Lack of Evidence For Association Between Serotonin
Transporter Gene Polymorphism and Obsessive
Compulsive Disorder
fienel Tot Acar*, M. Emin Erdal**, Kemal Yaz›c›***, Aylin Ertekin Yaz›c›****,
Ayfle Devrim Baflterzi*****
* Department of Psychiatry Mersin University, Mersin, Turkey
** Department of Medical Biology and Genetics, Mersin University, Mersin, Turkey *** Department of Psychiatry Mersin University, Mersin, Turkey
**** Department of Psychiatry Mersin University, Mersin, Turkey ***** Department of Psychiatry Mersin University, Mersin, Turkey Correspondence:
Dr. fienel Tot Acar
Department of Psychiatry Mersin University Zeytinlibahçe Cad. 33070 Mersin, Turkey Tel: +903243374300 (1139) Fax: +903243374305 E-mail: seneltot@mersin.edu.tr ABSTRACT
Objective: Although it is believed that obsessive compulsive disorder [OCD] has a genetic
compo-nent, the type and number of genes involved in this disorder have not been understood entirely. The serotonin transporter [5-HTT] gene has been considered a candidate gene for OCD. The aim of this study was to determine the association of the 5-HTT gene with OCD by examining the poly-morphisms in the promoter region [5-HTTLPR] and in the second intron [VNTR] in a Turkish samp-le.
Method: Sixty OCD patients and 85 control subjects were included in the study. All subjects were unrelated Turkish people.
Findings: The genotypic pattern of distribution of 5-HTTLPR and 5-HTT VNTR was not different
between the OCD patients and controls. There were no significant differences among patients with positive family history for OCD, those with negative family history for OCD and controls with respect to allele frequencies of 5-HTTLPR or 5-HTT VNTR polymorphisms. Allele frequencies were not statistically different in patients having tics themselves or in family compared to patients wit-hout such history. No significant genetic differences were observed between serotonin reuptake inhibitor responders and non-responders.
Discussion: The 5-HTT gene has been considered a candidate gene that could affect the risk of
OCD. Literature about this issue is quite controversial. Some studies reported an association of -HTTLPR or 5-HTT VNTR polymorphisms with OCD, whereas others including our study did not. Ho-wever, this does not exclude the possibility that there may be other mechanisms affecting seroto-nergic systems thought to be involved in OCD or polymorphisms of other genomic regions of 5-HTT may play role in the pathogenesis of the disorder.
Conclusion: We could not find any evidence for the association of 5-HTTLPR and 5-HTT VNTR
poly-morphisms with OCD, response to treatment with serotonin reuptake inhibitors, positive family history for OCD and presence of tics.
New/Yeni Symposium Journal • www.yenisymposium.net 32 Ocak 2010 | Cilt 48 | Say› 1
INTRODUCTION
Obsessive compulsive disorder [OCD] is a relati-vely common illness characterized by recurrent and disturbing thoughts, [obsessions] and/or repetitive, stereotyped behaviors that the person feels driven to perform [compulsions] but recognizes as irrational or excessive. OCD is now known to be among the most common of psychiatric disorders, with lifetime preva-lence estimates of 2-3% of the population (Hollander 1993). Etiology of the disorder is not clearly understo-od. Recent findings in neuroimaging and treatment studies indicate that some cases of OCD may be asso-ciated with specific autoimmune, receptor or neuro-anatomical abnormalities. These data suggest etiolo-gic heterogeneity within this diagnostic category; they have also increased interest in and provided some clu-es for understanding the possible genetic underpin-nings of obsessive-compulsive disorder.
Results of family and twin studies have led to con-sideration of a genetic factor in the etiology of OCD (Rasmussen 1993, Pauls et al 1995). Genetic studies on this field are new and limited in number. Although it is believed that OCD has a strong genetic component, the type and number of genes involved in this disor-der have not been undisor-derstood entirely.
It is known that serotonin reuptake inhibitors
[SRIs] are beneficial in OCD patients and serotonergic dysfunction has been thought to play role in the pat-hophysiology of OCD (Sullivan and Coplan 2000, Papp 2000). It was suggested that the 5-hydroxytryp-tamine [serotonin, 5-HT] related genes may be invol-ved in the pathogenesis of OCD. SRIs block the reup-take of 5-HT into the presynaptic neuron, a process mediated by the serotonin-transporter [5-HTT], which plays a critical role in the termination of serotonergic neurotransmission by sodium-dependent uptake of 5-HT into the presynaptic neuron (Amara and Kuhar 1993, Lesch and Bengel 1995). Changes in 5-HTT gene expression have been noted after chronic treatment with SRIs (Lesch et al 1993). The 5-HTT gene has been considered a candidate gene that could affect the risk of OCD in the last few years. The 5-HTT gene is loca-ted on chromosome 17q 11.2 (Ramamoorthy et al 1993, Gelertner et al 1995). Two polymorphic sites in 5-HTT gene attracted much interest: a variable-number-tan-dem-repeated [VNTR] of 17-bp repeats in the second intron and an insertion/deletion in 5'-flanking promo-ter region [5-HTT gene-linked polymorphic region-5-HTTLPR] creating a short [S] and a long [L] alleles. The L allele of 5-HTT produces expression levels three times greater than the short allele (Lesch et al 1996, Heils et al 1996, Collier et al 1996).
ÖZET
OBSES‹F KOMPULS‹F BOZUKLUK ‹LE SEROTON‹N TRANSPORTER GEN POL‹MORF‹ZM‹ ARASINDA ‹L‹fiK‹ EKS‹KL‹⁄‹
Amaç: Obsesif kompulsif bozuklu¤un [OKB] kal›tsal bir bileflene sâhip oldu¤u düflünülmekle
bera-ber, bu bozuklukla ilgili genlerin tipi ve say›s› tam olarak anlafl›lmam›flt›r. Serotonin tafl›y›c› prote-in [5-HTT] geni OKB içprote-in aday bir gen olarak düflünülmektedir. Bu çal›flman›n amac›, Türk hastalar-dan oluflan bir örneklemde 5-HTT geninin promoter bölge [5-HTTLPR] ve ikinci introndaki VNTR polimorfizmlerini inceleyerek, bu gen ile OKB iliflkisini belirlemekti.
Yöntem: Altm›fl OKB hastas› ve 85 kontrol dene¤i çal›flmaya dâhil edildi. Bunlar›n hepsi birbiri ile
akraba olmayan Türk hastalard›.
Bulgular: OKB hastalar› ve kontroller aras›nda, 5-HTTLPR ve 5-HTT VNTR polimorfizmlerinin
geno-tipik da¤›l›m örüntüsü farkl› de¤ildi. OKB aile öyküsü pozitif olanlar, negatif olanlar ve kontroller aras›nda 5-HTTLPR ve 5-HTT VNTR polimorfizmlerinin alel s›kl›klar› aç›s›ndan fark yoktu. Alel s›kl›k-lar› kendilerinde veya ailesinde tik olanlar ile olmayanlar aras›nda farkl›l›k göstermedi. Serotonin geri al›m inhibitörleri ile tedaviye yan›t verenler ile vermeyenler aras›nda incelenen genetik de¤ifl-kenler aras›nda fark bulunmad›.
Tart›flma: 5-HTT geninin OKB riskini etkileyebilecek bir aday gen oldu¤u düflünülmektedir. Bu
ko-nudaki literatür oldukça çeliflkilidir. Bâz› çal›flmalarda OKB ile 5-HTTLPR ve 5-HTT VNTR polimor-fizmleri aras›nda bir iliflki bildirmiflken, bizim çal›flmam›zda dâhil olmak üzere di¤er birtak›m çal›fl-malar iliflki bulamam›flt›r. Ancak, bu OKB ile ilgili oldu¤u düflünülen serotonerjik sistemleri etkile-yen di¤er mekanizmalar olabilece¤i veya bu bozuklu¤un patogenezinde 5-HTT geninin di¤er ge-nom bölgelerinin polimorfizmlerinin rol oynayabilece¤i ihtimalini ortadan kald›rmaz.
Sonuç: bu çal›flmada 5-HTTLPR ve 5-HTT VNTR polimorfizmleri ile OKB, serotonin geri al›m
inhibi-törleri ile tedaviye yan›t, ailede OKB öyküsü ve tiklerin varl›¤› aras›nda iliflki bulamad›k.
It has been reported that those two polymorphisms of the 5-HTT gene play role in the etiology of psychi-atric disorders and display ethnic variation also (Mu-rakami et al 1999, Y›lmaz et al 2001).
Studies conducted thus far have yielded controver-sial results concerning the association between 5-HTTLPR polymorphism and OCD. Two studies repor-ted an association between 5-HTT polymorphism and OCD (Mc Dougle et al 1998, Bengel et al 1999).
Altemus et al were unable to find a support for the role of a change in the primary structure of the coding region of the 5-HTT gene in OCD pathogenesis (Alte-mus et al 1996). Billet et al found no association of 5-HTT promoter region polymorphism and OCD; wever, they observed a trend towards increased ho-mozygosity in OCD patients (Billett 1997). Besides, they did not find a relationship between response to SRIs and polymorphism. Cavallini et al. found that only the factor containing counting and repeating ritu-als was associated with the homozygous long genoty-pe, raising the possibility that some symptoms are as-sociated with distinct genotypes (Cavallini at al 2002). Likewise, some recent studies also reported that no as-sociation was detected between the 5-HTTLPR poly-morphism and OCD (Chabane at al 2004, Meira-Lima at al 2004, Saiz at al 2008).
VNTR element of 17 bp has been identified in the second intron of the 5-HTT gene (Lesch et al 1994). There have been some studies investigating the asso-ciation of this polymorphism with major depressive disorder, bipolar disorder, anxiety disorder (Collier et al 1996, Ogilvie et al 1996, Evans et al 1997, Kunugi et al 1997). Ohara et al. (1998) found that the frequency of the allele containing 12 copies of the VNTR element [STin2.12] was significantly higher in the combined patient group, and among patients with OCD and GAD compared to the controls.
The aim of this study was to determine the associ-ation of the 5-HTT gene with OCD by examining the polymorphisms in the promoter region [5-HTTLPR] and in the second intron [VNTR] in a Turkish sample of OCD patients. In addition, this study evaluates the relationship between clinical features, treatment res-ponse and possible subtypes of OCD and 5-HTT gene polymorphism.
METHODS Subjects
Sixty OCD patients and 85 control subjects were included in the study. Control subjects were selected among healthy volunteers and none had a history of
any psychiatric disorder. Informed consent was obta-ined from all subjects participated in the study. The OCD patients and healthy controls were from the sa-me geographic region and of the sasa-me ethnic origin. All subjects in the study gave informed consent.
All patients were diagnosed by experienced psychiatrists following a clinical interview which inc-luded Yale-Brown Obsessive-Compulsive Scale [Y-BOCS] ratings, and incorporated mood, anxiety, and psychotic disorder questions based on the Structured Clinical Interview for DSM-IV [SCID-I] (APA 1994). The patients were unrelated. Those who had mental retardation, drug and/or alcohol dependence, meta-bolic, psychiatric or neurological diseases were exclu-ded. Subjects were asked to inform if they had suffe-red from vocal and/or motor tics at some time in the-ir life. All OCD patients and controls were Turkish pe-ople. Information about family history was obtained either by direct interviews with the person or through indirect interviews with close relatives.
Physical examinations were carried out and blood samples were taken for complete blood count and blo-od chemistry as well as for the molecular analysis of 5-HT2A receptor polymorphism.
Y-BOCS was administered to assess severity of ob-sessive compulsive symptoms (Goodman et al 1989a, Goodman et al 1989b). Validity and reliability of the Turkish version of Y-BOCS has been done by Tek et al (1995).
After clinical evaluation, patients were started on pharmacotherapy [29 patients on fluvoxamine 100-300 mg/day; 5 on fluoxetine 20-80 mg/day and 10 on sert-raline 100-200 mg/day]. Dosages were adjusted accor-ding to patients’ clinical condition and adverse effect status. Treatment response was evaluated with Clinical Global Impression Scale [CGI] at the end of 3rd month (Guy 1976). Responders were defined as very much improved or much improved, and non-responders as those who showed minimal or no change on CGI.
Molecular analysis:
DNA was extracted from whole blood by standard techniques. A functional 44-bp insertion/deletion polymorphism in the promoter region of the 5-HTT gene was typed by PCR amplification of DNA using flanking primers 5'-CTTGTTGGGGATTCTCCCGC-CTGGCGTT-3 (forward) and 5'-TCGAGGCT-GAGCGTCTAGAGGGACTGAGCTGG-3' [reversed]. PCR was performed with GC Rich PCR system [Roc-he Molecular Bioc[Roc-hemical] in a 25 ?l reaction mixture containing 100 ng DNA, 100 ?l dNTPs, 20 pmol of each
primer, 1.5 mM MgCl2. DNA was denatured at 96°C for 2 minutes and 35 cycles at 96°C for 1 minute for de-naturation, 1 minute at 60°C for annealing and 1 mi-nute at 72°C for extension, followed by 7 mimi-nutes at 72°C for final extension. Amplification products were resolved by electrophoresis on 2% agarose gels next to a DNA molecular weight standard and visualized with [UV] ethidium bromide staining. Alleles were designated S [484 bp] and L [528 bp] as described pre-viously (Lesch et al 1996).
The 17-bp VNTR polymorphism in the second int-ron of the 5-HTT gene was typed by PCR using primers 5'-TGGATTTCCTTCTCTCAGTGATTGG-3' [forward] and 5'-TCATGTTCCTAGTCTTACGCCAGTG-3' (re-versed). PCR was performed in a 25 ?l volume with 100 ng DNA, 100 ?m dNTPs, 20 pmol of each primer, 1,5 mM MgCl2, 1x PCR buffer with (NH4)2SO4 [Fermen-tas, Vilnius, Lithuania] and 2U Taq DNA polymerase [Fermentas, Vilnius, Lithuania]. PCR conditions were 2 minutes for initial denaturation at 95°C, 35 cycles at 95°C for 1 minute for denaturation, 1 minute at 57°C for annealing and 2 minutes at 72°C for extension, fol-lowed by 10 minutes at 72°C for final extension. Amp-lification products were resolved by electrophoresis on 2% agarose gels next to a DNA molecular weight stan-dard and visualized with UV ethidium bromide sta-ining. Alleles were designated 390 bp [12 copy, STin.2.12] 360 bp [10 copy, STin.2.10] or 345 bp [9 copy,
STin.2.9] as described previously (Ogilvie et al 1996).
Statistical analysis:
Statistical analyses were performed using SPSS for Windows [version 9.0, Chicago, IL]. Mann-Whitney U test, t test, chi square test and one way ANOVA were used for the statistical analyses of data. A p value less than 0.05 was considered statistically significant.
FINDINGS
The patient group consisted of 21 [35%] male and 39 [65%] female OCD patients with ages ranging from 17 to 56 years [mean=29±9 years]. The control group was composed of 39 male [45%] and 46 female [55%] subjects with ages ranging from 23 to 45 years [me-an=27?5]. The patients and the controls were not sig-nificantly different with respect to age [student’s t test; t=-1.86, df=158, p=0.065) and sex distribution [chi-square test; ?2=1.71, df=1, p=0.19].
The mean age of onset of OCD was 21?7 years [ran-ge=7-41] and the mean duration of disorder was 8?7 years [range=1-43]. All patients had at least 1 year du-ration of the disorder.
The mean total score of Y-BOCS was 20.6?6.7 [ran-ge 19-38]. The mean score of obsession subscale was 12.5?3.6 [range 3-20] and that of compulsion subscale was 8.4?5.6 [range 0-19].
The genotypic pattern of distribution of 5-HTTLPR
New/Yeni Symposium Journal • www.yenisymposium.net 34 Ocak 2010 | Cilt 48 | Say› 1 Tablo1: Allele frequencies of 5-HTTLPR genotypes
5-HTTLPR Genotypes n (%) n L/L L/S S/S Chi-square test Patients 60 14 (23.3) 34 (56.7) 12 (20) ?2=5,32 Df=2 Controls 75 19 (25.3) 29 (38.7) 27 (36) P=0.07 SRI responders 35 9 (25.7) 20 (57.1) 6 (17.1) ?2=1,75 Df=2 SRI non-responders 19 2 (10.5) 13 (68.4) 4 (21.1) P=0.42 Family history of OCD 28 7 (25) 16 (57.1) 5 (17.9) ?2=0,18
Df=2 No family history of OCD 32 7 (21.9) 18 (56.3) 7 (21.9) P=0.91 Tics present* 13 3 (23.1) 9 (69.2) 1 (7.7) ?2=1,72
Df=2 Tics not present 47 11 (23.4) 25 (53.2) 11 (23.4) P=0.42 *Presence of tics in patient or in family
[L and S alleles] and 5-HTT VNTR [10 and 12 repeat alleles] was not different between the OCD patients and controls. One of the control subjects showed 12/9 repeat allele [Table 1 and Table 2].
Eight patients had current or past history of tic di-sorder [13.3%], and none had a history of Tourette’s syndrome. Twenty eight patients had at least 1 first degree relative with OCD, 8 patients had tic disorder among relatives and 1 patient had Tourette’s syndrome in a first degree relative. There were no significant dif-ferences among the patients with positive family his-tory for OCD, those with negative family hishis-tory for OCD and the controls with respect to allele frequenci-es of 5-HTTLPR or 5-HTT VNTR polymorphisms. Al-lele frequencies were not statistically different in the patients having tics themselves or in the family compa-red to the patients without such history [Table 1 and 2]. Thirty-five patients were responders and 19 were non-responders according to evaluation by CGI scale. Six patients discontinued drug therapy and were exc-luded from the treatment response analysis. No signi-ficant genetic differences of 5-HTTLPR or 5-HTT VNTR were observed between SRI responders and SRI non-responders [Table 1 and 2].
DISCUSSION
During the past years, polymorphisms of the 5-HTT gene have been defined in various psychiatric disorders
(Collier et al 1996, Evans et al 1997, Kunugi et al 1997, Ogilvie et al 1998). The proved efficacy of SRIs in the treatment of OCD has led to the notion that serotoner-gic dysfunction plays a pivotal role in the etiology of this disorder (Sullivan and Coplan 2000, Papp 2000). Departing from this point, some studies investigating the association of OCD and 5-HTT polymorphisms ha-ve been conducted. The L allele of 5-HTT produces exp-ression levels three times greater than the S allele (Heils et al 1996). The S allele is associated with decreased 5-HT reuptake, leading to a longer duration of serotoner-gic activity. On the other hand, the L allele is associated with a more rapid reuptake of 5-HT causing shorter se-rotonergic activity. Within this frame, OCD patients and healthy subjects might be expected to differ in this res-pect. We did not find any significant differences betwe-en the OCD patibetwe-ents and the controls with respect to S and L alleles of 5-HTTLPR or 10 and 12 repeat alleles of 5-HTT VNTR. Altemus et al (1996) reported that no va-riations in amino acid sequence of the primary structu-re of the 5-HTT coding structu-region westructu-re identified among OCD patients or healthy controls. However the 5-HTT promoter region was not examined in that study. In a study of 72 OCD patients and matched controls, Billet et al. (1997) reported that there was no association bet-ween OCD and promoter region polymorphism of the 5-HTT gene, but found a trend towards increased ho-mozygosity [both L/L and S/S] in the patients. More
Tablo2: Allele frequencies of 5-HTT VNTR genotypes
5-HTT VNTR Genotypes n (%) n 12/12 10/12 10/10 12/9 Chi-square test Patients 60 26 (43.3) 28 (46.7) 6 (10) ?2=2,68 df=3 Controls 85 46 (54.1) 30 (35.3) 8 (9.4) 1 (1.2) P=0.44 SRI responders 35 14 (40) 16 (45.7) 5 (14.3) ?2=1,38 df=2 SRI non-responders 19 10 (52.6) 8 (42.1) 1 (5.3) P=0.50 Family history of OCD 28 14 (50) 13 (46.4) 1 (3.6) ?2=2,7
df=2 No family history of OCD 32 12 (37.5) 15 (46.9) 5 (15.6) P=0.26 Tics present* 13 5 (38.5) 8 (61.5) 0 (0) ?2=2,53
df=2 Tics not present 47 21 (44.7) 20 (42.6) 6 (12.8) P=0.28 *Presence of tics in patient or in family
recent studies also reported no association between the 5-HTTLPR polymorphism and OCD (Chabane et al 2004, Meira-Lima et al 2004, Saiz et al 2008). However, in a recent meta-analysis by Lin OCD was found to be associated with the S/S homozygous genotype, but was inversely associated with the LS heterozygous ge-notype (Lin 2007). No association with the L/L ho-mozygous genotype or the allelic distribution was fo-und in that study. Yet, in an even more recent meta-analysis study, Bloch et al. found no evidence of associ-ation between genetic variassoci-ation at the 5-HTTLPR locus and OCD (Bloch et al 2008).
On the other hand, Bengel et al (1999) found an as-sociation between a functional polymorphism in 5' re-gulatory region of the 5-HTT and OCD. Their results suggested that patients with OCD were more likely to carry two copies of the L allele as compared to cont-rols. Consistent with the above study, Mc Dougle et al (1998) reported an association and linkage disequilib-rium between the L allele of the HTTLPR polymorp-hism and OCD, using a within-family, transmission disequilibrium test design.
Lesch et al (1996) reported that individuals with the S allele had greater anxiety-related personality charac-teristics in healthy Caucasian subjects. Murakami et al. (1999) reported that populations with the S/S genotype of -HTTLPR have stronger anxiety-related personality traits than those with the L allele in healthy Japanese subjects. Comparison of these two studies showed that the distribution of alleles were significantly different between Japanese and Caucasian subjects and sugges-ted that allele frequencies might be different among va-rious ethnic groups. Osher et al (2000) also reported fin-dings in support of the above studies. However, several other studies found no association of the 5-HTTLPR with various personality measures (Ball et al 1997, Jorm et al 1998). Anxiety-related personality characteristics are encountered quite commonly in OCD patients. The-refore, one may expect to see higher frequency of the S allele in OCD patients, but we have not observed such an increased rate of the S allele in our patients.
Mc Dougle et al (1998) found that of the 22 SRI tre-atment responders, 14 transmitted the L and 8 trans-mitted the S allele (not significant), whereas of the 13 SRI non-responders, 10 transmitted the S and 3 trans-mitted the S allele [p=0.052]. They suggested that the L allele may be associated with poorer response to SRIs. We found no association of response to SRIs with 5-HTTLPR and 5-HTT VNTR polymorphisms. In ot-her words, polymorphisms of the 5-HTT gene did not predict SRI response in our OCD patients. Billet et al
(1997) reported similar findings in a retrospective study. Our patients were receiving fluvoxamine, flu-oxetine and sertraline as pharmacotherapy which constitutes a more homogenous group of drugs than in the above two studies. In addition, clomipramine used in both Mc Dougle et al (1998) and Billet et al. (1997) studies are not a selective serotonergic agent and this may be a potentially confounding variable. Overall, it seems that response to SRIs is not associ-ated with polymorphisms of the 5-HTT gene. Howe-ver, ethnic differences have been demonstrated to play a role in the association between 5-HTTLPR and SSRI response in depression in a meta-analysis (Smith et al 2004). It is possible that ethnic differences may exert a similar influence on treatment response in OCD also.
Polymorphisms of the 5-HTT VNTR were found to be associated with major depressive disorder, bipolar disorder and anxiety disorder, schizophrenia (Collier et al 1996, Ogilvie et al 1996, Evans et al 1997, Kunugi et al 1997). Ohara et al (1998) found that the frequency of the allele containing 12 copies of the VNTR element [STin2.12] was significantly higher in the combined patient group and among patients with OCD and GAD in comparison with controls. Saiz at al. provi-ded supporting evidence of an association between the Stin2 VNTR polymorphism of the SLC6A4 gene and OCD (Saiz 2008). Baca-Garcia et al found a signi-ficant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls (Baca-Garcia et al 2007).
The STin 2.12 allele frequency was 85.8% in Japane-se controls and about 50-60% in Caucasians (Lesch et al 1994). This rate was 89.4% in our Turkish sample which is similar to Japanese population. Two other studies of Turkish population have also reported simi-lar ratios [85.4%] (Herken et al 2001, Y›lmaz et al 2001). This ethnic variation may affect the results regarding the VNTR region of any 5-HTT genotyping study. Stin 2.10 and Stin 2.12 existed both in the patients and the controls. However, Stin 2.7 and Stin 2.11 were not de-tected at all, which means Stin 2.10 and Stin 12 are the polymorphic variants of VNTR which are frequently expressed in Turkish people.
A third variant, the Lg allele, has recently been desc-ribed (Hu et al 2006). The Lg allele has a single nucleoti-de polymorphism compared to the previous inucleoti-dentified long form of the allele [LA]. This single nucleotide polymorphism of the Lg allele results in lower transc-riptional activity of the gene despite having similar length to the LA allele (Hu et al 2006). The proportion of L alleles that are of Lg varies from 1-50 % in different
ethnic populations (Hu et al 2006). A meta-analysis study demonstrated a significant association between the L allele and OCD case status among Caucasian sub-jects, but not in Asian samples (Smits et al 2004).
Our study was conducted before that new allele was identified. We studied only the L and the S alleles, as in most of the previous studies and all meta-analy-sis studies to date, have been done using studies of those alleles. This is a considerable limitation for in-terpretation of our results. However, data of this study can still provide valuable information, as to our know-ledge there are no other studies about this polymorp-hisms and OCD conducted in Turkish population.
Twin and family studies provide evidence that so-me forms of obsessive-compulsive disorder may be etiologically related to Tourette’s syndrome. Family studies have shown that relatives of patients with To-urette’s syndrome had a high rate of OCD and relati-ves of patients with OCD had a high rate of Tourette’s syndrome and/or tics. It has been reported that a subgroup of OCD patients had a variety of tics (Ras-mussen 1986, Pauls et al 1986, Swedo et al 1989). We did not find any difference between OCD patients with and without tic disorders with respect to genetic polymorphisms of 5-HTTLPR and 5-HTT VNTR. Va-rious studies have investigated whether OCD patients with tics constituted a specific subgroup and contro-versial results have emerged from studies of genetic polymorphisms related with various neurotransmitter systems. Cavallini et al (2000) did not find significant differences with respect to 5-HTTLPR polymorphism in patients with Tourette’s syndrome compared to the controls. Nicolini et al (1996) reported that homozygo-sity for the allele dopamine D2 receptor A2 could be associated with the presence of tics in OCD patients and suggested that these patients constituted a geneti-cally different subgroup of patients with tics. Huang et al. (2001) found a significant relationship between Tourette’s syndrome associated with OCD and t102 polymorphism of the 5-HT2A gene. Our study does not bring any evidence that the OCD patients with tics are a different genetic subgroup.
One family-controlled study reported significant evidence of association (Mc Dougle et al 1998), but ot-her family-based studies found none (Camarena et al 2001, Chabane et al 2004, Walitza et al 2004). We did not find significant differences in the allele distributi-ons of the patients with positive family history for OCD compared to those with negative family history. This could provide additional information about gene-tic transmission of OCD, if an association was found.
CONCLUSION
As conclusion, we could not find any evidence for the association of 5-HTTLPR and 5-HTT VNTR poly-morphisms with OCD, response to SRI treatment, po-sitive family history for OCD, presence of tics. Howe-ver, this does not exclude the possibility that there may be other mechanisms affecting serotonergic sys-tems thought to be involved in OCD or polymorp-hisms of other genomic regions of 5-HTT may play ro-le in the pathogenesis of the disorder. It is highly pos-sible that multiple interactions of several different ne-urotransmitter systems and signal transduction path-ways are involved in OCD.
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