Summary.
This study investigated the potential interaction between the polymorphisms of serotonin transporter gene (SLC6A4, a 44 base pair insertion/deletion in the promoter region, 5-HTTLPR) and tumor necrosis factor-α gene (TNFA; −238G/A and −308G/A polymorphisms) on the development of schizophrenia, as well as the interaction of the three polymorphisms in relation to symptomatology, family history, onset age and antipsychotic treatment response. Genomic DNA analyses with polymerase chain reaction (PCR) was used for the genotyping. One hundred and fifty-two (152) patients with schizophrenia and 152 normal controls participated in the study. Any associations between the individual polymorphism and schizophrenia were not found. However, marginal association between subjects with both TNFA −238 A allele (genotype AA plus AG) and 5-HTTLPR s allele (ss plus sl) and presence of family history was found (p = 0.023; p = 0.026). The subjects with TNFA −308 AG genotype showed higher change in PANSS total score (p = 0.028). No significant interaction effect between 5-HTTLPR and TNFA −238/−308 polymorphisms either on the development of schizophrenia or on antipsychotics treatment response and psychopathology was found, although a significant interaction effect for subjects carrying TNFA −238 AG and −308 AA genotypes on a positive family history was observed (p = 0.017). These results suggest that the interaction effects between 5-HTTLPR and TNFA −238/−308 polymorphisms gives no significant contribution to the susceptibility to schizophrenia, and is not associated with clinical variables, antipsychotic treatment response and psychopathological features, except for family history of disease, at least in the Korean population.
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References
InstitutionalAuthorNameAmerican Psychiatric Association (1994) DSM-IV: Diagnostic and statistical manual of mental disorder EditionNumber4 American Psychiatric Press Washington DC
MJ Arranz AA Bolonna J Munro CJ Curtis DA Collier RW Kerwin (2000) ArticleTitleThe serotonin transporter and clozapine response Mol Psychiatry 5 124–125 Occurrence Handle10822334 Occurrence Handle1:STN:280:DC%2BD3c3osVWktQ%3D%3D Occurrence Handle10.1038/sj.mp.4000652
F Boin R Zanardini R Pioli CA Altamura M Maes M Gennarelli (2001) ArticleTitleAssociation between −G308A tumor necrosis factor alpha gene polymorphism and schizophrenia Mol Psychiatry 6 79–82 Occurrence Handle11244489 Occurrence Handle1:CAS:528:DC%2BD3MXhtlKgtbg%3D Occurrence Handle10.1038/sj.mp.4000815
KR Bonson JW Buckholtz DL Murphy (1996) ArticleTitleChronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans Neuropsychopharmacology 14 425–436 Occurrence Handle8726753 Occurrence Handle1:CAS:528:DyaK28XjslCnt7o%3D Occurrence Handle10.1016/0893-133X(95)00145-4
PB Bradley G Engel W Feniuk JR Fozard PPA Humphrey DN Middlemiss EJ Mylecharane BP Richardson PR Saxena (1986) ArticleTitleProposal for the classification and nomenclature of functional receptors for 5-hydroxytryptamine Neuropharmacology 25 563–576 Occurrence Handle2875415 Occurrence Handle1:CAS:528:DyaL28XkvFWqsbs%3D Occurrence Handle10.1016/0028-3908(86)90207-8
SA Chong WL Lee CH Tan AH Tay AO Chan EC Tan (2000) ArticleTitleAttempted suicide and polymorphism of the serotonin transporter gene in Chinese patients with schizophrenia Psychiatr Res 97 101–106 Occurrence Handle1:CAS:528:DC%2BD3MXpt12gtQ%3D%3D Occurrence Handle10.1016/S0165-1781(00)00229-8
S Duan Y Xu W Chen Z Liu T Guo J Gao L Bian Y Zhen X Li X Zhang Y Pan N Gu G Feng L He (2004) ArticleTitleNo association between the promoter variants of tumor necrosis factor alpha (TNF-alpha) and schizophrenia in Chinese Han population Neurosci Lett 366 139–143 Occurrence Handle15276234 Occurrence Handle1:CAS:528:DC%2BD2cXmtVSqurY%3D Occurrence Handle10.1016/j.neulet.2004.05.039
AB Erbagci H Herken O Koyluoglu N Yilmaz M Tarakcioglu (2001) ArticleTitleSerum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment Mediators Inflamm 10 109–115 Occurrence Handle11545247 Occurrence Handle1:CAS:528:DC%2BD3MXmslyqs78%3D Occurrence Handle10.1080/09629350120072761
MB First RL Spitzer M Gibbon JBW Williams (Eds) (1997) Structured Clinical Interview for DSM-IV-Clinician Version (SCID-CV) American Psychiatric Press Washington DC
J Gelernter AJ Pakstis KK Kidd (1995) ArticleTitleLinkage mapping of serotonin transporter protein gene SLC6A4 on choromosome 17 Hum Genet 95 677–680 Occurrence Handle7789954 Occurrence Handle1:CAS:528:DyaK2MXnsVeisb0%3D Occurrence Handle10.1007/BF00209486
RA Glennon (1990) ArticleTitleDo classical hallucinogens act as 5-HT2 agonists or antagonists? Neuropsychopharmacology 3 509–517 Occurrence Handle2078284 Occurrence Handle1:CAS:528:DyaK3MXkt1Wgtbw%3D
DC Goff AW Brotman M Waites S McCormick (1990) ArticleTitleTrial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients Am J Psychiatry 147 492–494 Occurrence Handle1969245 Occurrence Handle1:STN:280:By%2BC1MnjvVc%3D
M Hamone L Lanfumey S Mestikawy C Boni M Miquel F Bolanos L Schechter H Gozlan (1990) ArticleTitleThe main features of central 5-HT1 receptor Neuropsychopharmacology 3 349–360
HY Handoko DJ Nancarrow NK Hayward JU Ohaeri H Aghanwa JJ McGrath DF Levinson C Johns MK Walters DA Nertney TN Srinivasan R Thara BJ Mowry (2003) ArticleTitleTumor necrosis factor haplotype analysis amongst schizophrenia probands from four distinct populations in the Asia-Pacific region Am J Med Genet B Neuropsychiatr Genet 121 1–6 Occurrence Handle12898567 Occurrence Handle10.1002/ajmg.b.20059
R Hashimoto M Yoshida N Ozaki Y Yamanouchi N Iwata T Suzuki T Kitajima M Tatsumi K Kamijima H Kunugi (2004) ArticleTitleAssociation analysis of the −308G>A promoter polymorphism of the tumor necrosis factor alpha (TNF-alpha) gene in Japanese patients with schizophrenia J Neural Transm 111 217–221 Occurrence Handle14767724 Occurrence Handle1:CAS:528:DC%2BD2cXhtVOlsLo%3D Occurrence Handle10.1007/s00702-003-0089-4
A Heils A Teufel S Petri M Seemann D Bengel U Balling P Riederer KP Lesch (1995) ArticleTitleFunctional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene J Neural Transm (Gen Sect) 102 247–254 Occurrence Handle1:CAS:528:DyaK28Xhs1Kmu7w%3D Occurrence Handle10.1007/BF01281159
RJ Holden IS Pakula (1999) ArticleTitleTumor necrosis factor-alpha: is there a continuum of liability between stress, anxiety states and anorexia nervosa? Med Hypotheses 52 155–162 Occurrence Handle10340296 Occurrence Handle1:CAS:528:DyaK1MXivVCmuro%3D Occurrence Handle10.1054/mehy.1997.0641
D Hranilovic J Stefulj S Schwab M Borrmann-Hassenbach M Albus B Jernej D Wildenauer (2004) ArticleTitleSerotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression Biol Psychiatry 55 1090–1094 Occurrence Handle15158428 Occurrence Handle1:CAS:528:DC%2BD2cXktF2murg%3D Occurrence Handle10.1016/j.biopsych.2004.01.029
R Kaiser B Muller-Oerlinghausen D Filler PB Tremblay A Berghofer I Roots J Brockmoller (2002) ArticleTitleCorrelation between serotonin uptake in human blood platelets with the 44-bp polymorphism and the 17-bp variable number of tandem repeat of the serotonin transporter Am J Med Genet 114 323–328 Occurrence Handle11920857 Occurrence Handle10.1002/ajmg.10119
W Kaluza E Reuss S Grossmann R Hug RE Schopf PR Galle E Maerker-Hermann T Hoehler (2000) ArticleTitleDifferent transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism J Invest Dermatol 114 1180–1183 Occurrence Handle10844563 Occurrence Handle1:CAS:528:DC%2BD3cXktlyqt70%3D Occurrence Handle10.1046/j.1523-1747.2000.00001.x
SR Kay LA Opler JP Lindenmayer (1988) ArticleTitleReliability and validity of the positive and negative syndrome scale for schizophrenics Psychiatr Res 23 99–110 Occurrence Handle1:STN:280:BieB3czpvV0%3D Occurrence Handle10.1016/0165-1781(88)90038-8
T Kubota J Fang Z Guan RA Brown JM Krueger (2001) ArticleTitleVagotomy attenuates tumor necrosis factor-alpha-induced sleep and EEG delta-activity in rats Am J Physiol Regul Integr Comp Physiol 280 R1213–R1220 Occurrence Handle11247847 Occurrence Handle1:CAS:528:DC%2BD3MXjtV2htLY%3D
KP Lesch D Bengel A Heils SZ Sabol BD Greenberg S Petri J Benjamin CR Muller DH Hamer DL Murphy (1996) ArticleTitleAssociation of anxiety related traits with a polymorphism in the serotonin transporter gene regulatory region Science 274 1527–1531 Occurrence Handle8929413 Occurrence Handle1:CAS:528:DyaK28Xnt1ansL8%3D Occurrence Handle10.1126/science.274.5292.1527
CM Lewis DF Levinson LH Wise LE DeLisi RE Straub I Hovatta et al. (2003) ArticleTitleGenome scan meta-analysis of schizophrenia and bipolar disorder, part II. Schizophrenia Am J Hum Genet 73 34–48 Occurrence Handle12802786 Occurrence Handle1:CAS:528:DC%2BD3sXlsVOitL8%3D Occurrence Handle10.1086/376549
AK Malhotra D Goldman C Mazzanti A Clifton A Breier D Pickar (1998) ArticleTitleA functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics Mol Psychiatry 3 328–332 Occurrence Handle9702741 Occurrence Handle1:CAS:528:DC%2BD3cXlslegsLk%3D Occurrence Handle10.1038/sj.mp.4000412
IV Meira-Lima AC Pereira GF Mota M Floriano F Araujo AJ Mansur JE Krieger H Vallada (2003) ArticleTitleAnalysis of a polymorphism in the promoter region of the tumor necrosis factor alpha gene in schizophrenia and bipolar disorder: further support for an association with schizophrenia Mol Psychiatry 8 718–720 Occurrence Handle12888800 Occurrence Handle1:CAS:528:DC%2BD3sXlvVGjtLg%3D Occurrence Handle10.1038/sj.mp.4001309
JR Mendes de Oliveira PA Otto H Vallada V Lauriano H Elkis B Lafer L Vasquez V Gentil MR Passos Bueno M Zatz (1998) ArticleTitleAnalysis of a novel functional polymorphism within the promoter region of the serotonin transporter gene (5-HTT) in Brazilian patients affected by bipolar disorder and schizophrenia Am J Med Genet 81 225–227 Occurrence Handle9603609 Occurrence Handle1:STN:280:DyaK1c3msVOksA%3D%3D Occurrence Handle10.1002/(SICI)1096-8628(19980508)81:3<225::AID-AJMG4>3.0.CO;2-V
P Monteleone M Fabrazzo A Tortorella M Maj (1997) ArticleTitlePlasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment Psychiatr Res 71 11–17 Occurrence Handle1:CAS:528:DyaK2sXltlWrt7o%3D Occurrence Handle10.1016/S0165-1781(97)00036-X
R Mossner A Heils G Stober O Okladnova S Daniel KP Lesch (1998) ArticleTitleEnhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6 Neurochem Int 33 251–254 Occurrence Handle9759920 Occurrence Handle1:CAS:528:DyaK1cXmtlCitrs%3D Occurrence Handle10.1016/S0197-0186(98)00026-6
J Naudin C Capo B Giusano JL Mege JM Azorin (1997) ArticleTitleA differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res 26 227–233 Occurrence Handle9323355 Occurrence Handle1:STN:280:ByiH28vmsVU%3D Occurrence Handle10.1016/S0920-9964(97)00059-5
L Naylor B Dean A Pereira A Mackinnon A Kouzmenko D Copolov (1998) ArticleTitleNo association between the serotonin transporter-linked promoter region polymorphism and either schizophrenia or density of the serotonin transporter in human hippocampus Mol Med 4 671–674 Occurrence Handle9848084 Occurrence Handle1:CAS:528:DyaK1cXnsFGrsb4%3D
CU Pae JH Chae WM Bahk H Han TY Jun KS Kim YS Kwon A Serretti (2003a) ArticleTitleTumor necrosis factor-alpha gene polymorphism at position −308 and schizophrenia in the Korean population Psychiatry Clin Neurosci 57 399–403 Occurrence Handle1:CAS:528:DC%2BD3sXntVSltLg%3D Occurrence Handle10.1046/j.1440-1819.2003.01138.x
CU Pae JJ Kim SJ Lee CU Lee C Lee IH Paik HR Park S Yang A Serretti (2003b) ArticleTitlePolymorphism of the serotonin transporter gene and symptomatic dimensions of schizophrenia in the Korean population Neuropsychobiology 47 182–186 Occurrence Handle1:CAS:528:DC%2BD3sXkvVegs7k%3D Occurrence Handle10.1159/000071212
A Reichenberg R Yirmiya A Schuld T Kraus M Haack A Morag T Pollmacher (2001) ArticleTitleCytokine-associated emotional and cognitive disturbances in humans Arch Gen Psychiatry 58 445–452 Occurrence Handle11343523 Occurrence Handle1:STN:280:DC%2BD3M3ltlCrtA%3D%3D Occurrence Handle10.1001/archpsyc.58.5.445
M Riedel H Kronig MJ Schwarz RR Engel KU Kuhn C Sikorski S Sokullu M Ackenheil HJ Moller N Muller (2002) ArticleTitleNo association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia Eur Arch Psychiatry Clin Neurosci 252 232–234 Occurrence Handle12451465 Occurrence Handle10.1007/s00406-002-0386-1
CJ Schmidt SM Sorensen JH Kehne AA Carr MG Palfreyman (1995) ArticleTitleThe role of 5-HT receptors in antipsychotic activity Life Sci 56 2209–2222 Occurrence Handle7791509 Occurrence Handle1:CAS:528:DyaK2MXls12qt7s%3D Occurrence Handle10.1016/0024-3205(95)00210-W
SG Schwab J Hallmayer M Albus B Lerer GN Eckstein M Borrmann (2000) ArticleTitleA genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6 Mol Psychiatry 5 638–649 Occurrence Handle11126394 Occurrence Handle1:CAS:528:DC%2BD3cXosFSgs7w%3D Occurrence Handle10.1038/sj.mp.4000791
SG Schwab S Mondabon M Knapp M Albus J Hallmayer M Borrmann-Hassenbach M Trixler M Gross TG Schulze M Rietschel B Lerer W Maier DB Wildenauer (2003) ArticleTitleAssociation of tumor necrosis factor alpha gene −G308A polymorphism with schizophrenia Schizophr Res 65 19–25 Occurrence Handle14623370 Occurrence Handle10.1016/S0920-9964(02)00534-0
PC Sham D Curtis (1995) ArticleTitleMonte Carlo test for association between disease and alleles at highly polymorphic loci Ann Hum Genet 59 97–105 Occurrence Handle7762987
TV Shcherbatykh VD Golimbet VA Orlova VG Kaleda (2000) ArticleTitlePolymorphism in the human serotonin transporter gene in endogenous psychoses Genetika 36 1712–1715 Occurrence Handle11190480 Occurrence Handle1:STN:280:DC%2BD3M7hs12nuw%3D%3D
G Stober S Jatzke A Heils G Jungkunz E Fuchs M Knapp P Riederer KP Lesch (1998) ArticleTitleSusceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene Eur Arch Psychiatry Clin Neurosci 248 82–86 Occurrence Handle9684917 Occurrence Handle1:STN:280:DyaK1czkvVSmuw%3D%3D Occurrence Handle10.1007/s004060050022
RM Strieter SL Kunkel RC Bone (1993) ArticleTitleRole of tumor necrosis factor-alpha in disease states and inflammation Crit Care Med 21 S447–S463 Occurrence Handle8403983 Occurrence Handle1:STN:280:ByuD3cjptVA%3D
A Serretti M Catalano E Smeraldi (1999a) ArticleTitleSerotonin transporter gene is not associated with symptomatology of schizophrenia Schizophr Res 35 33–39 Occurrence Handle1:STN:280:DyaK1M7ktlertg%3D%3D Occurrence Handle10.1016/S0920-9964(98)00111-X
A Serretti F Macciardi C Cusin E Lattuada R Lilli D Di Bella M Catalano E Smeraldi (1999b) ArticleTitleNo interaction of GABA(A) alpha-1 subunit and dopamine receptor D4 exon 3 genes in symptomatology of major psychoses Am J Med Genet 88 44–49 Occurrence Handle1:STN:280:DyaK1M7lvVamsQ%3D%3D Occurrence Handle10.1002/(SICI)1096-8628(19990205)88:1<44::AID-AJMG8>3.0.CO;2-Y
A Serretti R Lilli C Lorenzi E Lattuada C Cusin E Smeraldi (2002) ArticleTitleSerotonin transporter gene (5-HTTLPR) and major psychoses Mol Psychiatry 7 95–99 Occurrence Handle11803453 Occurrence Handle1:CAS:528:DC%2BD38XhsVGlsrw%3D Occurrence Handle10.1038/sj.mp.4001936
EC Tan SA Chong CH Tan YY Teo K Peng R Mahendran (2003) ArticleTitleTumor necrosis factor-alpha gene promoter polymorphisms in chronic schizophrenia Biol Psychiatry 54 1205–1211 Occurrence Handle14643088 Occurrence Handle1:CAS:528:DC%2BD3sXpt1Wiu7Y%3D Occurrence Handle10.1016/S0006-3223(03)00345-7
SJ Tsai CJ Hong YW Yu CH Lin HL Song HC Lai KH Yang (2000) ArticleTitleAssociation study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response Schizophr Res 44 177–181 Occurrence Handle10962219 Occurrence Handle1:STN:280:DC%2BD3cvotVGktA%3D%3D Occurrence Handle10.1016/S0920-9964(99)00170-X
SJ Tsai CJ Hong YW Yu CH Lin LL Liu (2003) ArticleTitleNo association of tumor necrosis factor alpha gene polymorphisms with schizophrenia or response to clozapine Schizophr Res 65 27–32 Occurrence Handle14623371 Occurrence Handle10.1016/S0920-9964(02)00531-5
AG Wilson C Gordon FS di Giovine N de Vries LB van de Putte P Emery GH Duff (1994) ArticleTitleA genetic association between systemic lupus erythematosus and tumor necrosis factor alpha Eur J Immunol 24 191–195 Occurrence Handle8020556 Occurrence Handle1:CAS:528:DyaK2cXnsFehsg%3D%3D
X Xie J Ott (1993) ArticleTitleTesting linkage disequilibrium between a disease gene and marker loci Am J Hum Genet [Suppl] 53 1107
JH Zhao (2004) ArticleTitle2LD, Genecounting and HAP: computer programs for linkage disequilibrium analysis Bioinformatics 20 1325–1326 Occurrence Handle14871868 Occurrence Handle1:CAS:528:DC%2BD2cXkt1Srtb0%3D Occurrence Handle10.1093/bioinformatics/bth071
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Pae, CU., Serretti, A., Artioli, P. et al. Interaction analysis between 5-HTTLPR and TNFA −238/−308 polymorphisms in schizophrenia. J Neural Transm 113, 887–897 (2006). https://doi.org/10.1007/s00702-005-0358-5
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DOI: https://doi.org/10.1007/s00702-005-0358-5