Pharmacogenetics of Depression in the Mexican-American Population
Major depressive disorder (MDD) is a severe and incapacitating disease characterized by at least one of the following referring to depressed mood or loss of interest, motivation, or pleasure . For diagnosis, these symptoms must be accompanied by at least four of several additional symptoms related to appetite, sleep, pain, or lack of energy, psychomotor symptoms, and symptoms related to cognitive functions such as inability to plan or decide, slowed thinking, memory problems, attention problems or thoughts of death or dying, suicide, guilt . Depression is a widely known diagnosis with more than 300 million people affected worldwide, however, its severity and complexity are not sufficiently understood . A study conducted in October 2010 by Dong, et al. aimed to identify genes that are important in an individual’s predisposition for MDD or response to treatment and to the mechanism of action of antidepressant drugs. In this study, seven candidate genes that are important in the pathophysiology of MDD were sequenced . Researchers focused on a group of genes that reflects a sequence of events relevant to drug action at four levels including brain entry, binding to monoaminergic transporters, and effects at the transcription level, resulting in changes in neurotrophin and neuropeptide receptors .
Materials and methods
Control Group (264 Participants) Experimental Group (272 Participants)
7 day single-blind placebo phase 7 day single-blind placebo phase
Fluoxetine 10-40 mg per day Desipramine 50-200mg
Figure 1: Flow Chart explaining research progression.
MDD was diagnosed by referencing the DSM-IV description of a major depressive episode. All study participants underwent an initial medical and psychiatric assessment and had weekly follow-up assessments for 9 weeks. The study began with a 7-day single-blind placebo starting phase whose purpose was to reduce the impact of the placebo effect. Participants were randomly assigned to one of two treatment groups: fluoxetine 10–40 mg per day and desipramine 50–200 mg per day. Treatments were administered for the following 8 weeks in a double-blind manner. At the start of the study, researchers collected blood samples for DNA sequencing of the seven genes in focus.
Researchers identified 419 SNVs through the re-sequencing of approximately 105 kb of exonic sequence in the seven selected genes. Out of the 419 SNVs identified, 204 were new, including 86 in introns, 72 in untranslated regions (UTRs), 19 in coding regions, 18 in upstream and 9 in downstream regions .
Figure 2: Histograms display the total number of single nucleotide polymorphisms (SNPs) detected in intronic and exonic regions in the seven genes in 272 MDD patients and 264 healthy controls.
SNP based allelic and genotypic association analyses led researchers to conclude that 16 polymorphisms present in 5 genes were associated with MDD. This included two common 3′ UTR polymorphisms in gene NTRK2 and one rare 5′ UTR polymorphism in gene SLC6A4 . Among the nine SNPs in both allelic and genotypic tests, seven of these were uncommon. This included one in gene CREB1, two in gene ABCB1 and four in gene SLC6A4. In this study, there were 142 MDD affected patients who participated in the pharmacogenetic trial, 68 treated with desipramine and 74 treated with fluoxetine, which fully completed the 8-week antidepressant treatment. SNP-based allelic or genotypic association analyses of this group revealed that clinical remission status was associated with multiple polymorphisms in or near genes ABCB1, NTRK2 and SLC6A2.
In this study, researchers described a total of 204 new SNPs, the number of novel SNPs identified in the Mexican-American participants ranging between 12 and 57. Only a few of the novel SNPs were in coding regions and of those only 7 were non-synonymous. Results revealed minor associations of eight SNPs and four haplotypes with susceptibility for MDD located in four genes: ABCB1, CREB1, NTRK2 and SLC6A3. In addition, eight SNPs in SLC6A4 and one haplotype in SLC6A2 were also associated with MDD. SNPs in gene ABCB1 were associated with MDD and antidepressant response. Gene ABCB1 encodes a large transporter protein that functions as an active efflux pump helping to transport a wide variety of drugs from the brain to the blood . SNPs in the CREB1 gene were associated with MDD which concurs with other similar studies . CREB encodes a transcription factor that controls key growth factors that are important for synaptogenesis and neurogenesis . SNPs in gene NTRK2 were associated with susceptibility to MDD and antidepressant response. Gene NTRK2, also known as tyrosine kinase receptor B, and its ligand, brain-derived neurotropic factor, help to regulate short- and long-term synaptic functions and neural plasticity . SNPs in gene SLC6A2 were associated with reduction of HAM-D21 scores. This gene codes for a transporter that regulates norepinephrine homeostasis and the reuptake of norepinephrine into presynaptic nerve terminals . SNPs or haplotypes in gene SLC6A3, which encodes a transporter that is important in dopaminergic neurotransmission, were associated with risk for MDD. . Sequence variations in SLC6A4, which encodes a transporter that mediates antidepressant action and the behavioral effects of cocaine and amphetamines, have been investigated and may be associated with some neuropsychiatric conditions including MDD and may influence anxiety-related personality traits .
Since the Mexican American population is the most rapidly growing group in the United States, it is important that it is represented appropriately in research studies. This study helped to highlight some important genes in the pathophysiology of MDD, but even still, replication and confirmation from additional studies is required to gain a deeper understanding of the genetic influence and gene-environment interplay of this disorder. Currently, there is a lack of research studies focused on ethnic minority groups, therefore, discovering novel genetic variants in these growing populations has become increasingly important.
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