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Background and Aims: Hepatocyte growth factor (HGF) has previously been associated with risk of stroke, coronary heart disease, and atherosclerosis. We hypothesized that higher circulating HGF is associated with greater progression of measures of atherosclerosis: coronary artery calcium (CAC) and carotid plaque., Methods: Participants aged 45-84 years from the prospective cohort study Multi-Ethnic Study of Atherosclerosis had HGF measured at baseline (between 2000 and 2002) and were followed for progression of atherosclerosis for up to 12 years. CAC was measured at all five exams using the Agatston method. Mixed-effects models were used to examine the association of HGF and CAC progression among 6695 participants with available data. Relative risk regression was used to assess the association between HGF and new or additional carotid plaque between exams 1 and 5 in 3400 participants with available data. All point estimates were adjusted for potential confounding variables., Results: Each standard deviation higher HGF at baseline was associated with 2.9 Agatston units/year greater CAC progression (95% CI: 1.6-4.2, p < 0.0001), and the magnitude of this association differed by race/ethnicity (p value for interaction by race = 0.003). Each standard deviation higher HGF at baseline was associated with a 4% higher risk of new or additional carotid plaque (95% CI: 1.01-1.08, p = 0.005)., Conclusions: Higher levels of HGF were significantly associated with greater progression of atherosclerosis in this large and diverse population. Circulating HGF continues to show promise as a potential clinical biomarker for cardiovascular disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: ABO blood type is associated with cardiovascular disease, although the underlying mechanisms are presumed to be complex. While the relationship between non-O blood types and von Willebrand Factor (vWF) is well-established, associations with cellular adhesion molecules (CAMs) across diverse populations are understudied., Methods: We genetically inferred ABO alleles for N = 6202 participants from the Multi-Ethnic Study of Atherosclerosis. Linear regression was used to evaluate associations between major ABO allele dosages and log-transformed measurements of vWF (N = 924), soluble E-selectin (sE-selectin, N = 925), soluble P-selectin (sP-selectin, N = 2392), and soluble ICAM-1 (sICAM-1, N = 2236) by race/ethnicity., Results: For the selectins, the A1 allele was associated with significantly lower levels for all races/ethnicities, with each additional allele resulting in a 28-39% decrease in sE-selectin and 10-18% decrease in sP-selectin relative to Type O subjects. However, the A2 allele demonstrated effect heterogeneity across race/ethnicity for sE-selectin, with lower levels for non-Hispanic whites (p = 0.0011) but higher levels for Hispanics (p = 0.0021). We also identified elevated sP-selectin levels for B-allele carriers solely in Hispanic participants (p = 1.0E-04). ABO-by-race/ethnicity interactions were significant for both selectins (p < 0.0125). More modest associations were observed between A1 allele dosage and levels of sICAM-1, with ABO alleles explaining 0.8-1.1% of the total phenotypic variation within race/ethnicity. ABO associations with vWF activity were consistent across race/ethnicity, with B allele carriers corresponding to the highest vWF activity levels., Conclusions: ABO blood type demonstrates complex associations with endothelial markers that are largely generalizable across diverse populations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: P-selectin is a cellular adhesion molecule that has been shown to be crucial in development of coronary heart disease (CHD). We sought to determine the role of P-selectin on the risk of atherosclerosis in a large multi-ethnic population., Methods: Data from the Multi-Ethnic Study of Atherosclerosis (MESA), including 1628 African, 702 Chinese, 2393 non-Hispanic white, and 1302 Hispanic Americans, were used to investigate the association of plasma P-selectin with CHD risk factors, coronary artery calcium (CAC), intima-media thickness, and CHD. Regression models were used to investigate the association between P-selectin and risk factors, Tobit model for CAC, and Cox regression for CHD events., Results: Mean levels of P-selectin differed by ethnicity and were higher in men (P<0.001). For all ethnic groups, P-selectin was positively associated with measures of adiposity, blood pressure, current smoking, LDL, and triglycerides and inversely with HDL. A significant ethnic interaction was observed for the association of P-selectin and prevalent diabetes; however, P-selectin was positively associated with HbA1c in all groups. Higher P-selectin levels were associated with greater prevalence of CAC. Over 10.1 years of follow-up, there were 335 incident CHD events. There was a positive linear association between P-selectin levels and rate of incident CHD after adjustment for traditional risk factors. However, association was only significant in non-Hispanic white Americans (HR: 1.81, 95% CI 1.07 to 3.07, P=0.027)., Conclusion: We observed ethnic heterogeneity in the association of P-selectin and risk of CHD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To determine the association of circulating P-selectin with prevalent and incident peripheral artery disease (PAD), the ankle brachial index (ABI), and change in the ABI., Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective population-based cohort study including 6814 European descent, African American, Hispanic and Chinese men and women aged 45-84 at baseline. Four clinical exams took place after the baseline exam. After excluding those with ABI>1.4, prevalent and incident PAD were defined as an ABI≤0.90. ABI progression was defined as progression from a normal ABI (0.91-1.4) to abnormal (≤0.90 or >1.4) at a later exam., Results: In adjusted models, each SD (13 ng/mL) higher P-selectin was significantly associated with 0.007 lower ABI (95% CI ((-0.011, -0.004)), p < 0.001), and an average change in the ABI of -0.006 ((-0.010, -0.003, p < 0.001). P-selectin was significantly associated with a 1.17-fold greater odds of prevalent PAD ((1.02, 1.33), p = 0.03), and a 30% greater risk of incident PAD ((1.11, 1.53), p = 0.001), as well as progression from a normal ABI to an ABI≤ 0.90 (p = 0.003), but not to an ABI>1.4 (p = 0.96). Addition of P-selectin to models containing traditional PAD risk factors and markers of inflammation/coagulation significantly improved the net reclassification for ABI progression (p = 0.03), but was only marginally significant for incident PAD (p = 0.06)., Conclusions: P-selectin is significantly associated with the development of PAD. However, further research is needed in population-based studies to confirm prospective associations of P-selectin with incident PAD and change in the ABI, as well as its potential predictive ability., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Polymorphisms within the ICAM1 structural gene have been shown to influence circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) but their relation to atherosclerosis has not been clearly established. We sought to determine whether ICAM1 SNPs are associated with circulating sICAM-1 concentration, coronary artery calcium (CAC), and common and internal carotid intima medial thickness (IMT)., Methods and Results: 3550 black and white Coronary Artery Risk Development in Young Adults (CARDIA) Study subjects who participated in the year 15 and/or 20 examinations and were part of the Young Adult Longitudinal Study of Antioxidants (YALTA) ancillary study were included in this analysis. In whites, rs5498 was significantly associated with sICAM-1 (p<0.001) and each G-allele of rs5498 was associated with 5% higher sICAM-1 concentration. In blacks, each C-allele of rs5490 was associated with 6% higher sICAM-1 level; this SNP was in strong linkage disequilibrium with rs5491, a functional variant. Subclinical measurements of atherosclerosis in either year 15 or year 20 were not significantly related to ICAM1 SNPs., Conclusions: In CARDIA, ICAM1 DNA segment variants were associated with sICAM-1 protein level including the novel finding that levels differ by the functional variant rs5491. However, ICAM1 SNPs were not strongly related to either IMT or CAC. Our findings in CARDIA suggest that ICAM1 variants are not major early contributors to subclinical atherosclerosis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may be important contributors to the development and progression of atherosclerosis. Using a stratified random sample of 2880 participants of the Multi-Ethnic Study of Atherosclerosis we investigated the relationship of 12 ICAM1 and 17 VCAM1 SNPs and coronary artery calcium (CAC) and ICAM1 SNPs and circulating levels of soluble ICAM-1 (sICAM-1). There were no ICAM1 or VCAM1 SNPs significantly associated with CAC in any of the four race/ethnic groups. In a subset of 1451 subjects with sICAM-1 measurements, we observed a significant association with rs5491 in all four race/ethnic groups corroborating previous research that has shown that the T-allele of rs5491 interferes with the monoclonal antibody used to measure sICAM-1 in this study. After excluding all rs5491 T-allele carriers, several ICAM1 SNPs were significantly associated with sICAM-1 levels; rs5496 in African Americans, rs5498 and rs3093030 in European Americans, and rs1799969 in Hispanics. Our results identified ICAM1 polymorphisms that were significantly associated with sICAM-1 level but not CAC, a subclinical marker of atherosclerosis.

Atherogenesis is a chronic inflammatory process in which intercellular adhesion molecule 1 (ICAM-1) plays a critical role. Circulating soluble ICAM-1 (sICAM-1) is thought to be the result of cleavage of membrane-bound ICAM-1 and its concentration in serum/plasma has been shown to be heritable. Genome-wide linkage scans were conducted for quantitative trait loci influencing sICAM-1. Phenotype and genetic marker data were available for 2617 white and 531 black individuals in the NHLBI Family Heart Study follow-up examination. Heritability for sICAM-1 was 0.39 in whites and 0.59 in blacks. Significant linkage was observed on chromosome 19 (LOD=4.0 at 14cM) in whites near the ICAM gene cluster that includes the structural gene for ICAM-1. The T-allele of ICAM-1 SNP rs5491 has been strongly associated with the specific sICAM-1 assay we used in our study. Through additional genotyping we were able to rule out rs5491 as the cause of the linkage finding. This study provides preliminary evidence linking genetic variation in the ICAM1 structural gene to circulating sICAM-1 levels.