Tsai, Michael Y.

AbstractAimsTo test the hypothesis that soluble cellular adhesion molecules would be positively and independently associated with risk of diabetes.MethodsSoluble levels of six cellular adhesion molecules (ICAM‐1, E‐selectin, VCAM‐1, E‐cadherin, L‐selectin and P‐selectin) were measured in participants in the Multi‐Ethnic Study of Atherosclerosis, a prospective cohort study. Participants were then followed for up to 10 years to ascertain incident diabetes.ResultsSample sizes ranged from 826 to 2185. After adjusting for age, sex, race/ethnicity, BMI and fasting glucose or HbA1c, four cellular adhesion molecules (ICAM‐1, E‐selectin, VCAM‐1 and E‐cadherin) were positively associated with incident diabetes and there was a statistically significant trend across quartiles. Comparing the incidence of diabetes in the highest and lowest quartiles of each cellular adhesion molecule, the magnitude of association was largest for E‐selectin (hazard ratio 2.49; 95% CI 1.26–4.93) and ICAM‐1 (hazard ratio 1.76; 95% CI 1.22–2.55) in fully adjusted models. Tests of effect modification by racial/ethnic group and sex were not statistically significant for any of the cellular adhesion molecules (P > 0.05).ConclusionsThe finding of significant associations between multiple cellular adhesion molecules and incident diabetes may lend further support to the hypothesis that microvascular endothelial dysfunction contributes to risk of diabetes.

ObjectiveAt the cellular level, how excess adiposity promotes atherogenesis is not fully understood. One pathway involves secretion of adipokines that stimulate endothelial dysfunction through increased expression of adhesion molecules. However, the relationship of adiposity to adhesion molecules that promote atherosclerosis is largely unknown.MethodsLinear regression models were used to assess the sex‐specific associations of soluble cellular adhesion molecules (sP‐ and sL‐selectin, sICAM‐1, sVCAM‐1, and sHGF) and adiposity in 5,974 adults examined as part of the Multi‐Ethnic Study of Atherosclerosis (MESA). Adiposity measures included body mass index (BMI), waist‐to‐hip‐ratio (WHR), and computed tomography measures of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT).ResultsThe mean age was 64 years and 52% were female. In multivariable models adjusting for traditional cardiovascular risk factors, sHGF was positively associated with BMI, WHR, and VAT in both males and females, and sP‐selectin with WHR and VAT in males. sVCAM‐1 was inversely associated with VAT in females only.ConclusionsOur results showed the relation of adiposity to soluble cellular adhesion proteins was similar across adiposity measures and for both sexes. However, the relationship between adiposity and sVCAM‐1 and P‐selectin may be modified by sex and the measure used to assess adiposity.

SummaryHepatocyte growth factor (HGF) is a mesenchyme‐derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding which genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity‐stratified single‐variant association analysis and trans‐ethnic meta‐analysis of 6201 participants of the Multi‐Ethnic Study of Atherosclerosis (MESA), we discovered five statistically significant common and low‐frequency variants: HGF missense polymorphism rs5745687 (p.E299K) as well as four variants (rs16844364, rs4690098, rs114303452, rs3748034) within or in proximity to HGFAC. We also identified two significant ethnicity‐specific gene‐level associations (A1BG in African Americans; FASN in Chinese Americans) based upon low‐frequency/rare variants, while meta‐analysis of gene‐level results identified a significant association for HGFAC. However, identified single‐variant associations explained modest proportions of the total trait variation and were not significantly associated with coronary artery calcium or coronary heart disease. Our findings indicate that genetic factors influencing circulating HGF levels may be complex and ethnically diverse.