Page 23 - Biennial Report 2018-20 Jun 2021

arising from a combination of biological factors, social stigma, poor diagnosis, and limited access
to effective treatment. Genetic variation in the form of differences in the DNA sequence can
affect the severity of major depressive disorder. Moreover, such variations can also affect the
efficacy of treatment with the available drugs. One of the major biological reasons for
depression is thought to be low levels of serotonin. Serotonin is a neurotransmitter that is
released from one neuron and taken up by another across synapses. When the serotonin
released at the synapse, is only partly transmitted across the synapse, the rest is taken up by a
process called serotonin reuptake. Serotonin reuptake inhibitors, thus ensure prolonged
availability of serotonin, counteracting the low levels in the brain of patients suffering from
depression. Thus, genes of the pathway by which neurons make serotonin are prime candidates
for finding genetic variations that impact both disease severity and drug efficacy.

At IGIB, Ritushree Kukreti is working in close association with clinicians at the All India Institute
of Medical Sciences (AIIMS), under the ambit of a ICMR funded project to study distribution of
known functional genetic variants in serotonergic pathway genes, enzymes involved in
metabolism, drug transporters genes in depression patients and explore their role in disease
susceptibility, serum drug levels and inter-individual variability in therapeutic response. The
project aims firstly, to assess the depression patients treated with optimal antidepressant dosing
of escitalopram, fluoxetine and sertraline and monitor their respective serum drug levels at
steady state. Further, re-sequencing of candidate loci identified in the initial analyses, is
expected to identify additional single nucleotide polymorphisms including novel genetic variants
and haplotype blocks in Indian population with a role in disease severity, drug efficacy and safety.
Such novel variants may be taken up to perform functional follow-up studies using in-vitro cell
culture to understand their biological basis.

A well characterized patient cohort is the backbone of such clinical studies. Here, a total pool of
194 patients with clear major depressive disease diagnosis form a sizable cohort while 120
patients are being followed up to establish if they respond well to the prescribed SSRI (selective
serotonin reuptake inhibitor). Patient phenotypes such as age, gender, ethnicity, disease type
and subtypes, disease severity, duration of illness, dose, serum drug levels and response to drugs
are studied. Further plasma, RNA and DNA were isolated from the blood samples and stored at
-80°C for biochemical, gene expression and genotypic studies, respectively. Moreover, genetic
variants for drug response would be screened using a commercially available Bead Chip array
called Illumina Infinium Global Screening Array (GSA). GSA contains the multi-ethnic genome-
wide content, curated clinical research variants and quality control (QC) markers for precision
medicine research. This chip is an advanced genotyping array that includes ~6,50,000 markers.
It can help in pharmacogenomics research, disease characterization, disease association and risk
profiling studies, and markers for complex disease discovery. Along with this, optimization of
real-time polymerase chain reaction (RT-PCR) for genes involved in serotonergic pathways to
look at static as well as dynamic information is also a part of this study, which is aimed at
biomarker identification.

CENTRE OF EXCELLENCE FOR APPLIED DEVELOPMENT OF AYURVEDA, PRAKRITI
AND GENOMICS

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