The Pharmacogenomics Journal (2004) 4, 29–33 & 2004 Nature Publishing Group All rights reserved 1470-269X/04 $25.00 www.nature.com/tpj ORIGINAL ARTICLE Association between a G-protein b3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders H-J Lee1 ABSTRACT 1 The genes involved in signal transduction are major candidates in association J-H Cha studies on affective disorders and responses to antidepressants. We 1 B-J Ham investigated whether the C825T polymorphism of the b3 subunit of G C-S Han1 protein (GNB3) gene is associated with the symptom severity or treatment Y-K Kim1 response of major depressive disorders (MDDs) in a Korean sample of 106 S-H Lee2 MDD patients; our study also included 133 healthy controls. Hypertensive 3 subjects were excluded from the study because association between GNB3 S-H Ryu variants and hypertension has been reported in previous studies. We found R-H Kang1 significantly more carriers of the 825T allele in MDD patients than in normal M-J Choi1 controls (w2 ¼ 6.37, P ¼ 0.012; OR ¼ 2.19, 95% CI 1.18–4.05). The T-allele M-S Lee1 carriers showed higher scores than those with the CC genotype in the baseline total and in some subcategories of the Hamilton Depression Rating 1Department of Psychiatry, Korea University Scale (Po0.05). We also found a statistically significant association between College of Medicine, Seoul, Korea; 2Department T-allele carriers and antidepressant treatment response (Po0.05). These of Psychiatry, Inje University College of Medicine, results suggest that the T allele of the C825T polymorphism in the GNB3 3 Seoul, Korea; Department of Psychiatry, Konkuk gene is associated with MDD. It was also demonstrated that MDD patients University College of Medicine, Seoul, Korea bearing the T allele had a severe symptomatology and a better response to Correspondence: antidepressant treatment than patients without the T allele. Dr M-S Lee, Department of Psychiatry, The Pharmacogenomics Journal (2004) 4, 29–33. doi:10.1038/sj.tpj.6500217 Anam Hospital, Korea University College of Published online 2 December 2003 Medicine, 126-1, 5-Ka, Anam-Dong, Sungbuk-Ku, Seoul 136-705, Korea. Tel: þ 82-2-9205815 Keywords: G protein; GNB3; polymorphism; major depressive disorder; antidepres- Fax: þ 82-2-9272836 sants; treatment response E-mail: [email protected] INTRODUCTION Hundreds of cell-surface receptors for neurotransmitters and other ligands use G proteins to transduce intracellular signaling pathways. G proteins play important roles in determining the specificity and temporal characteristics of cellular responses to signals. Gb proteins form dimeric complexes with Gg subunits that interact with Ga subunits to generate a heterotrimeric G protein. Upon receptor activation, G proteins dissociate into free Ga and Gbg subunits that can activate various effectors. Effector proteins of the Gbg complex include phospholipases, adenylyl cyclases, ion channels, G-protein-coupled receptor kinases, and Received: 19 June 2003 phosphoinositide-3 kinases.1,2 Revised: 05 October 2003 3 Accepted: 14 October 2003 Recently, Siffert et al detected a single-nucleotide polymorphism (SNP) of Published online 2 December 2003 C825T in exon 10 of the gene encoding the b3 subunit of G protein (GNB3). The Association between GNB3 gene and depression H-J Lee et al 30 T allele of this SNP is associated with the occurrence of a df ¼ 1, P ¼ 0.041; OR ¼ 1.46, 95% CI 1.02–2.10). The geno- splice variant (Gb3s) that leads to the deletion of 41 amino types of C825T SNP were classified into two groups: T þ (TT acids. The Gb3s variant has been reported to be not only and CT genotypes) and TÀ (CC genotype), because the associated with increased signal transduction and ion expression of the more active splice variant of GNB3 transport, but also with pathophysiological conditions such depends on the presence of at least one T allele.3 At least as hypertension3–7 and obesity.8,9 one copy of the T allele (T þ ) was carried by 82.1 and 67.7% More recently, Zill et al10 found an association between of those in the MDD and control groups, respectively, and the C825T SNP of GNB3 and depression. They reported that the presence of T allele (T þ ) was associated with an the frequency of the T allele was significantly higher in increased likelihood of MDD (w2 ¼ 6.37, df ¼ 1, P ¼ 0.012; depressive patients than in healthy controls and schizo- OR ¼ 2.19, 95% CI 1.18–4.05) (Table 1). phrenic patients. They also found a significant association Table 2 presents a comparison of characteristics between between the TT genotype and responses to antidepressant genotype groups of the MDD patients, including sex, age, treatment. Most recently, Serretti et al11 reported the same baseline symptom clusters, and therapeutic response. Sig- results on treatment response to selective serotonin reuptake nificant differences between the two subject groups were inhibitors in a large sample of depressive Italian patients. present in the baseline total, core, psychic anxiety, and Bondy et al12 also reported a significant increase in the delusion HAM-D scores, and in the baseline CGI-S scores GNB3T allele in depressive disorder, and that the TT (Table 2). A total of 106 of the MDD patients completed 8 genotype in the presence of the D allele of the angioten- weeks of antidepressant treatment and underwent evalua- sin-I-converting-enzyme gene is associated with a more than tion using the HAM-D and CGI-S scores. There were no five-fold increase in the risk of major depression. However, significant differences in end-point (8-week) total and no association between depression and the GNB3T allele was subcategory HAM-D scores (total HAM-D scores; found in an Asian population.13,14 TT ¼ 7.376.4, TC ¼ 6.574.9, CC ¼ 8.776.2; F ¼ 0.97, In the present study, the relationships between the C825T P ¼ 0.38; the other data were not presented). However, the SNP of the GNB3 gene and the clinical symptoms of major percentage changes in the HAM-D (total and psychic depressive disorders (MDDs) in a Korean sample of 106 MDD anxiety) score and CGI-S score after 8-week treatment were patients are compared with 133 healthy controls. In higher for the T þ genotype group than for the TÀ group addition, the association between the C825T SNP and (Table 2). Further, the responder percentage was higher for antidepressant therapeutic response was tested. the T þ group than for the TÀ group. Interestingly, however, frequencies of remitters were not significantly different RESULTS between the subject groups (Table 2). The genotypes and allele distributions for the GNB3 C825T SNP for the MDD patients and controls are given in Table 1. DISCUSSION The sex distributions of the MDD patients and the control The results of our study suggest that the T allele of a population were not different (male : female, MDD 28 : 78, functional polymorphism (C825T) in the GNB3 gene is controls 44 : 89; w2 ¼ 1.25, P ¼ 0.26), but their age distribu- associated with MDD. It was also demonstrated that MDD tions were different (MDD, 47.1713.3 years; controls, patients bearing the T allele had a more severe symptoma- 43.4710.2 years; t ¼ 2.32, P ¼ 0.021). The distributions of tology and a better response to antidepressant treatment the C825T SNP genotypes for these two groups were in than patients without it. Although this finding is consistent Hardy–Weinberg equilibrium (MDD: w2 ¼ 2.04, df ¼ 1, with previous studies in Caucasians,4,10,12 it differs from that P ¼ 0.15; controls: w2 ¼ 0.41, df ¼ 1, P ¼ 0.52). in a Japanese population.13 There was a significant difference in the genotype The frequencies of the T allele in Asian populations (42– distribution between MDD patients and the controls 53%) are different from those in Caucasians (27–42%). In (w2 ¼ 6.37, df ¼ 2, P ¼ 0.041). Comparison of allele frequen- the Japanese sample of the study of Kunugi et al,13 the cies revealed an excess of T allele in MDD patients (w2 ¼ 4.19, frequency of the T allele was 0.53 in both depressive and Table 1 Genotypes, allele, and allele carrier frequencies of C825T polymorphism of the G-protein b3 subunit among patients with major depressive disorder and normal controls Genotypes Allele frequencies Allele carrier frequencies TT CT CC T C T+ TÀ Major depressive disorder (n ¼ 106) 27 (25.5%) 60 (56.6%) 19 (17.9%) 0.54 0.46 0.82 0.18 Controls (n ¼ 133) 28 (21.1%) 62 (46.6%) 43 (32.3%) 0.44 0.56 0.68 0.32 T+, allele subjects include TT or CT genotypes; TÀ, allele subjects include CC genotype only. Genotypes: w2 ¼ 6.37, df ¼ 2, P ¼ 0.041; alleles: w2 ¼ 4.19, df ¼ 1, P ¼ 0.041 (OR ¼ 1.46, 95% CI 1.02–2.10); allele carriers: w2 ¼ 6.37, df ¼ 1, P ¼ 0.012 (OR ¼ 2.19, 95% CI 1.18–4.05). The Pharmacogenomics Journal Association between GNB3 gene and depression H-J Lee et al 31 Table 2 Demographic data and antidepressant treatment response among C825T SNP genotypes and allele carrier status in patients with major depressive disorder TT TC CC ANOVA T+ vs TÀ FPP Sex (F/M) 6/21 16/44 6/13 w2 ¼ 0.51 0.78 0.57 Age 46.3 (11.7) 47.5 (12.9) 46.9 (17.1) 0.82 0.92 0.94 Baseline HAM-D Core 12.9 (3.9)a 11.6 (3.1)b 9.5 (2.6)a,b 4.98 0.009 0.007 Sleep 3.5 (1.7) 3.7 (2.5) 3.1 (1.7) 0.62 0.54 0.325 Activity 4.0 (1.8) 3.8 (1.6) 3.9 (1.1) 0.16 0.85 0.887 Psychic anxiety 4.1 (1.5)a 3.5 (1.5) 2.6 (1.1)a 4.26 0.017 0.016 Somatic anxiety 4.1 (1.4) 4.2 (1.4) 4.2 (1.4) 0.024 0.98 0.991 Delusion 3.0 (1.4) 3.1 (1.4) 2.1 (1.6) 2.95 0.058 0.017 Total 26.8 (7.0)a 25.5 (6.7)b 21.4 (4.9)a,b 3.41 0.038 0.014 Baseline CGI-S 4.5