Carotid Intima-Media Thickness

ObjectiveCarotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis.Approach and resultsWe performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P-8. Seven novel loci (ZNF385D, ADAMTS9, EDNRA, HAND2, MYOCD, ITCH/EDEM2/MMP24, and MRTFA) were identified in all 3 phenotypes. An additional new locus (LOXL1) was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus (SYNE3) in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci (APOB, FIP1L1, and LOXL4). Transcriptome-wide association analyses implicated additional genes ARHGAP42, NDRG4, and KANK2. Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease rg=0.21 (P=1.4×10-7), peripheral artery disease rg=0.45 (P=5.3×10-5), and systolic blood pressure rg=0.30 (P=4.0×10-18). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found rg=-0.12 (P=7.0×10-4).ConclusionsGenome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.

ObjectiveAtherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM software to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease.ConclusionsThese findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

We examined the longitudinal associations of fat mass, lean mass, and blood pressure (BP) from childhood through young adulthood with changes in carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT). We included 3863 participants from the Avon Longitudinal Study of Parents and Children birth cohort. Fat mass and lean mass, measured by dual-energy X-ray absorptiometry, and BP were measured at ages 9, 17 and 24 years and classified into low, moderate, and high tertiles. cfPWV and cIMT were measured at 17 and 24 years of age. Associations were examined via linear mixed effect models and adjusted for cardiometabolic and lifestyle factors. Among 1720 [44.5%] male and 2143 [55.5%] female participants, cumulative high exposures to lean mass (effect estimate 0.006 m/s [95% CI 0.001 to 0.010; p = 0.022]), systolic BP (0.013 m/s [0.009 to 0.017; p < 0.0001]) and diastolic BP (0.023 m/s [0.019 to 0.027; p < 0.0001]) from 9-24 years of age were positively associated with the 7-year increase in cfPWV. Persistent high exposures to lean mass (0.012 mm; [0.008 to 0.016; p < 0.0001]), body mass index (0.007 mm [0.003 to 0.011; p = 0.001]), and systolic BP (0.010 mm; [0.006 to 0.014; p < 0.0001]) from ages 9-24 years were positively associated with thicker cIMT at 17-24 years of age. Total fat and trunk fat mass from childhood had no association with cfPWV or cIMT progression. In conclusion, increased lean mass and BP but not fat mass from childhood drives arterial remodeling in young adulthood.

BACKGROUND: Iron overload promotes atherosclerosis in mice and causes vascular dysfunction in humans with Hemochromatosis. However, data are controversial on whether systemic iron availability within physiological limits affects the pathogenesis of atherosclerosis. We, therefore, performed an individual participant data (IPD) meta-analysis and studied the association between serum iron biomarkers with common carotid intima-media thickness (CC-IMT); in addition, since sex influences iron metabolism and vascular diseases, we studied if there are sex-specific differences. METHODS: We pooled the IPD and analysed the data on adults (age≥18y) by orthogonal approaches: machine learning (ML) and a single-stage meta-analysis. For ML, we tuned a gradient-boosted tree regression model (XGBoost) and subsequently, we interpreted the features using variable importance. For the single-stage metaanalysis, we examined the association between iron biomarkers and CC-IMT using spline-based linear mixed models, accounting for sex interactions and study-specific effects. To confirm robustness, we repeated analyses on imputed data using multivariable regression adjusted for key covariates identified through machine learning. Further, subgroup analyses were performed in children and adolescents (age 233 ng/mL: β = 0.04, 95% CI (0.002, 0.08), p = 0.037], while transferrin showed negative associations at specific ranges [ Transferrrin 231–263 mg/dL: β=-0.21, 95% CI (-0.43, 0.003), p = 0.054; Transferrrin > 263 mg/dL: β=-0.73, 95% CI (-1.48, 0.01), p = 0.05]; No significant associations were found between CC-IMT in those with HFE genotypes in either sex in the UK Biobank. CONCLUSION: Our observational data show that iron biomarkers - ferritin and transferrin are non-linearly associated with CC-IMT specifically in females, while a significant causal association between the HFE genotype and CC-IMT could not be demonstrated in the UK Biobank data. We conclude that our observational findings may reflect residual confounding, reverse causation, or other non-causal mechanisms rather than a direct causal relationship. OTHER: No financial support was received for this meta-analysis. The protocol for this study is registered in the PROSPERO database ( CRD42020155429; https://www.crd.york.ac.uk/ ).