Jian-Kang Chao1, Ming-Chang Yang2, Chia-Sheng Chen3, I-Chou Wang4, Wei-Tsung Kao5, Ming-Der Shi6. 1. Department of Psychiatry, Pingtung Branch, Kaohsiung Veterans General Hospital, Pingtung 91245, Taiwan; Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien 98142, Taiwan; Department of Social Work, National Pingtung University of Science & Technology, Pingtung 91201, Taiwan. 2. Laboratories of Medical Research, Center for Education and Faculty Development, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan. 3. Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan. 4. Department of Rehabilitation, Kaohsiung Veterans General Hospital Tainan Branch, Tainan 71051, Taiwan. 5. Laboratories of Medical Research, Center for Education and Faculty Development, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan; Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan. Electronic address: 030854@gmail.com. 6. Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital Tainan Branch, Tainan 71051, Taiwan; Department of Medical Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan, R.O.C.. Electronic address: shimd@mail.vhyk.gov.tw.
Abstract
BACKGROUND: COMT rs4680 Val158 allele is associated with high MB-COMT protein expression and elevated activity compared to the Met158 allele in post-mortem brains. A meta-analysis study suggested the link between COMT SNPs and MDD risk; in addition, MB membrane-bound (MB-COMT) specific genetic variation was reported that influences predisposition to depression amongst females. METHODS: Four tagSNPs, including rs4680, were genotyped. 268 MDD subjects and 223 controls were enrolled. MDD severity was rated by HDRS. Total-COMT and MB-COMT mRNA were detected by quantitative PCR. COMT protein and activity were assayed by western blot and methyltransferase assay, respectively. RESULTS: Haplotype TG of rs4633-rs4680, rs4646312 C, and rs4633 T allele might be linked to MDD vulnerability. Haplotype TG may interact with gender and affect MDD risk, since female haplotype TG carriers were estimated for a 9.17-fold higher risk than counterparts. COMT SNPs were not associated with HDRS scores. Haplotype TG female controls had higher MB-COMT protein, whereas non-TG female controls had higher soluble cytoplasmic (S-COMT) protein than other groups. COMT activity was much higher in controls than in MDD subjects. LIMITATIONS: Restricted numbers of homozygous TG carriers were recruited and analyzed for COMT mRNA, protein and activity. Only peripheral blood samples were used. CONCLUSIONS: A female-specific haplotype (haplotype TG)-MDD vulnerability association was found. TG female controls had higher MB-COMT protein and S-COMT. Altogether, high COMT protein and activity in female TG controls may be predisposing factors for enhanced MDD risk, though not correlated to MDD severity as rated by HDRS.
BACKGROUND:COMTrs4680 Val158 allele is associated with high MB-COMT protein expression and elevated activity compared to the Met158 allele in post-mortem brains. A meta-analysis study suggested the link between COMT SNPs and MDD risk; in addition, MB membrane-bound (MB-COMT) specific genetic variation was reported that influences predisposition to depression amongst females. METHODS: Four tagSNPs, including rs4680, were genotyped. 268 MDD subjects and 223 controls were enrolled. MDD severity was rated by HDRS. Total-COMT and MB-COMT mRNA were detected by quantitative PCR. COMT protein and activity were assayed by western blot and methyltransferase assay, respectively. RESULTS: Haplotype TG of rs4633-rs4680, rs4646312 C, and rs4633 T allele might be linked to MDD vulnerability. Haplotype TG may interact with gender and affect MDD risk, since female haplotype TG carriers were estimated for a 9.17-fold higher risk than counterparts. COMT SNPs were not associated with HDRS scores. Haplotype TG female controls had higher MB-COMT protein, whereas non-TG female controls had higher soluble cytoplasmic (S-COMT) protein than other groups. COMT activity was much higher in controls than in MDD subjects. LIMITATIONS: Restricted numbers of homozygous TG carriers were recruited and analyzed for COMT mRNA, protein and activity. Only peripheral blood samples were used. CONCLUSIONS: A female-specific haplotype (haplotype TG)-MDD vulnerability association was found. TG female controls had higher MB-COMT protein and S-COMT. Altogether, high COMT protein and activity in female TG controls may be predisposing factors for enhanced MDD risk, though not correlated to MDD severity as rated by HDRS.