Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

Sunil Vasu Kalmady, Ganesan Venkatasubramanian, Venkataram Shivakumar, S Gautham, Aditi Subramaniam, Dania Alphonse Jose, Arindam Maitra, Vasanthapuram Ravi, Bangalore N Gangadhar, Sunil Vasu Kalmady, Ganesan Venkatasubramanian, Venkataram Shivakumar, S Gautham, Aditi Subramaniam, Dania Alphonse Jose, Arindam Maitra, Vasanthapuram Ravi, Bangalore N Gangadhar

Abstract

Background: Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls.

Methodology: We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms.

Results: Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women.

Conclusion: Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia. Moreover, this relationship was antithetical in healthy controls and this effect was observed in men but not in women. Together, these observations support a "differential susceptibility" effect of rs1800795 in schizophrenia pathogenesis mediated through hippocampal volume deficit that is of possible neurodevelopmental origin.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Cerebral MRI depicting manual segmentation…
Figure 1. Cerebral MRI depicting manual segmentation of hippocampus.
Figure shows MRI with segmented hippocampus in axial, sagittal & coronal sections within 3D-Slicer software interface.
Figure 2. Significant diagnosis-by-genotype interaction on hippocampal…
Figure 2. Significant diagnosis-by-genotype interaction on hippocampal volumes.
Figure shows significant diagnosis by genotype interaction involving both right and left hippocampal volumes – i.e. the effect of rs1800795 genotypes [GG & GG/GC] on hippocampal volume was found to be antithetical between patients and controls.
Figure 3. Box plot depicting significant diagnosis-by-genotype…
Figure 3. Box plot depicting significant diagnosis-by-genotype interaction on hippocampus volume between patients and controls.
Figure shows box plot depicting significant diagnosis by genotype interaction involving both right and left hippocampal volumes – i.e. the effect of rs1800795 genotypes [GG & GG/GC] on hippocampal volume was found to be antithetical between patients and controls; the interaction boxplot shows the five statistics of hippocampal volume (minimum, first quartile, median, third quartile, and maximum) for each genotype per group.
Figure 4. Significant effect of diagnosis-by-genotype interaction…
Figure 4. Significant effect of diagnosis-by-genotype interaction on hippocampus volume as demonstrated by voxel based morphometry analysis.
Red blobs in the figures show significant diagnosis by genotype interaction involving both right and left hippocampal volumes by VBM in parallel to those that were observed in manual analyses.
Figure 5. Scatter plot depicting the relationship…
Figure 5. Scatter plot depicting the relationship between plasma IL-6 level and hippocampal volumes in schizophrenia patients and healthy controls.
Figure 6. Illustration of the differential susceptibility…
Figure 6. Illustration of the differential susceptibility in contrast to diathesis-stress model.
Total hippocampal volume is represented against environmental adversity and polygenic liability that are known to be associated with schizophrenia (not quantified in this study). Pink and blue lines depict homozygous G and carrier of C rs1800795 genotypes respectively, that differ in their responsiveness to environmental and epistatic factors: the “plasticity” conferred by homozygous G is disproportionately more affected by influences compared to the “fixed” C carrier group. The gray line depicts “vulnerability”, that is affected only when exposed to an adversity, and this diathesis-stress view is not supported by data in the current study. In relation to these models, the bottom panel shows predicted probability of 'schizophrenia' outcome as the function of total hippocampal volume.

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