The Polygenic Score - Rare Variant Causal Pivot: A Conditional Approach to Discovery in Complex Disease Genetics DOI Open Access
Chad A. Shaw,

Christopher Williams,

Tan Tao

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

Abstract We present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages one established factor to detect contribution of second suspected cause. Specifically, polygenic risk scores (PRS) serve known causes, while rare variants (RV) or RV ensembles are evaluated candidate causes. incorporates outcome-induced association by conditioning on disease status. derive conditional maximum likelihood procedure binary and quantitative traits develop Likelihood Ratio Test (CP-LRT) signals. Through simulations, we demonstrate CP-LRT’s robust power superior error control compared alternatives. apply CP-LRT UK Biobank (UKB) data, three exemplar diseases: hypercholesterolemia (HC, LDL-c ≥ 4.9 mmol/L; n c =24,656), breast cancer (BC, ICD10 C50; =12,479), Parkinson’s (PD, G20; =2,940). For PRS, utilize UKB-derived values, RVs, analyze ClinVar pathogenic/likely pathogenic loss-of-function mutations disease-relevant genes: LDLR HC, BRCA1 BC, GBA PD. Significant signals were detected all Cross-disease synonymous variant analyses controls. further ancestry adjustment using matching inverse probability weighting, extend examine oligogenic burden lysosomal storage pathway reveals an approach address is extensible method inference discovery genetics.

Language: Английский

Striving Towards Equity in Cardiovascular Genomics Research DOI Creative Commons

Javier Jurado Vélez,

Nekayla Anderson,

Ivree Datcher

et al.

Current Atherosclerosis Reports, Journal Year: 2025, Volume and Issue: 27(1)

Published: Feb. 18, 2025

Language: Английский

Citations

0
Triglyceride/high density lipoprotein cholesterol index and future cardiovascular events in diabetic patients without known cardiovascular disease DOI Creative Commons
Ryosuke Nakashima, Shota Ikeda, Keisuke Shinohara

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 17, 2025

The triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) index, calculated as TG divided by HDL-C, has been suggested a predictor of cardiovascular disease (CVD). We investigated the association between TG/HDL-C index and CVD events in type 2 diabetes mellitus (T2DM) patients with retinopathy hyperlipidemia but no known CVD, enrolled EMPATHY study, which compared intensive standard statin therapy (targeting LDL-C levels < 70 mg/dL ≥ 100 to 120 mg/dL, respectively). A total 4665 were into high (TG/HDL-C 2.5, n = 2013) low 2652) groups. During median follow-up 36.8 months, 260 occurred. group had higher risk than (HR 1.89, 95% CI 1.45–2.47, p 0.001). This remained consistent across subgroups. trend toward interaction treatment allocation for was observed (p 0.062). Intensive reduced not group. In conclusion, 2.5 associated T2DM without history CVD. may identify who benefit from treatment.

Language: Английский

Citations

0
Beyond Cholesterol: Emerging Risk Factors in Atherosclerosis DOI Open Access
Makhabbat Bekbossynova, Timur Saliev, T Ivanova-Razumova

et al.

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(7), P. 2352 - 2352

Published: March 29, 2025

Atherosclerosis remains a leading cause of cardiovascular morbidity and mortality worldwide, traditionally linked to elevated cholesterol levels, particularly low-density lipoprotein (LDL-C). However, despite aggressive lipid-lowering strategies, residual risk persists, underscoring the need explore additional contributing factors. This review examines emerging factors beyond cholesterol, including chronic inflammation, gut microbiota composition, oxidative stress, environmental exposures. Inflammation plays pivotal role in atherogenesis, with markers such as C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) serving indicators disease activity. The microbiome, metabolites like trimethylamine N-oxide (TMAO), has been implicated vascular inflammation plaque development, while beneficial short-chain fatty acids (SCFAs) demonstrate protective effects. Oxidative stress further exacerbates endothelial dysfunction instability, driven by reactive oxygen species (ROS) lipid peroxidation. Additionally, factors, air pollution, heavy metal exposure, endocrine disruptors, psychological have emerged significant contributors disease. Understanding these novel offers broader perspective on atherosclerosis pathogenesis provides new avenues for targeted prevention therapeutic interventions.

Language: Английский

Citations

0
Lipoprotein cholesterol ratios and cardiovascular disease risk in US adults: a cross-sectional study DOI Creative Commons

Xiu‐Ming Yang,

Qiuyun Chen, Qing‐Yu Zhang

et al.

Frontiers in Nutrition, Journal Year: 2025, Volume and Issue: 12

Published: April 17, 2025

The ratio of non-high-density lipoprotein cholesterol to high-density (NHHR) has been introduced as a novel indicator evaluate lipid metabolism. study explored the association between NHHR and cardiovascular disease (CVD). A cross-sectional was achieved by utilizing data obtained from NHANES (2003-2016). CVD assessed multivariate logistic regression analysis (LRA) restricted cubic spline (RCS) analysis. Also, interaction tests subgroup analyses were employed explore whether associations differ subgroups. Then, threshold conducted for interval delineation detection effects with two-segment piecewise LR model. cohort 11,471 individuals involved. results indicated that linear relationship not significant (P trend >0.05). RCS revealed non-linear J-shaped risk. model established assess effect NHHR. log-likelihood test < 0.001) suggested exhibited better performances compared single-line Additionally, tangent point occurred at 2.82, likelihood increased 21% one unit (OR = 1.21, 95% CI 1.10-1.34). detected prevalence CVD, suggesting could serve assessment marker identifying high-risk populations. However, further studies are needed confirm this finding.

Language: Английский

Citations

0
Cardiovascular disease risk factors are associated with conventional lipids and apolipoproteins in South African adults of African ancestry DOI Creative Commons
AA Vorster, Ruan Kruger, Catharina M. C. Mels

et al.

Lipids in Health and Disease, Journal Year: 2025, Volume and Issue: 24(1)

Published: May 15, 2025

Although conventional lipids (high density lipoprotein cholesterol (HDLC), low (LDLC), total (TC) and triglycerides (TG)) are therapeutic targets to manage prevent atherosclerotic cardiovascular disease (CVD), apolipoprotein (Apo) levels have sparked interest for their potential improve CVD risk prediction. This study explored the relationships of traditional factors with lipids, as well ApoA1, ApoB its ratio (ApoB: ApoA1) in South African adults ancestry. included 1697 (aged 29 94) from Prospective Urban Rural Epidemiology (PURE) study. The markers body mass index (BMI), physical activity index, tobacco use, dietary fat intake, γ-glutamyl transferase (γGT) glycated haemoglobin (HbA1C). Conventional were measured serum samples using standard methodology, while ApoA1 a multiplex magnetic bead immunoassay. Stratified into tertiles lipid Apo levels, trends emerged across multiple markers, including BMI, γGT HbA1C levels. Higher LDLC, TC, TG, ApoB: along lowest HDLC exhibited higher prevalence Type II diabetes mellitus (all p ≤ 0.024) overweight or obesity except 0.024). was negatively associated TG positively BMI < 0.001) 0.005). Similarly, (β=-0.067 (-0.125; -0.010), = 0.022) (β=-0.071 (-0.122; -0.020), 0.007), (β 0.168 (0.117; 0.218), 0.001). showed positive associations 0.213 (0.163; 0.263), 0.123 (0.074; 0.172), In ancestry, various established suggests that these apolipoproteins may provide additional mechanistic insights beyond understand aetiology early cardiometabolic development.

Language: Английский

Citations

0
The Polygenic Score - Rare Variant Causal Pivot: A Conditional Approach to Discovery in Complex Disease Genetics DOI Open Access
Chad A. Shaw,

Christopher Williams,

Tan Tao

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

Abstract We present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages one established factor to detect contribution of second suspected cause. Specifically, polygenic risk scores (PRS) serve known causes, while rare variants (RV) or RV ensembles are evaluated candidate causes. incorporates outcome-induced association by conditioning on disease status. derive conditional maximum likelihood procedure binary and quantitative traits develop Likelihood Ratio Test (CP-LRT) signals. Through simulations, we demonstrate CP-LRT’s robust power superior error control compared alternatives. apply CP-LRT UK Biobank (UKB) data, three exemplar diseases: hypercholesterolemia (HC, LDL-c ≥ 4.9 mmol/L; n c =24,656), breast cancer (BC, ICD10 C50; =12,479), Parkinson’s (PD, G20; =2,940). For PRS, utilize UKB-derived values, RVs, analyze ClinVar pathogenic/likely pathogenic loss-of-function mutations disease-relevant genes: LDLR HC, BRCA1 BC, GBA PD. Significant signals were detected all Cross-disease synonymous variant analyses controls. further ancestry adjustment using matching inverse probability weighting, extend examine oligogenic burden lysosomal storage pathway reveals an approach address is extensible method inference discovery genetics.

Language: Английский

Citations

0