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


METHODS
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.


CONCLUSIONS
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.
The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India; Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Sunil Vasu
SV
Kalmady
The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India; Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Ganesan
G
Venkatasubramanian
The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India; Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Venkataram
V
Shivakumar
Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
S
S
Gautham
The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India; Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Aditi
A
Subramaniam
The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India; Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Dania Alphonse
DA
Jose
National Institute of Biomedical Genomics, Kalyani, India.
Arindam
A
Maitra
Department of Neurovirology, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Vasanthapuram
V
Ravi
The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Bangalore N
BN
Gangadhar
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D066128:Gray Matter / Q000473:pathology; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*
D014150:Antipsychotic Agents; D015850:Interleukin-6