Elsevier

Atherosclerosis

Volume 199, Issue 1, July 2008, Pages 172-178
Atherosclerosis

Circulating soluble ICAM-1 levels shows linkage to ICAM gene cluster region on chromosome 19: The NHLBI Family Heart Study follow-up examination

https://doi.org/10.1016/j.atherosclerosis.2007.10.006Get rights and content

Abstract

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 14 cM) 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.

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

References (25)

  • I. Malik et al.

    Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis

    Lancet

    (2001)
  • R.G. Collins et al.

    P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice

    J Exp Med

    (2000)
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