Association of ICAM3 Genetic Variant with Severe Acute Respiratory Syndrome

Abstract

Genetic polymorphisms have been demonstrated to be associated with vulnerability to human infection. ICAM3, an intercellular adhesion molecule important for T cell activation, and FCER2 (CD23), an immune response gene, both located on chromosome 19p13.3, were investigated for host genetic susceptibility and association with clinical outcome. A case-control study based on 817 patients with confirmed severe acute respiratory syndrome (SARS), 307 health care worker control subjects, 290 outpatient control subjects, and 309 household control subjects unaffected by SARS from Hong Kong was conducted to test for genetic association. No significant association to susceptibility to SARS infection caused by the novel coronavirus (SARS-CoV) was found for the FCER2 and the ICAM3 single nucleotide polymorphisms. However, patients with SARS homozygous for ICAM3 Gly143 showed significant association with higher lactate dehydrogenase levels (P=.0067; odds ratio [OR], 4.31 [95% confidence interval {CI}, 1.37-13.56]) and lower total white blood cell counts (P=.022; OR, 0.30 [95% CI, 0.10-0.89]) on admission. These findings support the role of ICAM3 in the immunopathogenesis of SARS.

Polymorphisms in the C-type lectin genes cluster in chromosome 19 and predisposition to severe acute respiratory syndrome coronavirus (SARS-CoV) infection

“…More recently, Chan et al re-examined additional non-synonymous coding SNPs of FCER2 and one SNP in ICAM3 28. Their data were consistent with our findings in that there was no association between the SNPs in FCER2 and SARS.…”

CD209 (DC-SIGN) −336A>G promoter polymorphism and severe acute respiratory syndrome in Hong Kong Chinese

“…The study was approved by the Clinical Research Ethics Committee of the Institute Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. The SARS patients were recruited as described previously [27]. Further recruitment of additional serologically confirmed SARS patients increased the total number of cases for this study to 824.…”

“…Binding of ICAM3 to CD209 is mediated at domain 2 of the soluble ICAM3 [35]. Our previous association study for SARS-CoV infection showed that the ICAM3 Asp143Gly SNP (ϩ443AϾG; dbSNP: rs2304237) demonstrated significant association with higher LDH levels and lower total white blood cell counts on admission [27]. Replacement of a charged aspartate by a neutral glycine of this ICAM3 SNP may affect exposure of an N-linked glycosylation site, possibly affecting interaction between ICAM3 and CD209.…”

“…Host genetic factors have been shown to result in differences in outcome of the disease. These include the genetic polymorphisms in ACE1 [26], ICAM3 [27], MxA [28], and Fc␥RIIA [29]. In the CD209 promoter region, a putative functional variant Ϫ336AϾG (dbSNP: rs4804803) affecting a Sp1-like binding site has been described [30].…”

“…In this study, using in vitro competitive electrophoretic mobility shift assay and luciferase promoter activity assay, we confirm the findings reported by Sakuntabhai et al [30], showing that CD209 promoter Ϫ336AϾG SNP could affect the binding of nuclear extract proteins and regulate promoter activity. Given our previously observed significant association between the ICAM3 SNP with high standardized LDH levels and low white blood cell (WBC) counts [27], and the functional relationship of ICAM3 with CD209, we hypothesized that the CD209 Ϫ336AϾG SNP may also show a similar association, and may have a synergistic effect with the ICAM3 SNP.…”