Catechol O-methyltransferase pharmacogenomics and selective serotonin reuptake inhibitor response

Abstract

We applied a systematic pharmacogenetic approach to investigate the role of genetic variation in the gene encoding catechol O-methyltransferase (COMT) in individual variation in selective serotonin reuptake inhibitor (SSRI) response among depressed patients. In all, 23 single-nucleotide polymorphisms (SNPs) in COMT were genotyped using DNA from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study (N=1914). One SNP, rs13306278, located in the distal promoter region of COMT, showed significant association with remission in White non-Hispanic (WNH) subjects (P=0.038). Electromobility shift assay for rs13306278 showed alternation in the ability of the variant sequence to bind nuclear proteins. A replication study was performed using samples from the Mayo Clinic Pharmacogenetics Research Network Citalopram/Escitalopram Pharmacogenomic study (N=422) that demonstrated a similar trend for association. Our findings suggest that novel genetic markers in the COMT distal promoter may influence SSRI response phenotypes.

Trial registration: ClinicalTrials.gov NCT00613470.

Figure 1

Human COMT genetic polymorphisms and linkage disequilibrium in European-American (EA) subjects. (A) Human COMT genetic polymorphisms. Arrows, locations and frequencies of polymorphisms. Black and gray rectangles, coding exons, with the gray area specific for the MB-COMT open reading frame (ORF). Open rectangles, noncoding exons. I/D, insertion/deletion. The well characterized Val108/158Met polymorphism and the 5′-FR(−485) polymorphism are boxed. * = polymorphisms that were genotyped in the STAR*D samples. (B) COMT linkage disequilibrium (LD) displayed by the use of Haploview 3.3. On the left is the COMT LD structure in the STAR*D White Non-Hispanic population (WNH), and on the right is COMT LD structure derived from polymorphisms identified during our COMT resequencing studies performed with 60 EA DNA samples., Polymorphisms with minor allele frequencies of greater than 5% were included in the LD analyses.

Figure 2

COMT functional genomic studies. (A) EMS assay for the 5′-FR(−485) COMT SNP. U87G glioma cell nuclear extract was incubated with biotin-labeled oligonucleotides. (B) In silico analysis by AliBaba 2.1 for possible transcription binding motif(s) within the 5′-FR(−485) locus.