SIR – Schizophrenia is a heterogenous disorder with a polygenic mode of transmission and additionally contributing environmental factors. The involvement of an immune process, characterized by a reduced activation of the cellular immune response has been proposed.1 Recent findings describe reduced serum levels of soluble intercellular adhesion molecule (sICAM-1) in unmedicated and medicated schizophrenic patients.2 ICAM-1 plays an important role in the activation of the cellular immune response.
The two ligands of ICAM-1 on lymphocytes and macrophages are lymphocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (MAC-1).3 The human ICAM-1 gene, located on chromosome 19p13.3–p13.2, contains two important single-nucleotide polymorphisms (SNPs), both leading to an amino-acid change: The G→A SNP at position 241 coding for the Mac-1 binding domain and the A→G SNP at position 469 (LFA-1 binding site).4 Significant differences in allele frequencies of both polymorphisms have been detected in several diseases with immune-related pathophysiology including rheumatoid arthritis (RA) and insulin-dependent diabetes mellitus (IDDM).5,6
We performed a case–control association study investigating the ICAM-1 gene G241A and A469G SNPs in schizophrenia.
Patients: A total of 190 unrelated Caucasian patients with schizophrenia (109 male, 81 female; mean age 33.6±12.0 (17–71) years). Diagnoses were established according to the criteria of the DSM-IV by two independent experienced psychiatrists. The mean age of onset was 28.6±10.2 years. Controls group: A total of 190 unrelated healthy Caucasians from the general population (88 male, 102 female; mean age 45.0±13.6 (22–76) years). All controls were screened for past or present psychiatric illness. History of psychiatric illness in a first-degree relative was asked for by interviewing the control persons and was considered an exclusion criterion. Physical health was evaluated by extensive examinations including blood tests to exclude infectious or inflammatory disease in both study groups.
The study was approved by the local Ethics Committee and all patients and controls gave their written informed consent after the aim of the study had been fully explained.
Genotyping was performed according to a previously reported method.4 Differences in genotype were calculated by χ2 test using SPSS 10.1.
There was no significant difference between patients and controls in genotype distribution of the G241A (χ2=0.512; df=2; P=0.771) or the A469G (χ2=0.098; df=2; P=0.952) SNPs. Details are shown in Table 1. Moreover, no association between age of onset or clinical subtypes and genotype distribution was observed among patients. Hardy–Weinberg equilibrium was fulfilled regarding both polymorphisms in the populations of schizophrenic patients and healthy control persons.
Based on the above-stated immunological hypotheses of schizophrenia and on the central role of ICAM-1 in the regulation of lymphocyte and macrophage activity, we hypothesised that the ICAM-1 gene may be a candidate gene in schizophrenia research.
We report here a candidate gene approach study investigating the G241A and the A469G SNPs of the ICAM-1 gene in schizophrenic patients and healthy control persons. However, we could not show an association between these polymorphisms with schizophrenia. An increased frequency of the A allele of the G241A polymorphism was described in RA,5 while the 469G allele was described to be related to IDDM.6 Both disorders are characterised by an inflammatory cellular immune response of the Th1 type.7,8
In contrast, several data show a reduced activation of the cellular immune system in schizophrenic patients, while the humoral arm of the immune response seems to be activated. Moreover, a negative correlation between schizophrenia and rheumatoid arthritis has repeatedly been described.9 In this context, our findings are in accordance with the hypothesis of a reduced Th1 activation in schizophrenia.
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Supported by the Theodore and Vada Stanley Foundation.
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Riedel, M., Krönig, H., Schwarz, M. et al. Investigation of the ICAM-1 G241A and A469G gene polymorphisms in schizophrenia. Mol Psychiatry 8, 257–258 (2003). https://doi.org/10.1038/sj.mp.4001320
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