015156).

A graph neural network-based interpretable framework reveals a novel DNA fragility-associated chromatin structural unit.

BACKGROUND: DNA double-strand breaks (DSBs) are among the most deleterious DNA lesions, and they can cause cancer if improperly repaired. Recent chromosome conformation capture techniques, such as Hi-C, have enabled the identification of relationships between the 3D chromatin structure and DSBs, but little is known about how to explain these relationships, especially from global contact maps, or their contributions to DSB formation. RESULTS: Here, we propose a framework that integrates graph neural network (GNN) to unravel the relationship between 3D chromatin structure and DSBs using an advanced interpretable technique GNNExplainer. We identify a new chromatin structural unit named the DNA fragility-associated chromatin interaction network (FaCIN). FaCIN is a bottleneck-like structure, and it helps to reveal a universal form of how the fragility of a piece of DNA might be affected by the whole genome through chromatin interactions. Moreover, we demonstrate that neck interactions in FaCIN can serve as chromatin structural determinants of DSB formation. CONCLUSIONS: Our study provides a more systematic and refined view enabling a better understanding of the mechanisms of DSB formation under the context of the 3D genome.

Truncating Variants in OBSCN Gene Associated With Disease-Onset and Outcomes of Hypertrophic Cardiomyopathy.

BACKGROUND: The presence of variants in OBSCN was identified to be linked to hypertrophic cardiomyopathy (HCM), but whether OBSCN truncating variants were associated with HCM remained unknown. METHODS: Whole-exome sequencing was performed in 986 patients with HCM and 761 non-HCM controls to search for OBSCN truncating variants, and the result was tested in a replication cohort consisting of 529 patients with HCM and 307 controls. The association of the OBSCN truncating variants with baseline characteristics and prognosis of patients with HCM were ascertained. RESULTS: There were 28 qualifying truncating variants in the OBSCN gene detected in 26 (2.6%) patients with HCM and 6 (0.8%) controls. The OBSCN truncating variants were more prevalent in patients with HCM than controls (odds ratio, 3.4, P=0.004). This association was confirmed in the replication cohort (odds ratio, 3.8, P=0.024). The combined effects of the two cohorts estimated the odds ratio to be 3.58 (P<0.001). Patients with or without OBSCN truncating variants shared similar demographic and echocardiographic variables at baseline. During 3.3±2.4 years (4795 patient-years) follow-up, the patients with OBSCN truncating variants were more likely to experience cardiovascular death (adjusted hazard ratio, 3.1 [95% CI, 1.40-6.70], P=0.005) and all-cause death (adjusted hazard ratio, 2.63 [95% CI, 1.21-5.71], P=0.015). CONCLUSIONS: Our data indicated that OBSCN truncating variants contributed to the disease-onset of HCM, and increased the risk of malignant events in patients with HCM.