Circulating soluble ICAM-1 levels shows linkage to ICAM gene cluster region on chromosome 19: The NHLBI Family Heart Study follow-up examination
Introduction
Atherogenesis is a chronic inflammatory process in which the arterial intima undergoes significant changes including the deposition of lipids, recruitment of leukocytes and smooth muscle cells, and accumulation of extracellular matrix. Leukocyte infiltration into the extravascular space is mediated in part by binding of complementary adhesion molecules. Intercellular adhesion molecule 1 (ICAM-1) plays a critical role in firm adhesion of all leukocytes to the endothelium. Circulating soluble ICAM-1 (sICAM-1) is thought to originate from proteolytic cleavage of cell-bound ICAM-1 and has been shown to retain most of the structure and function of the membrane-bound form [1].
Several human studies have found an association between high levels of sICAM-1 and cardiovascular disease. The ARIC study reported the odds ratios of coronary heart disease and carotid artery atherosclerosis were 5.5 and 2.6, respectively, for those with levels of sICAM-1 in the highest quartile compared with those in the lowest quartile [2]. Using a nested case-control design in the Physicians Health Study, Ridker et al. [3] found a significant association between increasing sICAM-1 levels and future risk of myocardial infarction in men. Furthermore, they report a multivariate adjusted relative risk (RR) = 1.8 for myocardial infarction in participants whose baseline sICAM-1 levels were in the highest quartile compared to the lowest. Using a similar nested case-control design in the British Regional Heart Study, Malik et al. [4] found a RR = 1.68 for CHD comparing participants in the top and bottom third of baseline sICAM-1 levels, but this decreased to RR = 1.11 after controlling for other CHD risk factors. In the Women's Health Study, the highest quartile of sICAM-1 level was associated with increased risk of cardiovascular events (RR = 2.6) compared to the lowest quartile [3].
In normal vasculature, ICAM-1 is expressed at low levels but can be upregulated by endothelial dysfunction. High levels indicate on-going inflammatory activity. An apo E knockout mouse model with ICAM-1 deficiency (ICAM-1−/−) showed a 30% reduction in intimal lesions and a lack of advanced calcified lesions compared to ICAM-1 wild type mice [5]. Nakashima et al. [6] observed that ICAM-1 expression was independent of plasma cholesterol and appeared to be upregulated by biomechanical forces. The stress-response element identified in the promoter of the ICAM-1 gene supports this observation [7]. Genetic factors may partly account for interindividual variation in sICAM-1. Heritabilities of sICAM-1 levels ranging from 0.34 to 0.50 have been reported [8], [9]. Genome-wide linkage scans for sICAM-1 were conducted in 1269 Hispanics in the San Antonio Family Heart Study and 1054 whites in the Framingham Heart Study. In Hispanics, a significant linkage was observed on chromosome 19 over the region containing the structural gene for ICAM1[9]. However, no significant linkage signals were observed for this trait in the Framingham Heart Study.
To identify genes contributing to variation in sICAM-1 and to decipher the inconsistent results of the previous two genome scans, we conducted a genome-wide scan for quantitative trait locus (QTL) influencing sICAM-1 levels in a large family study. The identification of genes contributing to variation in circulating levels may point to etiological pathways that further clarify the role of inflammation in atherogenesis.
Section snippets
Subjects
In its follow-up examination, the NHLBI FHS enrolled previously examined and genotyped participants from the original NHLBI FHS and hypertension epidemiology network (HyperGEN). The NHLBI FHS originally recruited three-generation pedigrees from three population-based studies with approximately half the pedigrees randomly selected and the other half selected on the basis of having higher than expected rates of CHD. HyperGEN recruited hypertensive siblings and a random sample of the population.
Results
Phenotype and genetic marker data were available on 2617 white subjects in 482 pedigrees and 531 black subjects in 160 pedigrees. Pedigree characteristics are shown in Table 1. In whites, significant associations between sICAM-1 levels and age, sex, BMI, waist circumference, smoking status, lifetime smoking exposure, diabetes status, and field center were observed using mixed effect models as implemented in SOLAR to account for the lack of independence due to familial aggregation. In blacks,
Discussion
We observed heritabilities of 0.39 in whites and 0.59 in blacks suggesting a genetic component influencing sICAM-1 levels. These estimates are consistent with previously published reports in whites in the Framingham Heart Study [8] (h2 = 0.34) and Mexican Americans in the San Antonio Family Heart Study (SAFHS, h2 = 0.50) [9]. Significant linkage was observed near the ICAM gene cluster region on chromosome 19 in whites (LOD = 4.0 at 14 cM). There was minimal evidence for linkage in this region in our
Conclusion
This investigation into the genetics of sICAM-1 revealed heritabilities of 0.39 in white and 0.59 in black populations. Significant linkage was observed in whites on chromosome 19 near the ICAM gene cluster that includes the structural gene for ICAM-1. Genotyping of the 10 pedigrees providing the most evidence for linkage excluded rs5491 as the cause of the linkage finding. We observed no regions of significant linkage in blacks. This study provides preliminary evidence linking genetic
Acknowledgements
We are grateful for resources from the University of Minnesota Supercomputing Institute, the NIH Training Grant in Cardiovascular Disease Genetic Epidemiology (#5 T32 HL007972). Support was provided by the National Heart, Lung, and Blood Institute cooperative agreement grants U01 HL67893, U01 HL67894, U01 HL67895, U01 HL67896, U01 HL67897, U01 HL67898, U01 HL67899, U01 HL67900, U01 HL67901, U01 HL67902. Support was also partially provided by the National Heart, Lung, and Blood Institute
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Genomic Biomarkers in Human Population Studies
2013, Genomic and Personalized MedicineGenomic Biomarkers in Human Population Studies
2012, Genomic and Personalized MedicinePolymorphisms in the ICAM1 gene predict circulating soluble intercellular adhesion molecule-1(sICAM-1)
2011, AtherosclerosisCitation Excerpt :The Women's Health Study reported a relative risk of 2.6 for cardiovascular events for women in the highest quartile of sICAM-1 levels compared to lowest [11]. Results from three genome-wide linkage scans of sICAM-1 showed significant linkage on chromosome 19 near the ICAM1 structural gene [6,12,13]. Polymorphisms within the ICAM1 structural gene have been shown to influence circulating levels of sICAM-1 but the relation of these polymorphisms and atherosclerosis remains inconclusive [14,15].
Candidate genes for respiratory disease associated with markers of inflammation and endothelial dysfunction in elderly men
2009, AtherosclerosisCitation Excerpt :The etiology of cardiovascular disease (CVD) involves a confluence of genetic, environmental and lifestyle components which is not fully understood. Studies have also established a link between genes and levels of biomarkers related to inflammation and endothelial function [1–3], suggesting that polymorphisms in the genetic sequence may alter the functionality of genes and the proteins that they encode. Long-term exposure to even low levels of inflammation triggers a cascade of events promoting lipid dysregulation, atherosclerosis and endothelial dysfunction, which are precursors of CVD [4,5].