Making Novel Genetic Associations With Carotid Intima-Media Thickness Using the UK Biobank.
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ABSTRACT:
SUBMITTER: Guo L
PROVIDER: S-EPMC7033653 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
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Making Novel Genetic Associations With Carotid Intima-Media Thickness Using the UK Biobank.
Guo Liang L Cornelissen Anne A Sakamoto Atsushi A Finn Aloke V AV
Arteriosclerosis, thrombosis, and vascular biology 20200122 2
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Project description:Background and aimsUltrasound derived carotid intima-media thickness (cIMT) is valuable for cardiovascular risk stratification. We assessed the relative importance of traditional atherosclerosis risk factors and plasma proteins in predicting cIMT measured nearly a decade later.MethodWe examined 6,136 UK Biobank participants with 1,461 proteins profiled using the proximity extension assay applied to their baseline blood draw who subsequently underwent a cIMT measurement. We implemented linear regression, stepwise Akaike Information Criterion-based, and the least absolute shrinkage and selection operator (LASSO) models to identify potential proteomic as well as non-proteomic predictors. We evaluated our model performance using the proportion variance explained (R 2).ResultThe mean time from baseline assessment to cIMT measurement was 9.2 years. Age, blood pressure, and anthropometric related variables were the strongest predictors of cIMT with fat-free mass index of the truncal region being the strongest predictor among adiposity measurements. A LASSO model incorporating variables including age, assessment center, genetic risk factors, smoking, blood pressure, trunk fat-free mass index, apolipoprotein B, and Townsend deprivation index combined with 97 proteins achieved the highest R 2 (0.308, 95% C.I. 0.274, 0.341). In contrast, models built with proteins alone or non-proteomic variables alone explained a notably lower R 2 (0.261, 0.228-0.294 and 0.260, 0.226-0.293, respectively). Chromogranin b (CHGB), Cystatin-M/E (CST6), leptin (LEP), and prolargin (PRELP) were the proteins consistently selected across all models.ConclusionPlasma proteins add to the clinical and genetic risk factors in predicting a cIMT measurement. Our findings implicate blood pressure and extracellular matrix-related proteins in cIMT pathophysiology.
| S-EPMC11480011 | biostudies-literature
Project description: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.
| S-EPMC6975521 | biostudies-literature
Project description:AimAtherosclerosis is a chronic inflammatory process of the arterial wall and carotid intima-media thickness (cIMT) is regarded as its early marker. Several members of the IL-17 family are involved in pro-inflammatory functions. The specific aim of the study was to explore the relationships of common genetic variants on IL-17 genes with cIMT thickening.MethodsIn the discovery stage, 146 SNPs on 11 IL-17 genes were screened for their relationships with cIMT by a case-control study that enrolled 284 and 464 subjects who had thicker and normal cIMT, respectively. Findings were replicated by an independent case-control study that enrolled 282 subjects who had thicker cIMT and 282 age-sex-matched subjects who had normal cIMT.ResultsAmong 134 eligible SNPs in the discovery study, only IL-17RC rs279545 was significantly correlated with cIMT (p=6.9×10-5). The rs279545 and 2 nearby linked SNPs rs55847610 and rs3846167 were included in the validation study. We found that the rs279545＊G, rs55847610＊G, and rs3846167＊C were correlated with significantly higher likelihoods of having thicker cIMT. The corresponding multivariate-adjusted ORs were 1.462 (95% CI: 1.055-2.027), 1.481 (95% CI:1.090-2.013), and 1.589 (95% CI: 1.147-2.200), respectively. Analyses of rs279545-rs55847610 haplotypes showed that the multivariate-adjusted OR for A-A haplotype was significantly decreased (OR=0.665, 95% CI: 0.487-0.908) and for G-G haplotype was significantly increased (OR=1.539, 95% CI: 1.097-2.161).ConclusionsWe first correlated cIMT, a preclinical clinical cardiovascular marker, with IL-17RC, the key molecule in the IL-17 signaling pathway. Our results indicated that IL-17RC may play critical role in the development of atherosclerotic diseases.
| S-EPMC6224208 | biostudies-literature
Project description:Background Uncertainty persists about carotid intima-media thickness (CIMT) as a marker of subclinical atherosclerosis and the independent relevance of different measures of adiposity for CIMT. We assessed the independent relevance of general adiposity (body mass index), central adiposity (waist circumference), and body composition (fat mass index and fat-free mass index) with CIMT among adults in the United Kingdom. Methods and Results Multivariable linear regression of cross-sectional analyses of UK Biobank assessed the mean percentage difference in CIMT associated with equivalent differences in adiposity measures. To assess independent associations, body mass index and waist circumference were mutually adjusted, as were fat mass index and fat-free mass index. Among 39 367 participants (mean [SD] age 64 [8] years, 52% female, 97% White), median (interquartile range) CIMT was 0.65 (0.14) mm in women and 0.69 (0.18) mm in men. All adiposity measures were linearly and positively associated with CIMT after adjusting for confounders. Fat-free mass index was most strongly associated with CIMT after adjustment for fat mass index (% difference in CIMT: 1.23 [95% CI 0.93-1.53] women; 3.44 [3.01-3.86] men), while associations of fat mass index were attenuated after adjustment for fat-free mass index (0.28 [-0.02, 0.58] women; -0.59 [-0.99, -0.18] men). After mutual adjustment, body mass index remained positively associated with CIMT, but waist circumference was completely attenuated. Conclusions Fat-free mass index was the adiposity measure most strongly associated with CIMT, suggesting that CIMT may reflect vascular compensatory remodeling rather than atherosclerosis. Hence, screening for subclinical atherosclerosis should evaluate carotid plaques in addition to CIMT.
| S-EPMC9939056 | biostudies-literature
Project description:ObjectiveDiabetes and atherosclerosis may share common genetic determinants. A prior study in Hispanics found association of haplotypes in the diabetes gene calpain-10 (CAPN10) with carotid artery intima-media thickness (CIMT). This study sought to replicate this association in an independent cohort.MethodsFour CAPN10 SNPs were genotyped and haplotypes determined in 487 Hispanic Americans from 143 families ascertained via an index case with hypertension. CIMT was measured from B-mode ultrasound, and glycemic traits quantified from euglycemic clamps. Association of SNPs and haplotypes with CIMT was determined.ResultsThe minor alleles of SNP-56 and SNP-63 were associated with increased CIMT in dominant and additive models. The association of haplotype 1112 with increased CIMT was replicated. No associations with fasting insulin, insulin secretion, or insulin sensitivity were observed.ConclusionsCAPN10 association with CIMT was replicated, further supporting its role as a common genetic determinant of diabetes and atherosclerosis in Hispanics.
| S-EPMC2717175 | biostudies-literature
Project description:BACKGROUND- Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these 2 arteries; yet, they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components. METHODS AND RESULTS- IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS using 931219 single-nucleotide polymorphisms was undertaken with 6 internal and common carotid artery IMT phenotypes using an additive measured genotype model. The most robust association detected was for 2 single-nucleotide polymorphisms (rs16983261, rs6113474; P=1.60e(-7)) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1. We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at P<5.0e(-6). The genetic correlation between the 2 carotid IMT arterial segments was 0.51. CONCLUSIONS- This study represents the first large-scale GWAS of carotid IMT in a non-European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments, but the moderate genetic correlation implies both common and unique genetic components.
| S-EPMC3865281 | biostudies-literature
Project description:BackgroundIntima-media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events.MethodsWe measured the mean intima-media thickness of the common carotid artery and the maximum intima-media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovascular-disease outcomes were evaluated for an average follow-up of 7.2 years. Multivariable Cox proportional-hazards models were generated for intima-media thickness and risk factors. We evaluated the reclassification of cardiovascular disease on the basis of the 8-year Framingham risk score category (low, intermediate, or high) after adding intima-media thickness values.ResultsA total of 296 participants had a cardiovascular event. The risk factors of the Framingham risk score predicted these events, with a C statistic of 0.748 (95% confidence interval [CI], 0.719 to 0.776). The adjusted hazard ratio for cardiovascular disease with a 1-SD increase in the mean intima-media thickness of the common carotid artery was 1.13 (95% CI, 1.02 to 1.24), with a nonsignificant change in the C statistic of 0.003 (95% CI, 0.000 to 0.007); the corresponding hazard ratio for the maximum intima-media thickness of the internal carotid artery was 1.21 (95% CI, 1.13 to 1.29), with a modest increase in the C statistic of 0.009 (95% CI, 0.003 to 0.016). The net reclassification index increased significantly after addition of intima-media thickness of the internal carotid artery (7.6%, P<0.001) but not intima-media thickness of the common carotid artery (0.0%, P=0.99). With the presence of plaque, defined as intima-media thickness of the internal carotid artery of more than 1.5 mm, the net reclassification index was 7.3% (P=0.01), with an increase in the C statistic of 0.014 (95% CI, 0.003 to 0.025).ConclusionsThe maximum internal and mean common carotid-artery intima-media thicknesses both predict cardiovascular outcomes, but only the maximum intima-media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. (Funded by the National Heart, Lung, and Blood Institute.).
| S-EPMC3153949 | biostudies-literature
Project description:Atherosclerosis precedes the onset of 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; 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 for mean-max cIMT, SIRPA (p = 4.7E-08), and FBXL17 (p = 2.5E-08), were identified. Sex-stratified analysis revealed associations with one male-specific locus, SNX29 (p = 6.3E-09), and two female-specific loci, LARP6 (p = 2.4E-09) and PROK1 (p = 1.0E-08). We replicate previous cIMT associations with different lead SNPs in linkage disequilibrium with SNPs primarily identified in European populations. Our study find significant enrichment for genes involved in oestrogen response from female-specific signals. The genes identified show biological relevance to atherosclerosis and/or CVDs, sex-differences and transferability of signals from non-African studies.
| S-EPMC8844072 | biostudies-literature
Project description:Carotid intima-media thickness (IMT) is a surrogate marker of subclinical atherosclerosis and a strong predictor of stroke and myocardial infarction. The object of this study was to determine the association between carotid IMT and 702 single nucleotide polymorphisms in 145 genes.B-mode carotid ultrasound was performed among 408 Hispanics from the Northern Manhattan Study. The common carotid artery IMT and bifurcation IMT were phenotypes of interest. Genetic effects were evaluated by the multivariate regression model adjusting for traditional vascular risk factors. For each individual, we calculated a gene risk score (GRS) defined as the total number of the significant single nucleotide polymorphisms in different genes. Subjects were then divided into 3 GRS categories using the 2 cutoff points: mean GRS +/-1 SD.We identified 6 significant single nucleotide polymorphisms in 6 genes for common carotid artery IMT and 7 single nucleotide polymorphisms in 7 genes for bifurcation IMT using the probability value of 0.005 as the significant level. There were no common significant genes for both phenotypes. The most significant genes were the tissue plasminogen activator (P=0.0005 for common carotid artery IMT) and matrix metallopeptidase-12 genes (P=0.0004 for bifurcation IMT). Haplotype analysis did not yield a more significant result. Subjects with GRS >or=9 had significantly increased IMT than those with GRS <or=5 (P<0.001). GRS was an independent predictor of both common carotid artery IMT (P=2.3x10(-9)) and bifurcation MT (P=7.2x10(-8)).Multiple genes contributed to the variation in carotid IMT. IMT in different carotid segments may be regulated by different sets of susceptibility genes.
| S-EPMC2676928 | biostudies-literature
Project description:AimTo evaluate the relationship between periodontal diseases and subclinical atherosclerosis in a younger and lean South Asian population.MethodsWe conducted a cross-sectional study in 917 subjects (mean age 46 years and mean body mass index 21.1 kg/m2 ) from the Health Effects of Arsenic Longitudinal Study in Bangladesh. Multivariate linear regression models were used to assess the associations between multiple clinical measures of periodontal diseases and carotid intima-media thickness (IMT).ResultsMean attachment loss (AL) and percentage of sites with AL ≥ 4 mm (% AL ≥ 4) were associated with increased IMT. The IMT was 20.0-μm (95% CI: 2.2, 37.8) and 26.5-μm (95% CI: 8.9, 44.1) higher in subjects in the top quartile of mean AL (>3.72 mm) and % AL ≥ 4 (>58.4%), respectively, compared to those in the bottom quartile. In a subset of 366 subjects, mean AL was positively associated with plasma levels of matrix metalloproteinase-9 (p < 0.05) and soluble intercellular adhesion molecule-1 (p < 0.01).ConclusionsAttachment loss was associated with subclinical atherosclerosis in this young and lean Bangladeshi population. Future prospective studies are needed to confirm this association.
| S-EPMC5063685 | biostudies-literature