Abstract:Objective:
Atherosclerosis 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 effor… Show more
“…Our study replicated (see criteria in Methods section) the locus for association with cIMT in the CBFA2T3 region with a SNP that is 18979 bp from and associated SNP reported in Europeans: rs9934287 (p = 6.6E-06) was suggestively associated in our study in the CBFA2T3 region. The rs844396 (p = 6.00E-09) that was previously reported by Franceschini and colleagues in a European ancestry population (Franceschini et al, 2018) and later replicated by a UK Biobank analysis of cIMT (Strawbridge et al, 2020), did not replicate in our study (p = 0.85). The rs9934287 SNP (MAF=0.047 in our study) is monomorphic in populations of European ancestry from the 1000 Genomes Project.…”
Atherosclerosis precedes the onset of many clinical manifestations of cardiovascular diseases (CVDs). We used carotid intima-media thickness (cIMT) to investigate genetic susceptibility to atherosclerosis in 7894 unrelated adults (3963 women, 3931 men) aged 40 to 60 years resident in four sub-Saharan African countries. cIMT was measured by ultrasound and genotyping was performed on the H3Africa SNP Array. Two new African-specific genome-wide significant loci, SIRPA (p=4.7E-08), and FBXL17 (p=2.5E-08), were identified in the combined dataset. Sex-stratified analysis revealed associations with two male-specific loci, SNX29 (p=6.3E-09) and MAP3K7 (p=5.3E-08), and two female-specific loci, LARP6 (p=2.4E-09) and PROK1 (p=1.0E-08). Regional associations were replicated with known risk loci for atherosclerosis and CVDs with different lead SNPs than in Europeans and significant enrichment for oestrogen response genes for female-specific signals were identified. The genes identified showed biological relevance to atherosclerosis and/or CVDs, as well as sex-differences and transferability of signals from non-African studies.
“…Our study replicated (see criteria in Methods section) the locus for association with cIMT in the CBFA2T3 region with a SNP that is 18979 bp from and associated SNP reported in Europeans: rs9934287 (p = 6.6E-06) was suggestively associated in our study in the CBFA2T3 region. The rs844396 (p = 6.00E-09) that was previously reported by Franceschini and colleagues in a European ancestry population (Franceschini et al, 2018) and later replicated by a UK Biobank analysis of cIMT (Strawbridge et al, 2020), did not replicate in our study (p = 0.85). The rs9934287 SNP (MAF=0.047 in our study) is monomorphic in populations of European ancestry from the 1000 Genomes Project.…”
Atherosclerosis precedes the onset of many clinical manifestations of cardiovascular diseases (CVDs). We used carotid intima-media thickness (cIMT) to investigate genetic susceptibility to atherosclerosis in 7894 unrelated adults (3963 women, 3931 men) aged 40 to 60 years resident in four sub-Saharan African countries. cIMT was measured by ultrasound and genotyping was performed on the H3Africa SNP Array. Two new African-specific genome-wide significant loci, SIRPA (p=4.7E-08), and FBXL17 (p=2.5E-08), were identified in the combined dataset. Sex-stratified analysis revealed associations with two male-specific loci, SNX29 (p=6.3E-09) and MAP3K7 (p=5.3E-08), and two female-specific loci, LARP6 (p=2.4E-09) and PROK1 (p=1.0E-08). Regional associations were replicated with known risk loci for atherosclerosis and CVDs with different lead SNPs than in Europeans and significant enrichment for oestrogen response genes for female-specific signals were identified. The genes identified showed biological relevance to atherosclerosis and/or CVDs, as well as sex-differences and transferability of signals from non-African studies.
“…This cohort comprised 122,733 cases and 424,528 controls. Data for the association of SNPs with subclinical atherosclerosis were drawn from the latest and single largest study with consistent cIMT measures in 22,179 UK Biobank participants [ 34 ]. Fig.…”
Background and aims: Observational studies have reported an association between periodontitis and cardiovascular disease but whether this association is causal is uncertain. We therefore used Mendelian randomization to test whether periodontitis is causally associated with stroke, coronary artery disease, or subclinical atherosclerosis. Methods: A two-sample Mendelian randomization analysis was carried out using five single nucleotide polymorphisms previously associated with periodontitis in genome-wide association studies. Summary data were drawn from MEGASTROKE and combined with de novo analyses of UK Biobank for stroke and its major subtypes (up to 44,221 cases, 739,957 controls) and CARDIoGRAMplusC4D and UK Biobank for coronary artery disease (122,733 cases, 424,528 controls). We used existing data on carotid intima-media thickness in UK Biobank as a marker of subclinical atherosclerosis (N = 22,179). Causal estimates were obtained using inverse-variance weighted Mendelian randomization. Sensitivity analyses were performed using weighted median and MR-Egger approaches. Results: No association was found between periodontitis and any stroke (odds ratio [OR] per doubling in the odds of periodontitis 0.99, 95% confidence interval [CI] 0.97 to 1.02), ischaemic stroke (OR 1.00, 95% CI 0.97 to 1.03) or its major subtypes (p > 0.4), or coronary artery disease (OR 1.01, 95% CI 0.99 to 1.03). Similarly, we found no association for periodontitis and subclinical atherosclerosis (β − 0.002, 95% CI-0.004 to 0.001). These results were consistent across a series of sensitivity analyses. Conclusions: These findings provide no robust evidence for a causal relationship between periodontitis and stroke or coronary artery disease. This suggests that associations reported in observational studies may represent confounding.
“…These studies did not consider interaction effects. The findings have been confirmed by replication only recently 29 . Estimates of heritability of carotid atherosclerosis vary between 20 and 75% 28 , 30 , 31 .…”
The relationship between intake of saturated fats and subclinical atherosclerosis, as well as the possible influence of genetic variants, is poorly understood and investigated. We aimed to investigate this relationship, with a hypothesis that it would be positive, and to explore whether genetics may modulate it, using data from a European cohort including 3,407 participants aged 54–79 at high risk of cardiovascular disease. Subclinical atherosclerosis was assessed by carotid intima-media thickness (C-IMT), measured at baseline and after 30 months. Logistic regression (OR; 95% CI) was employed to assess the association between high intake of food rich in saturated fat (vs. low) and: (1) the mean and the maximum values of C-IMT in the whole carotid artery (C-IMTmean, C-IMTmax), in the bifurcation (Bif-), the common (CC-) and internal (ICA-) carotid arteries at baseline (binary, cut-point ≥ 75th), and (2) C-IMT progression (binary, cut-point > zero). For the genetic-diet interaction analyses, we considered 100,350 genetic variants. We defined interaction as departure from additivity of effects. After age- and sex-adjustment, high intake of saturated fat was associated with increased C-IMTmean (OR:1.27;1.06–1.47), CC-IMTmean (OR:1.22;1.04–1.44) and ICA-IMTmean (OR:1.26;1.07–1.48). However, in multivariate analysis results were no longer significant. No clear associations were observed between high intake of saturated fat and risk of atherosclerotic progression. There was no evidence of interactions between high intake of saturated fat and any of the genetic variants considered, after multiple testing corrections. High intake of saturated fats was not independently associated with subclinical atherosclerosis. Moreover, we did not identify any significant genetic-dietary fat interactions in relation to risk of subclinical atherosclerosis.
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