ارتباط بین ژن ناقل سروتونین و اختلال شخصیت مرزی

Abstract Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability in regulation of emotion, interpersonal relationships, self-image, and impulse control beginning in early adulthood. BPD affects about 1–2% of the general population and has a high mortality rate as a result of suicide and impulsive behaviour. The serotonin transporter gene (5-HTT) is considered as a candidate gene for BPD as multiple lines of evidence have suggested that it plays an important role in suicide, impulsive behaviour, and emotional liability. To test for an association between 5-HTT and BPD, we genotyped three common polymorphisms: the serotonin transporter linked promoter region (5-HTTLPR); a variable number of tandem repeat (VNTR) in intron 2, and a single nucleotide variant (A/G) within the LPR region. Eighty-nine Caucasian patients with BPD and 269 Caucasian healthy controls were analyzed. The program UNPHASED was used to compare allele and haplotype frequencies between cases and controls. Significant differences in allele frequencies of the VNTR marker (p = 0.012) and haplotype frequencies (p = 0.002) between patients and controls were found. Compared with healthy controls, patients with BPD showed higher frequencies of the 10 repeat of the VNTR marker and the S-10 haplotype, and lower 12 repeat and LA-12 haplotype. Our results suggest that the serotonin transporter gene may play a role in the aetiology of borderline personality disorder.

1. Introduction Borderline personality disorder (BPD) is a chronic, disabling, and high-risk mental disorder characterized by a pervasive pattern of instability in regulation of emotion, interpersonal relationships, self-image, and impulse control beginning in early adulthood. It affects about 1–2% of the general population, up to 10% of psychiatric outpatients and 20% of psychiatric inpatients (Torgersen et al., 2001). The disease has a high mortality rate as a result of suicide and impulsive behaviour – up to 10% of patients commit suicide, a rate almost 50 times higher than in the general population (APA, 2001). Due to substantial treatment utilization, patients with BPD require more mental-health resources than do individuals with other psychiatric disorders (Bender et al., 2001 and Zanarini et al., 2001). The cause of borderline personality disorder is complex with several factors, including genetic factors and adverse childhood experience, interacting in various ways (Lieb et al., 2004). Investigators found statistically significant increases in the rate of the disorder in relatives of BPD patients compared to relatives of controls, and observed familial transmission of BPD (Skodol et al., 2002 and Torgersen, 2000). The morbidity risk of BPD in first-degree relatives is 11.5%, much higher than 1–2% in the general population (Nigg and Goldsmith, 1994). In one twin study, BPD concordance rates were 35% and 7% in monozygotic and dizygotic twin pairs, respectively, suggesting a moderate genetic effect in the development of the disorder (Torgersen et al., 2000). Multiple lines of evidence suggest that the serotonin transporter gene (5-HTT) plays an important role in suicide (Bondy et al., 2000 and Simeon et al., 1992), impulsive behaviour (Coccaro et al., 1996, Frankle et al., 2005 and Lesch et al., 1996), and emotional liability (Collier et al., 1996 and Hoefgen et al., 2005), suggesting it as a candidate gene for borderline personality disorder. It has been reported that the long A variant of the 5-HTT gene linked polymorphic region (5-HTTLPR) and rs25531 is associated with high levels of 5-HTT mRNA while the long G and short variants with lower mRNA level (Goldman et al., 2004). For a variable number of tandem repeats (VNTR) in intron 2, higher expression of the 12-repeat was found when compared to 10-repeat (MacKenzie and Quinn, 1999). Furthermore, 5-HTTLPR was shown to be associated with amygdala activation in response to emotional faces (Hariri et al., 2005), and the amygdala was reported to be dysregulated in BPD (Donegan et al., 2003 and Ebner-Priemer et al., 2005). Recently, Steiger et al. (2005) studied 59 women with bulimia-spectrum disorders and found that bulimia patients with BPD (n = 13) showed a higher short (S) allele frequency of 5-HTTLPR ( Steiger et al., 2005). Commonly used polymorphic markers in 5-HTT are the 5-HTTLPR and the intron 2 VNTR in (Battersby et al., 1996 and Heils et al., 1996). Recently, a single nucleotide variant (A to G, rs25531) was detected in the region of 5-HTTLPR and shown to create an AP2 binding site (Goldman et al., 2004). In this paper we, for the first time, tested for an association between 5-HTT and BPD in 89 Caucasian BPD patients and 269 Caucasian healthy controls.

. Results Our case-control study had 80% power to detect a relative risk as low as 1.99. For both cases and controls, distributions of genotype frequencies of the 5-HTT polymorphisms were in Hardy–Weinberg equilibrium. There was no strong linkage disequilibrium between the 5-HTTLPR and VNTR markers in either cases or controls (D′ = 0.54 in total sample). Although there was a difference in the sex ratio between BPD patients and control samples (X2 = 30.46, p < 0.001), there were no differences in allele and genotype frequencies of the markers in 5-HTT between males and females (all p > 0.10). No significant differences in allele or genotype frequencies of 5-HTTLPR and A/G were detected between BPD patients and healthy controls (Table 1). When LG and S alleles were lumped together, there were still no significant differences in allele (X2 = 0.092, p = 0.762) or genotype (X2 = 0.334, p = 0.846) frequencies between patients and controls. We found that there was a trend toward statistical significance in the intron 2 VNTR genotypes (X2 = 9.44, p = 0.051). When comparing genotypes with and without 10 repeats, we found a significant association between the VNTR and BPD (X2 = 7.015, p = 0.008), with an OR of 2.02. There was also a significant association in allele frequencies of the VNTR between patients and controls (X2 = 8.874, p = 0.012) ( Table 1). BPD patients had a higher frequency of the 10 repeat (X2 = 8.155, p = 0.004) and less of 12 repeat (X2 = 8.849, p = 0.003) compared with controls. The ORs were 1.65 and 0.61 for 10 repeat and 12 repeat, respectively. We also found significant associations between 5-HTT haplotypes and BPD (X2 = 22.509, p = 0.002) ( Table 2). BPD patients had a higher frequency of the S-10 haplotype (X2 = 8.514, p = 0.004) and lower LA-12 haplotype (X2 = 5.436, p = 0.020). The ORs were 2.61 and 0.64 for S-10 and LA-12 haplotypes, respectively. After adjusting for the effects of age and gender, logistic regression analyses confirmed the association between intron 2 VNTR and BPD in allele (X2 = 8.54, p = 0.014) and in genotype frequencies in dominant inheritance model (X2 = 5.317, p = 0.021). Haplotype regression analysis also supported the finding of haplotype association analysis (X2 = 18.875, p = 0.009). The associations between 5-HTT and BPD based on allele and haplotype analyses remain statistically significant even after Bonferroni correction for multiple testing. Table 1. Comparison of allele and genotype frequencies of 5-HTTLPR A/G and VNTR in patients with borderline personality disorder and healthy controls Markers Case-control Genotype (genotype frequency) Allele (allele frequency) 5-HTTLPR LA/LA LA/LG LA/S LG/LG LG/S S/S X2 p LA LG S X2 p BPD 20 (0.22) 8 (0.09) 39 (0.44) 1 (0.01) 8 (0.09) 13 (0.15) 2.20 0.820 87 (0.49) 18 (0.10) 73 (0.41) 1.054 0.591 Control 68 (0.25) 22 (0.08) 112 (0.42) 1 (0.00) 17 (0.06) 49 (0.18) 270 (0.5) 41 (0.08) 227 (0.42) VNTR 9/10 9/12 10/10 10/12 12/12 X2 p 9 10 12 X2 p BPD 1 (0.01) 2 (0.02) 18 (0.20) 46 (0.52) 22 (0.25) 9.44 0.051 3 (0.02) 83 (0.47) 92 (0.52) 8.874 0.012 Control 1 (0.00) 5 (0.02) 32 (0.12) 121 (0.45) 110 (0.41) 6 (0.01) 186 (0.35) 346 (0.64) Table options Table 2. Haplotype analyses of the 5-HTT gene and borderline personality disorder using COCAPHASE in 89 Caucasian patients and 269 healthy Caucasian controls Haplotypes (5-HTTLPR–VNTR) BPD patients Controls X2 p X2 p LA–9 3 (0.017) 1.12 (0.002) 3.797 0.051 22.509 0.002 LA–10 57.41 (0.323) 152.7 (0.284) 1.502 0.220 LA–12 26.59 (0.149) 116.2 (0.216) 5.436 0.020 LG–9 0 4.88 (0.009) 2.615 0.106 LG–10 5.34 (0.030) 8.28 (0.015) 2.429 0.119 LG–12 12.66 (0.071) 27.84 (0.052) 0.743 0.389 S–10 20.25 (0.114) 25.02 (0.047) 8.514 0.004 S–12 52.75 (0.296) 202 (0.375) 3.066 0.080