Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia

Abstract

Interleukin-1beta (IL-1beta) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1beta gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53-41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (chi(2) = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 +/- 7.7 and 22.7 +/- 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…This was corroborated by in vitro analysis of transformed B-cells from G/T and G/G genotype carriers (T/T not examined) that showed increases in protein secretion levels of IL-6, TNF-α, and IL-8 in T-allele carriers compared with G/G genotype carriers; suggesting a link between NRG1 genetic variation and immune dysregulation (Marballi et al 2010). This distant eQTL association between a NRG1 SNP and immune markers aligns with a clinical study in Finland reporting an interaction between a NRG1 SNP (SNP8NRG221533) and a SNP (rs16944) within the interleukin 1 beta gene, a pro-inflammatory cytokine (Hanninen et al 2008) as well as a preclinical study that showed developmental stage-specific deficits in phentoypes related to schizophrenia (i.e. social behavior, spatial working memory, PPI) among TM Nrg1 mice exposed to maternal immune activation (O'Leary et al 2014).…”

Functional Polymorphism in the Interleukin-6 and Interleukin-10 Genes in Patients with Paranoid Schizophrenia —A Case-Control Study

“…The research on polymorphism of IL-1β (−511 C/T) and NRG-1 (rs35753505 -C/T) (neuregulin 1) encoding genes was previously conducted. It has been shown that the risk of schizophrenia development is 10-fold higher if there is a combination of genotypes IL-1β and NRG-1 (IL-1β 2.2 and CC of NRG) in comparison with the combination IL-1β 2.2 and TT of NRG (Hänninen et al 2008). The polymorphism of IL-1 genes complex (IL-1α, IL-1β, IL-1 receptor antagonist) was also analyzed in schizophrenic patients representing the Japanese population.…”

Phenotypic effects of maternal immune activation and early postnatal milieu in mice mutant for the schizophrenia risk gene neuregulin-1

“…Several studies have also reported an association between NRG1 and disrupted neuroinflammatory processes in schizophrenia. Interaction between NRG1 and IL-1β is associated with increased risk for schizophrenia, as well as earlier age at onset (Hänninen et al, 2008). Additionally, a missense mutation within the transmembrane region of NRG1 increases activation of pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α in patients with schizophrenia (Marballi et al, 2010).…”