0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Brief Report   |    
Association of an Interleukin-1ß Genetic Polymorphism With Altered Brain Structure in Patients With Schizophrenia
Eva M. Meisenzahl, M.D.; Dan Rujescu, M.D.; Andre Kirner; Ina Giegling, M.S.; Norbert Kathmann, Ph.D.; Gerda Leinsinger, M.D.; Klaus Maag, M.D.; Ulrich Hegerl, M.D.; Klaus Hahn, M.D.; Hans-Jürgen Möller, M.D.
Am J Psychiatry 2001;158:1316-1319. doi:10.1176/appi.ajp.158.8.1316

Abstract

OBJECTIVE: This study investigated the effect on brain morphology of an interleukin-1β genetic polymorphism (C→T transition at position –511) in patients with schizophrenia. METHOD: In vivo magnetic resonance imaging and genotype analysis were used in the examination of 44 male schizophrenic patients and 48 healthy male comparison subjects. RESULTS: No association between the interleukin-1β polymorphism and schizophrenia was detected. Within the patient group, bifrontal-temporal gray matter volume deficits and generalized white matter tissue deficits in allele 2 carriers (genotype T/T or C/T) were found. In contrast, the interleukin-1β polymorphism had no influence on brain morphology within the healthy subjects. CONCLUSIONS: The data suggest that allele 2 within the promoter region of the interleukin-1β gene at position –511 contributes to structural brain alterations in patients with schizophrenia.

Abstract Teaser
Figures in this Article

Since higher plasma levels of interleukin-1β have been found in schizophrenic patients (1) and interleukin-1β levels are partly genetically determined (2), interleukin-1β has been regarded as a candidate gene in schizophrenia (2, 3). Interleukin-1β is a cytokine that is not only involved in inflammatory responses but which also plays a crucial role in the development of the central nervous system. Interleukin-1β has previously been shown to stimulate astrocytes to proliferate and produce a variety of cytokines and trophic factors, including nerve growth factor (4). Moreover, it is involved in acute and chronic neurodegeneration (5).

Two biallelic base-exchange polymorphisms, which are in nearly complete linkage disequilibrium, have been reported at positions –511 and –31 in the promoter region of the interleukin-1β gene (6). There is growing evidence that allele 2 at position –511 is associated with enhanced interleukin-1β production (6, 7). The interleukin-1β polymorphisms and a repeat polymorphism in the neighboring interleukin-1Ra gene are in much weaker linkage disequilibrium. Nevertheless, there is an interaction: interleukin-1β –511 allele 2 is associated with higher levels of interleukin-1Ra, while allele 2 (IL1RN*2) in the interleukin-1Ra gene is associated with higher levels of interleukin-1β (7, 8).

We investigated the effect on brain morphology of the interleukin-1β genetic polymorphism (C→T transition at position –511) in patients with schizophrenia and healthy comparison subjects.

For this study we examined 44 male right-handed medicated schizophrenic inpatients (mean age=30.2 years, SD=8.8, range=18–47). Demographic information and clinical history were obtained by using a semistructured interview. The patients had been ill for 6 months to 25 years (mean=7.1 years, SD=7.1). The comparison group consisted of 48 right-handed healthy male subjects who were recruited from the general population (mean age=30.3 years, SD=8.9, range=18–47). They were matched to the patients in a one-to-one fashion for age (range plus or minus 3 years) and educational achievement.

Neither the healthy subjects nor their first-degree relatives had a history of neurological or mental illness. Exclusion criteria for both groups were a history of serious neurological disorder, use of benzodiazepine or cortisol medication in the last 3 months, any mental disorder other than schizophrenia, or previous treatment with ECT. All patients and comparison subjects provided written informed consent after the procedures had been fully explained. Magnetic resonance imaging (MRI) data were acquired by using coronal T2 and proton-density-weighted dual-echo sequences and a three-dimensional magnetization-prepared rapid gradient echo sequence, described in detail elsewhere (9). Volumetric measurement was performed on the MRI data sets by using the software program BRAINS (10).

Genomic DNA was prepared from 10 ml blood by using the QIAamp DNA Blood Maxi Kit (Quiagen, Hilden, Germany). The promotor region of the interleukin-1β gene contains a polymorphic site at position –511 caused by a C→T transition, the C allele completing an AvaI restriction site. Genotyping was performed as described previously (7).

Frequency data were analyzed with chi-square tests. Possible confounding variables were compared by using t tests for independent data. Morphometric data were normally distributed. Results were subjected to univariate analyses of variance (ANOVAs) that assessed main and interaction effects, with brain region (frontal, temporal, parietal, occipital, subcortical, cerebellum) and hemisphere (left, right) as within-subject factors and diagnosis (schizophrenia, healthy) and genotype (1/1, 1/2, or 2/2) as between-subject factors. Significant interactions were resolved by separate analyses for each region and each diagnostic group.

An overview of the results is given in t1. Two allelic subgroups within each diagnostic group were formed by placing subjects homozygous for allele 1 into one group and collapsing allele 2 carriers (1/2 and 2/2) into the other. These subgroups (1/1 versus 1/2 and 2/2) did not differ significantly with respect to age, height, weight, education, verbal IQ, nicotine or alcohol consumption, age at onset of illness, or duration of illness (each t<1.05, df=90, p>0.30). Interleukin-1β genotype was not associated with diagnosis. The sample size allowed for sufficient power (0.80) to correctly accept the null hypothesis if the effect size was 0.60 (Cohen’s d) or larger.

Diagnosis and genotype had no main effects on either gray or white matter across the whole brain (t2). However, for gray matter volumes, the three-way interaction of diagnosis, genotype, and region indicated that there could be a region-specific effect. Separate three-factorial ANOVAs for each region revealed interaction effects of diagnosis and genotype in the frontal lobe (F=5.31, df=1, 88, p<0.03) and temporal lobe (F=4.26, df=1, 88, p=0.04). Further F tests showed that there was no genotype effect in the comparison subjects for frontal gray matter (F=0.97, df=1, 46, p=0.33) or temporal gray matter (F=0.07, df=1, 46, p=0.80), but among the schizophrenic patients allele 2 carriers had significantly smaller gray matter volumes in these areas than did 1/1 homozygotes (frontal: F=6.06, df=1, 42, p<0.02; temporal: F=11.62, df=1, 42, p=0.001). The ANOVA for white matter volumes showed a diagnosis-by-genotype interaction that was independent of brain region. Again, white matter volumes in comparison subjects were not affected by interleukin-1β genotype (F=1.36, df=1, 46, p=0.25), whereas schizophrenic patients had overall white matter deficits if they were allele 2 carriers (F=5.54, df=1, 42, p<0.03).

To our knowledge, this is the first study to examine the relationship between cytokine genetics and MRI brain structure in schizophrenia. Interleukin-1β–511 allele 2 carriers showed bifrontal-temporal gray matter volume deficits and generalized white matter tissue deficits. The data suggest that genetically determined interindividual differences in interleukin-1β may influence brain morphology in schizophrenia. The same presumably high-activity allele 2 in the promoter region of interleukin-1β (position –511) is associated with two other conditions that lead to altered brain morphology: Alzheimer’s disease and hippocampal sclerosis in temporal lobe epilepsy (11, 12).

We found no association between schizophrenia and the interleukin-1β genetic polymorphism at position –511. Since previous findings have suggested a lack of association with this polymorphic site, it is improbable that the allele 2 has a pathogenic effect per se (3). It is tentatively speculated that elevated levels of interleukin-1β interact with schizophrenia-specific risk factors, resulting in frontal-temporal gray matter deficits and more widespread white matter deficits.

It remains to be clarified whether the effect emerges during CNS development, or later, e.g., as a result of neurotoxicity caused by presumably high levels of pro-inflammatory cytokines. The present findings emphasize the interaction of disease-specific genetic risk factors with nonspecific environmental and other genetic vulnerability factors, leading in concert to altered neuronal networks.

   

Received June 16, 2000; revisions received Dec. 21, 2000, and Feb. 9, 2001; accepted Feb. 15, 2001. From the Departments of Psychiatry, Radiology, and Biostatistics and Epidemiology, Ludwig Maximilians University. Address correspondence to Dr. Rujescu, Psychiatrische Klinik, Ludwig-Maximilians-Universität München, Nuβbaumstrasse 7, 80336 München, Germany; Dan.Rujescu@psy.med.uni-muenchen.de (e-mail). Supported by Deutsche Forschungsgemeinschaft Nr. 231/96. The authors thank Nancy Andreasen, M.D., Ph.D., and her staff at the Mental Health Clinical Research Center, University of Iowa Hospitals and Clinics, who provided the segmentation program BRAINS.

Katila H, Appelberg B, Hurme M, Rimon R: Plasma levels of interleukin-1β and interleukin-6 in schizophrenia, other psychosis, and affective disorders. Schizophr Res  1994; 12:29-34
[PubMed]
[CrossRef]
 
Katila H, Hänninen K, Hurme M: Polymorphisms of the interleukin-1 gene complex in schizophrenia. Mol Psychiatry  1999; 4:179-181
[PubMed]
[CrossRef]
 
Laurent C, Thibaut F, Ravassard P, Campion D, Samolyk D, Lafargue C, Petit M, Martinez M, Mallet J: Detection of two new polymorphic sites in the human interleukin-1β gene: lack of association with schizophrenia in a French population. Psychiatr Genet  1997; 7:103-105
[PubMed]
[CrossRef]
 
Mousa A, Seiger A, Kjaeldgaard A, Bakhiet M: Human first trimester forebrain cells express genes for inflammatory and anti-inflammatory cytokines. Cytokine  1999; 11:55-60
[PubMed]
[CrossRef]
 
Rothwell NI, Hopkins SJ: Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci  1995; 18:130-136
[PubMed]
[CrossRef]
 
El-Omar E, Carrington M, Wong-Ho C, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan C, Rothman N, Lanyon G, Martin M, Fraumeni JF, Rabkin CS: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature  2000; 404:398-402
[PubMed]
[CrossRef]
 
Hurme M, Santtila S: IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1β genes. Eur J Immunol 1998; 28:2598-  2602
 
Santtila S, Savinainen K, Hurme M: Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1β production in vitro. Scand J Immunol  1998; 47:195-198
[PubMed]
[CrossRef]
 
Meisenzahl EM, Frodl T, Zetzsche T, Leinsinger G, Heiss D, Maag K, Hegerl U, Hahn K, Möller H-J: Adhesio interthalamica in male patients with schizophrenia. Am J Psychiatry  2000; 157:823-825
[PubMed]
[CrossRef]
 
Andreasen NC, Cizadlo T, Harris G, Swayze V II, O’Leary DS, Cohen G, Ehrhardt J, Yuh WT: Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatry Clin Neurosci  1993; 5:121-130
[PubMed]
 
Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilkock G, MacGowan S, Esiri MM, Murray LS, Dewar D, Love S, Moss T, Griffin WS: Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann Neurol  2000; 47:365-368
[PubMed]
[CrossRef]
 
Kanemoto K, Kawasaki J, Miyamoto T, Obayashi H, Nishimura M: Interleukin (IL)1β, IL-1 alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann Neurol  2000; 47:571-574
[PubMed]
[CrossRef]
 
+

References

Katila H, Appelberg B, Hurme M, Rimon R: Plasma levels of interleukin-1β and interleukin-6 in schizophrenia, other psychosis, and affective disorders. Schizophr Res  1994; 12:29-34
[PubMed]
[CrossRef]
 
Katila H, Hänninen K, Hurme M: Polymorphisms of the interleukin-1 gene complex in schizophrenia. Mol Psychiatry  1999; 4:179-181
[PubMed]
[CrossRef]
 
Laurent C, Thibaut F, Ravassard P, Campion D, Samolyk D, Lafargue C, Petit M, Martinez M, Mallet J: Detection of two new polymorphic sites in the human interleukin-1β gene: lack of association with schizophrenia in a French population. Psychiatr Genet  1997; 7:103-105
[PubMed]
[CrossRef]
 
Mousa A, Seiger A, Kjaeldgaard A, Bakhiet M: Human first trimester forebrain cells express genes for inflammatory and anti-inflammatory cytokines. Cytokine  1999; 11:55-60
[PubMed]
[CrossRef]
 
Rothwell NI, Hopkins SJ: Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci  1995; 18:130-136
[PubMed]
[CrossRef]
 
El-Omar E, Carrington M, Wong-Ho C, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan C, Rothman N, Lanyon G, Martin M, Fraumeni JF, Rabkin CS: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature  2000; 404:398-402
[PubMed]
[CrossRef]
 
Hurme M, Santtila S: IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1β genes. Eur J Immunol 1998; 28:2598-  2602
 
Santtila S, Savinainen K, Hurme M: Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1β production in vitro. Scand J Immunol  1998; 47:195-198
[PubMed]
[CrossRef]
 
Meisenzahl EM, Frodl T, Zetzsche T, Leinsinger G, Heiss D, Maag K, Hegerl U, Hahn K, Möller H-J: Adhesio interthalamica in male patients with schizophrenia. Am J Psychiatry  2000; 157:823-825
[PubMed]
[CrossRef]
 
Andreasen NC, Cizadlo T, Harris G, Swayze V II, O’Leary DS, Cohen G, Ehrhardt J, Yuh WT: Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatry Clin Neurosci  1993; 5:121-130
[PubMed]
 
Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilkock G, MacGowan S, Esiri MM, Murray LS, Dewar D, Love S, Moss T, Griffin WS: Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann Neurol  2000; 47:365-368
[PubMed]
[CrossRef]
 
Kanemoto K, Kawasaki J, Miyamoto T, Obayashi H, Nishimura M: Interleukin (IL)1β, IL-1 alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann Neurol  2000; 47:571-574
[PubMed]
[CrossRef]
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 44

Related Content
Articles
Books
Textbook of Traumatic Brain Injury, 2nd Edition > Chapter 3.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 10.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 1.  >
Textbook of Traumatic Brain Injury, 2nd Edition > Chapter 3.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 3.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles